Vaidlustus

Hankija: ⁠ SA Põhja-Eesti Regionaalhaigla (ühishankijad Aktsiaselts Ida-Tallinna Keskhaigla ja SA Tartu Ülikooli Kliinikum) Registrikood: 90006399 Postiaadress: J. Sütiste tee 19, Tallinn, 13419, Eesti Riigihanke kontaktisik Piret Viikholm E-posti aadress: [email protected] Telefon: +372 6171569 Vaidlustaja: Genekor SIA Registrikood: 40203443493 Postiaadress: Bruninieku 49k-2, Riga LV-1011 Seaduslik esindaja volikirja alusel (lisatud pakkumusele): Ilze Zarina, [email protected] Riigihanke kontaktisik: Tiina Kantsik, [email protected], +372 56391311 Vaidlustaja lepinguline esindaja vaidlustusmenetluses: Merily Rool, [email protected], +372 5634 2114 Kolmas isik (edukas pakkuja): OÜ Antegenes Registrikood: 14489312 Postiaadress: Raatuse 21, Tartu 50603, Eesti või Linnamä e tee 3, Tallinn, 13912, Eesti E-posti aadress: [email protected] Telefon: +372 5377 8141 VAIDLUSTUS Riigihankes “Test rinnavähi optimaalse adjuvantravi määratlemiseks” (261744) Genekor SIA (edaspidi: vaidlustaja) esitab Riigihangete vaidlustuskomisjonile (edaspidi: VAKO) vaidlustuse riigihankes “Test rinnavähi optimaalse adjuvantravi määratlemiseks”, riigihangete registri viitenumbriga 261744, (edaspidi: riigihange). Vaidlustaja taotlused 1. Tunnistada õigusvastaseks ja kehtetuks hankija 10.01.2024 otsused pakkuja OÜ Antegenes pakkumuse vastavaks tunnistamise, edukaks tunnistamise, kvalifitseerimise ja kõrvaldamata jätmise kohta. 2. Mõista vaidlustaja kasuks välja vaidlustusmenetlusega seotult kantud kulutused: riigilõiv vaidlustuse esitamiseks ja esindajatasu. 3. Lahendada asi kirjalikus menetluses. 1 Asjaolud 1. SA põhja-Eesti Regionaalhaigla (edaspidi: hankija) kuulutas 7.12.2023 ühishankijate esindajana riigihangete registris välja avatud hankemenetluse viitenumbriga 261744 „Test rinnavähi optimaalse adjuvantravi määratlemiseks“. Pakkumuste esitamise tähtajaks, 08.01.2024, esitas pakkumuse kaks pakkujat – Genekor SIA ja OÜ Antegenes (edaspidi: edukas pakkuja). 2. Hankija langetas 10.01.2024 koondotsuse pakkumuste vastavaks tunnistamise, pakkuja edukaks tunnistamise ja kõrvaldamata jätmise kohta. Allkirjastatud konteiner sisaldab ühtlasi faili kvalifitseerimisotsusega, kuid riigihankes puudusid kvalifitseerimistingimused. 3. Vaidlustaja hinnangul ei ole hankija järginud menetluse läbiviimisel riigihangete seadust (edaspidi: RHS), mistõttu taotleb vaidlustaja vastavaks tunnistamise, edukaks tunnistamise ning kõrvaldamata jätmise ja kvalifitseerimise otsuste kehtetuks tunnistamist. Põhjendused 4. Eduka pakkuja pakkumuse alusel soetatav test ei võimalda tõenduspõhiselt teenuse osutamist kõikidele patsientidele, mistõttu on pakkumus ebaõigesti vastavaks tunnistatud. 4.1. Hankes avaldatud tehnilise kirjelduse p 1.1 alusel on riigihanke objektiks rinnavähi koe geeniekspressioonanalüüsi teostamine, mis võimaldaks tellijatel teha patsientidel adjuvantse keemiaravi raviotsust vastavalt Tervisekassa tervishoiuteenuste loetelu koodile 66646. Raamlepingu projekti p 2.2 kohaselt on raamlepingu objektiks teenuse osutaja poolt rinnavähi koe geeniekspressioonanalüüsi teostamine, mis võimaldaks tellijal teha patsientidel adjuvantse keemiaravi raviotsust vastavalt raamlepingus kirjeldatule (edaspidi teenus). Teenus peab vastama riigihanke alusdokumentides (edaspidi RHAD) viitenumbriga 261744 (edaspidi riigihange) kirjeldatule ja selle alusel teenuse osutaja poolt esitatud pakkumusele. 4.2. RHS § 114 lg 1-2 alusel kohustub hankija kontrollima pakkumuste vastavust riigihanke alusdokumentides esitatud tingimustele ning teeb põhjendatud kirjaliku otsuse pakkumuste vastavaks tunnistamise või tagasilükkamise kohta. Hankija lükkab pakkumuse tagasi, kui see ei vasta riigihanke alusdokumentides esitatud tingimustele. 4.3. Vaidlustajale teadaolevalt on edukas pakkuja MammaPrint testi edasimüüja ja on esitanud pakkumuse selle testi pakkumiseks. Nimetatud test ei võimalda aga teostada tulemuslikku ja tõenduspõhist testimist kõikidele patsientidele. Hanke alusdokumendid nõuavad, et test oleks mõeldud kasutamiseks kõikidele patsientidele, erisuseta, mistõttu ei saa eduka pakkuja puhul olla tegemist hanke tingimustele vastava teenusega. Vaidlustaja poolt pakutavat Oncotype testi (ehk 21-geeni testi) on võimalik tõenduspõhiselt, tuginedes kliinilistele uuringutele kasutada nii post-menopausis kui premenopausis patsientidel. Eduka pakkuja pakutav MammaPrint ei ole aga premenopausis naistele kohane, kuna puuduvad uuringud, mis selle otstarbekat kasutamist viidatud sihtgrupile kinnitaksid, mistõttu jääb eduka pakkuja testi alusel üks osa teenuse sihtgrupist ilma vajaliku teenusta ning pakkumusei vasta riigihanke objektile (lisa 1, väljavõte allikast).1 NCCN juhisest lähtuvalt tuleb tungiva soovituse 1 Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update | Journal of Clinical Oncology (ascopubs.org): Recommendation 1.9. If a patient is 50 years of age or younger and has high clinical risk, node-negative or node-positive with 1-3 positive nodes breast cancer, the clinician should not use the MammaPrint test to guide decisions for adjuvant endocrine and chemotherapy (Type: 2  (strongly consider / kategooria: „preferred“) alusel patsientide ravimisel eelistada vaidlustaja pakutavat Oncotype 21-geeni testi, kuid hankija ei ole menetluse läbiviimisel nimetatud soovitustele kaalu andnud.2 4.4. Vaidlustaja hinnangul peab tervishoiuteenuse osutajal olema võimalik ravi määramisel valida parim võimalik testimisviis. Vaidlustaja pakutav Oncotype test loob nii patsiendile kui ka tervishoiuteenuse osutajale lisandväärtust, mida ei võimalda teadaolevalt ükski teine test, mis kokkuvõttes tagaks parima võimaliku ravi patsiendile. Hankija on aga välistanud võimaluse, et raviteenuse osutamisel oleks võimalik nende testide vahel kaaluda ja valida patsiendile parim lahendus. Hanke ülesehitus ei ole arvestanud pakutavate testide kvaliteeti ja tugineb vaid hinnal põhinevale kriteeriumile. Vaidlustaja pakutav test võimaldaks samas lisaks haiguse prognoosimisele (ehk võimaldab määrata vähi taasteket) ka anda hinnangu prediktiivselt keemiaravi kasulikkusele. MammaPrint test kirjeldatud lisandväärtust pakkuda ei saa, mistõttu ei ole tegemist ka parima hinna ja kvaliteedi suhtega teenuse hankimisega, milleks kohustab hankijat RHS § 3 p 5: hankija sõlmib hankelepingu parima võimaliku hinna ja kvaliteedi suhte alusel. 4.5. Eeltoodule tuginedes tuleb vastavaks tunnistamise otsus eduka pakkuja osas kehtetuks tunnistada ja edukas pakkumus riigihanke tingimustele mittevastamise tõttu tagasi lükata. 5. Hankija ei ole teostanud põhjendamatult madala maksumuse kontrolli ja on teinud sellest tulenevalt õigusvastase edukaks tunnistamise otsuse. 5.1. RHS § 115 lg 1 esimene lause sätestab, et kui hankija leiab, et pakkumuse maksumus on hankelepingu eset arvestades põhjendamatult madal, peab hankija kirjalikku taasesitamist võimaldavas vormis nõudma pakkujalt asjakohast samas vormis esitatud selgitust. Sama paragrahvi lg 8 kohaselt kontrollib hankija selgitust ja hindab esitatud tõendeid, konsulteerides vajaduse korral pakkujaga. Kui hankija leiab endiselt, et pakkumuse maksumus on põhjendamatult madal, või kui pakkuja ei esita hankijale nõutud selgitust, lükkab hankija pakkumuse põhjendatud kirjaliku otsusega tagasi. 5.2. RHS § 115 lõikest 1 tuleneb hankijale kaks kohustust. Esmalt tuvastada ja hinnata, kas pakkumuse maksumus on hankelepingu eset arvestades põhjendamatult madal ja teiseks nõuda sellise asjaolu tuvastamisel pakkujalt vastavasisulist selgitust. Vastuseks vaidlustaja päringule teavitas hankija järgmist: „Hankijal ei tekkinud kahtlusi, et edukaks tunnistatud pakkumus oleks põhjendamatult madala hinnaga. Pakutud hind vastab hankes toodud eeldatavale maksumusele.“ (teabevahetus riigihangete registris, hankija 15.01.2024 vastus vaidlustaja 11.01 2024 küsimusele). 5.3. Vaidlustus- ja kohtupraktikas on analüüsitud, millal on oodatav, et hankijal tekib kahtlus põhjendatult madala maksumuse esitamise kohta. Hankija viide, et selle hindamisel saab ühe alusena vaadelda riigihanke eeldatavat maksumust, on õige (nt RngK 12.10.2015 otsus asjas nr 3-15-1822, p 16, RK 02.12.2015 otsus asjas nr 3-3-1-50-15, p 26), kuid tõeseks ei saa pidada hankija ilma põhjenduseta antud hinnangut, mille kohaselt eduka pakkuja esitatud maksumus selles riigihankes vastab eeldavale maksumusele. Samuti ei evidence-based; Evidence quality: high; Strength of recommendation: strong). // Tõlge: Kui patsient on 50- aastane või noorem ja tal on kõrge kliiniline risk, ilma aksillaarse lümfisõlme metastaasita või 1-3 aksillaarse lümfisõlme metastaasiga rinnavähk, ei tohiks arst kasutada MammaPrint-testi adjuvantse endokriinse ja kemoteraapia otsuste tegemisel (tüüp: tõenduspõhine; tõenduspõhisuse kvaliteet: kõrge; soovituse tugevus: tugev). NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, Version 3.2022, (lisa 1). 2 Lisa 2 leheküljed 20, 21, 74 ja 75. 3  ole piisav vaadelda põhjendamatult madala maksumuse hindamisel üksnes riigihanke eeldatavat maksumust, vaid hinnata saab ja tuleb ka muid näitajaid (nt RngK 11.05.2015 otsus asjas nr 3-15-77, p 14; RHS kommenteeritud väljaanne, § 115, kommentaar 8: seadus ega direktiiv ei võrdle põhjendamatult madala maksumuse kontrolli eeldatava maksumusega). Eeldatav maksumus on vaid üks võimalik näitaja, mis pealegi on määratud hankija poolt vaidlustajale teadmata kriteeriumitele tuginedes. Arvestada tuleb, et ka eeldatava maksumuse määramine on alati hinnanguline, mistõttu sisaldab see teatavat subjektiivsuse komponenti. Vaidlustaja palub arvesse võtta vähemalt järgmiseid võrdlusandmeid ja kujundada põhjendamatult madala maksumuse esitamise kohta seisukoht nende näitajate kogumit hinnates. 5.3.1.Riigihankes avaldatud raamlepingu projekti punkt 3.3. kohaselt kehtib leping 36 kuud, punkti 3.4 kohaselt on raamlepingu eeldatav maksumus 1 140 000 eurot ja maksimaalne maksumus 1 600 000 eurot. Avaldatud tehnilise kirjelduse punkti 1.1 alusel on hanke eeldatav aastane kogus 190 analüüsi teenust (testi). Pakkumuste hindamiskriteeriumiks määras hankija ühe testi maksumuse. Raamlepingu eeldatava maksumuse alusel on ühe testi hinnaks (1 140 000 / 190 testi) / 3 aastat = 2000 eurot. Raamlepingu maksimaalset maksumust aluseks võttes on aga ühe testi eeldatavaks hinnaks (1 600 000 / 190 testi) / 3 aastat = 2807 eurot. Viimane näitaja ei kaldu märkimisväärselt kõrvale ka Tervisekassa poolt vastava testi rahastamise piirhinnast, milleks on Tervisekassa tervishoiuteenuste loetelu § 72 lg 1 alusel 2806,00.3 Tervisekassa piirhinda arvestades on raamlepingu maksimaalse mahu sellisel viisil esitamise aluseks hankija poolt võimalik pidada hankija eeldust, et riigihankes esitatud hinnad võivad kujuneda eeldatavast mõnevõrra kallimaks, mistõttu on asjakohane põhjendamatult madala maksumuse kahtluse tekkimise hindamisel ka seda näitajat arvestada. 5.3.2.Riigikohus on selgitanud, et hankijal peab tekkima kahtlus, et pakkumuse maksumus on põhjendamatult madal siis, kui pakkumuse hinna ja teostatavate tööde eeldatava maksumuse vahe on silmatorkavalt erinev. Edukaks tunnistatud pakkuja maksumus oli eeldatavast maksumusest pea ¼ võrra madalam, mis on selgelt tähelepanu vääriv erinevus, mille alusel tulnuks hankijal RHS § 115 lg 1 kohane hindamine läbi viia. Ka VAKO 09.01.2023 otsus asjas 164-22/254784, p 15.1, viitab ühemõtteliselt, et ¼ suurune erinevus pakkumuste maksumustes on piisav tekitamaks hankijas põhjendamatult madala maksumuse esitamise kahtluse. 5.3.3.Võttes aga aluseks riigihanke maksimaalse maksumuse (ühe testi läbiviimise maksumus 2807 eurot) ja Tervisekassa tervishoiuteenuste loetelu piirhinna (ühe testi läbiviimise maksumus 2806 eurot), on edukaks tunnistatud pakkumuse maksumus suisa 44,5% madalam. Sellise näitaja tuvastamisel ei saa hankija veenvalt väita, et tal põhjendamatult madala maksumuse kahtlust ei tekkinud. Vaidlustaja hinnangul tulnuks eeltoodut arvesse võttes hankijal selgitada nii eeldatava maksumuse kujunemist kui ka hinnata edukaks tunnistatud pakkuja esitatud maksumuse kujunemist, tuvastamaks, kas tegemist on põhjendamatult madala maksumusega. 5.3.4.Kahtlus võinuks hankijal tekkida aga ka pelgalt esitatud pakkumuste hinnavahet analüüsides. Vaidlustaja pakkumus oli 1950 eurot ühe testi läbiviimiseks, eduka 3 Rinnavähi koe geeniekspressioonanalüüs adjuvantse keemiaravi raviotsuseks, kood 66646, piirhind 2806,00. Kättesaadav veebilehel: https://www.riigiteataja.ee/akt/120122023023#para72 (19.01.2024). 4  pakkuja pakkumus 1557,38 eurot. Seega erines pakkumuste maksumuste vahe veidi enam kui 20% võrra, mis ei ole väheoluline näitaja. Kui sarnast testi on võimalik ühel juhul teostada viiendiku võrra odavama hinnaga, tuleks hankijal minimaalselt selgitada välja, millest taoline hinnaerinevus tekkida saab, mitte võimalikke kahtluseid sisulise analüüsita kõrvale jätta. Riigihanke üldpõhimõtted (RHS § 3 p 1 ja p 5) ja RHS § 115 regulatsioon kohustavad hankijat hea seisma, et hankeleping sõlmitaks pakkujaga, kes lepingut reaalselt täita suudab. Hoolsa hankija kohustuseks on seejuures analüüsida võimalikke riskikohti. Alapakkumuse esitanud pakkuja tagasi lükkamise üheks põhjuseks ongi just tema võimetus lepingut kokkulepitud tingimustel täita. 5.4. Eeltoodud näitajaid arvesse võttes pidanuks hankijal tingimata tekkima kahtlus põhjendamatult madala maksumuse esitamise osas. Hankija on aga jätnud täitmata olulise RHS § 115 lõikest 1 tuleneva kohustuse kontrollida põhjendamatult madala maksumuse esitamist ning teinud seetõttu õigusvastase edukaks tunnistamise otsuse, mis tuleb kehtetuks tunnistada. 5.5. Eeltoodule täienduseks tuleb võtta arvesse ka põhjendamatult madala maksumuse kontrolli läbiviimise kohustuse laiemaid eesmärke, milledeks on muuhulgas aidata kaasa riigihankes tegeliku konkurentsi tekkimisele ja avalike vahendite eest parima võimaliku toote või teenuse soetamine. Kui hankija jätab RHS § 115 lg 1 kohustuse täitmata, satub ohtu ka riigihanke üldpõhimõtete täitmine. RHS § 3 p 3 kohaselt peab hankija tagama riigihankel konkurentsi efektiivse ärakasutamise ja p 5 alusel tuleb hankijal kasutada rahalisi vahendeid säästlikult ja otstarbekalt, sõlmida hankeleping parima võimaliku hinna ja kvaliteedi suhte alusel. Nimetatud üldpõhimõtted on praegusel juhul jäänud täitmata. 5.5.1.Konkurentsi ei saa pakkujate vahel tekkida, kui üks pakkumus on esitatud põhjendamatult madala hinnaga. Kui hankija jätab asjaolud välja selgitamata ja põhjendatud otsuse tegemata, ei saa kuidagi olla tagatud õiglane konkurents vaidlustaja jaoks, kuna konkureerimiseks tulnuks ka vaidlustajal esitada alapakkumus. 5.5.2.Hankija ei ole kasutanud rahalisi vahendeid säästlikult ega otstarbekalt, kui ta on jätnud võimaliku alapakkumuse ja selle esitamise asjaolud välja selgitamata. Samuti võib selliselt sattuda ohtu hankelepingu hilisem täitmine, kuna edukaks tunnistatud pakkuja ei pruugi olla alapakkumuse alusel võimeline teenust tegelikult pakkuma. 6. Hankija ei ole kontrollinud ja kaalunud eduka pakkuja osas RHS § 95 lg 4 p 6 ja p 7 kõrvaldamise aluste esinemist ega teinud sellekohaseid põhjendatud otsuseid. 6.1. RHS § 95 lg 4 p 6 alusel võib hankija menetlusest kõrvaldada isiku, kui huvide konflikti ei ole muude vahenditega võimalik vältida ja p 7 alusel isiku, kelle pakkumuse või taotluse koostamisel on osalenud isik, kes on osalenud sama riigihanke ettevalmistamisel või on muul viisil hankijaga seotud, ja sellele isikule seetõttu teadaolev info annab talle eelise teiste riigihankes osalejate ees ning sellest tingitud konkurentsi moonutamist ei ole muude vahenditega võimalik vältida. 6.2. RHS § 95 lg 4 p 7 esinemisel peavad olema täidetud kolm tingimust: 6.2.1. pakkumuse koostamisel on osalenud isik, kes on osalenud sama riigihanke ettevalmistamisel või on muul viisil hankijaga seotud; 6.2.2. isikule seetõttu teadaolev info annab talle eelise teiste riigihankes osalejate ees; 6.2.3. eelnevatest asjaoludest tingitud konkurentsi moonutamist ei ole muude vahenditega võimalik vältida. 5  6.3. Edukaks tunnistatud pakkumuse esitanud isik on ühishankijaga SA Tartu Ülikooli Kliinikum seotud isik pikaajalise töösuhte kaudu. Edukaks tunnistatud pakkumuse on esitanud Antegenes OÜ, kelle suuromanikuks ja juhatuse liikmeks on läbi mitme osaühingu4 Tartu Ülikooli Kliinikumi hematoloogia-onkoloogiakliiniku juhataja P. Padrik5. Seega võib liialduseta öelda, et edukas pakkuja on esitanud pakkumuse iseendale teenuse kasutamiseks. Sellises olukorras puudub kahtlus, et tegemist on hankijaga seotud isikuga, kuna hankijaks ja raamlepingu osapooleks on ka SA Tartu Ülikooli Kliinikum. 6.4. Eluliselt usutavaks tuleb pidada, et sellises staatuses eduka pakkuja esindajal on ka informatsiooniline eelis teiste riigihankes osalejate ees. Seistes menetlusele ja selle alusel hangitavale teenusele sedavõrd lähedal, töötades teenuse pakkumiseks ja teisalt ka kasutamiseks igapäevaselt, ei pruugi olla mõistlikult võimalik eelise tekkimist vältida. Riigikohus on 17.04.2018 haldusasjas nr 3-17-2226 selgitanud ka, et tõendamiskoormus selles osas, kas ettevõtja, tema töötaja või muu isiku osalus riigihanke ettevalmistamisel ei mõjutanud selle ettevõtja pakkumust või taotlust, lasub ka hankijal. 6.5. Hankijal lasub minimaalselt kohustus selgitada, kas ja mil määral on pakkumuse koostamisel edukaks tunnistatud pakkuja informatsioonilise eelise saanud ja seda pakkumuse koostamisel kasutanud, kas nimetatud asjaolu on mõjutanud riigihankes osalemist. 6.6. Kas konkurentsi moonutust on võimalik vältida muude vahenditega, sõltub hankija järeldustest ja tuvastatud asjaoludest teiste RHS § 95 lg 4 p 7 eelduste osas. Kas selliseid vahendeid esineb ja mida hankija kasutusele on võtnud, peab hankija riigihankes tehtavas otsuses selgitama. 6.7. RHS § 4 p 8 defineerib huvide konflikti olukorra järgmiselt. Tegemist on olukorraga, kus hankija või tema nimel tegutseva isiku töötajal, ametnikul, juhatuse liikmel või muul pädeval esindajal, kes on kaasatud riigihanke ettevalmistamisse või korraldamisse või kes võib muul moel mõjutada selle riigihanke tulemust, on otseselt või kaudselt finantsalaseid, majanduslikke või muid isiklikke huvisid, mida võib käsitada tema erapooletust ja sõltumatust kahjustavatena. Pidades silmas eelpool kirjeldatud eduka pakkuja seotust hankijaga, tuleb hankijal otsuse tegemisel kontrollida, kas eduka pakkuja esindaja taolist seotust oli objektiivselt võimalik riigihanke ettevalmistamisel vältida, kuivõrd finantsalased ja majanduslikud huvid esinevad edukalt pakkujal tingimata – selleks on soov müüa on teenust ja teenida kasumit. 6.8. Riigikohtu 17.04.2018 otsuses asjas nr 3-17-2226, p 17, on kohus esitanud põhjaliku selgituse huvide konflikti kontrollimisel aluseks oleva kohtupraktika osas märkides muuhulgas järgmist. Kohus leidis, et potentsiaalselt huvide konfliktis olevale isikule tuleb anda võimalus tõendada, et see olukord ei mõjutanud tema käitumist 4 OÜ Antegenes osanik on 56.13% osalusega OÜ Personaalmeditsiin, mille juhatuse liikmeks on P. Padrik ja ainuomanikuks OÜ Art Med. Viimane on aga P. Padriku ainuomandis. Ühtlasi on kõikide nimetatud OÜ-de tegelikuks kasusaajaks avalikel andmetel P. Padrik. Kirjeldatud info on nähtav järgmistel allikatel: OÜ Antegenes andmed: https://www.teatmik.ee/et/personlegal/14489312-O%C3%9C-Antegenes (19.01.2024); OÜ Personaalmeditsiin andmed: https://www.teatmik.ee/et/personlegal/11221767-O%C3%9C- Personaalmeditsiin (19.01.2024); OÜ Art Med andmed: https://www.teatmik.ee/et/personlegal/11044897-O%C3%9C-Art-Med (19.01.2024). 5 Info nähtuv avalikust allikast: https://www.kliinikum.ee/ho/toeoetajad/15-toeoetajad/7-peeter-padrik (19.01.2024). 6  hankemenetluses ja et kõnealusel juhul ei kahjusta saadud kogemus konkurentsi (samas, p 36; vt ka C‑538/07: Assitur, p 30). Mis tahes vormis mõju ilmnemine on seevastu piisav selleks, et seotud ettevõtjad hankemenetlusest kõrvaldada (C-538/07, p 32). Hankija peab igal juhul kontrollima võimalike huvide konfliktide olemasolu ja võtma asjakohased meetmed huvide konfliktide ennetamiseks, tuvastamiseks ja heastamiseks. Seejuures ei saa tõendamiskoormust panna kaebajale (C-538/13: eVigilo, p‑d 43–44). 6.9. Hankija on aga jätnud otsuse kohaselt võimaliku huvide konflikti esinemise analüüsimata ega ole teinud vaidlustajale teadaolevalt sellekohast põhjendatud otsust, mistõttu on otsusega rikutud RHS § 95 lg 4 p 6 tulenevat kohustust. 6.10. RHS § 95 lg 4 vabatahtlik iseloom seisab selles, et hankijal on võimalik kaalumise järel teha põhjendatud otsus, kas pakkuja kõrvaldada või mitte. Selle hankemenetluse raames tehtud otsusest ei nähtu, et hankija põhjendatud otsuse teinud oleks ja seda tõdeb ka hankija ise vastuseks vaidlustaja päringule (teabevahetus riigihangete registris, hankija 15.01.2024 vastus vaidlustaja 11.01 2024 küsimusele). Vaidlustaja hinnangul tuleb kahtlemata RHS § 95 lg 4 punktide 6 - 7 alusel esinevate asjaolude alusel kõrvaldamist kaaluda. Ainuüksi otsuse puudumine ja kaalutlemise teostamata jätmine on hankija poolt RHS sätte rikkumine. 6.11. Eeltoodust tulenevalt tuleb hankija 10.01.2024 eduka pakkuja osas tehtud kõrvaldamata jätmise otsus tunnistada kehtetuks RHS § 95 lg 4 p 6 ja p 7 alusel. Menetluslikud küsimused 7. Vaidlustaja hinnangul on asi võimalik lahendada kirjalikus menetluses. 8. Vaidlustaja on vaidlustusele lisanud maksekorralduse (lisa 2), mis kinnitab asja menetlemiseks nõutava riigilõivu tasumist suuruses 1280 eurot. Vaidlustaja palub vaidlustuse rahuldamisel nimetatud summa hankijalt välja mõista. 9. Vaidlustaja esindajaks VAKO menetluses on jurist Merily Rool, kelle volikiri on lisatud (lisa 3). 10. Vaidlustus on esitatud tähtaegselt. Hankija on otsuse teinud riigihangete registrist nähtuvalt 10.01.2024 ja teavitanud seejärel otsusest pakkujatele. RHS § 189 lg 1 alusel peab vaidlustus olema laekunud vaidlustuskomisjonile kümne päeva jooksul alates päevast, kui vaidlustaja sai teada või pidi teada saama oma õiguste rikkumisest või huvide kahjustamisest. Seega langes vaidlustuse esitamise tähtpäev nädalavahetusele, 20.01.2024 kuupäevale, mistõttu saabub vaidlustuse esitamise tähtaeg tsiviilseadustiku üldosa seaduse § 135 lg 1 ja § 136 lg 8 alusel 22.01.2024. Austusega Merily Rool Genekor SIA lepinguline esindaja 7 Lisad: 1. Lisa 1. Väljavõte ASCO soovitus, NCCN juhis; 2. Lisa 2. NCCN juhis 2023; 3. Lisa 3. Maksekorraldus; 4. Lisa 4. Volikiri M. Rool. 8  Genekor Medical S.A. 52, Spaton Ave. | 15344 Gerakas Greece | MGA GUIDELINES Genekor Medical S.A. Tel. +302106032138 | Fax.+302106032148 | www.genekor.com [email protected] | genekor.com Genekor Medical S.A. www.genekor.com  NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Breast Cancer Version 5.2023 — December 5, 2023 NCCN.org NCCN Guidelines for Patients® available at www.nccn.org/patients Continue Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion *William J. Gradishar, MD/Chair ‡ † Chau Dang, MD † Sameer A. Patel, MD Ÿ Robert H. Lurie Comprehensive Cancer Memorial Sloan Kettering Cancer Center Fox Chase Cancer Center Center of Northwestern University Anthony D. Elias, MD † Lori J. Pierce, MD § *Meena S. Moran, MD/Vice-Chair § University of Colorado Cancer Center University of Michigan Yale Cancer Center/Smilow Cancer Hospital Sharon H. Giordano, MD, MPH † Rogel Cancer Center *Jame Abraham, MD ‡ † The University of Texas Laura H. Rosenberger, MD, MS ¶ Case Comprehensive Cancer Center/ MD Anderson Cancer Center Duke Cancer Institute University Hospitals Seidman Cancer Center Matthew P. Goetz, MD ‡ † Hope S. Rugo, MD † and Cleveland Clinic Taussig Cancer Institute Mayo Clinic Comprehensive Cancer Center UCSF Helen Diller Family Vandana Abramson, MD † Lori J. Goldstein, MD † Comprehensive Cancer Center Vanderbilt-Ingram Cancer Center Fox Chase Cancer Center Cesar Santa-Maria, MD, MSCI † *Rebecca Aft, MD, PhD ¶ Sara A. Hurvitz, MD † The Sidney Kimmel Comprehensive Cancer Siteman Cancer Center at Barnes- UCLA Jonsson Comprehensive Cancer Center Center at Johns Hopkins Jewish Hospital and Washington Bryan Schneider, MD † University School of Medicine Rachel C. Jankowitz, MD † Indiana University Melvin and Abramson Cancer Center at the Bren Simon Comprehensive Cancer Center Doreen Agnese, MD ¶ University of Pennsylvania The Ohio State University Comprehensive Mary Lou Smith, JD, MBA ¥ Cancer Center - James Cancer Hospital Sara H. Javid, MD ¶ Research Advocacy Network and Solove Research Institute Fred Hutchinson Cancer Center Jairam Krishnamurthy, MD † Hatem Soliman, MD † Kimberly H. Allison, MD ≠ Moffitt Cancer Center Stanford Cancer Institute Fred & Pamela Buffet Cancer Center A. Marilyn Leitch, MD ¶ Erica M. Stringer-Reasor, MD † ‡ *Bethany Anderson, MD § O'Neal Comprehensive University of Wisconsin UT Southwestern Simmons Cancer Center at UAB Carbone Cancer Center Comprehensive Cancer Center *Janice Lyons, MD § Melinda L. Telli, MD † Þ Janet Bailey, MD § Stanford Cancer Institute University of Michigan Case Comprehensive Cancer Center/ Rogel Cancer Center University Hospitals Seidman Cancer Center Mei Wei, MD ‡ † and Cleveland Clinic Taussig Cancer Institute Huntsman Cancer Institute Harold J. Burstein, MD, PhD † at the University of Utah Dana-Farber/Brigham and Women’s Susie McCloskey, MD, MSHS § Cancer Center UCLA Jonsson Comprehensive Cancer Center Kari B. Wisinski, MD † University of Wisconsin Carbone Cancer Center *Helen Chew, MD † Melissa McShane, MD † UC Davis Comprehensive Cancer Center Fox Chase Cancer Center Kay Yeung, MD Þ † UC San Diego Moores Cancer Center Nan Chen, MD ‡ Joanne Mortimer, MD † The UChicago Medicine Comprehensive City of Hope National Medical Center *Jessica S. Young, MD ¶ Cancer Center Roswell Park Comprehensive Cancer Center NCCN ‡ Hematology/Hematology § Radiation oncology/ Rashmi Kumar, PhD Continue oncology Þ Internal medicine Radiotherapy Ÿ Reconstructive surgery Mary Dwyer, MS Ryan Schonfeld, BA † Medical oncology ¶ Surgery/Surgical oncology ≠ Pathology * Discussion Section Writing NCCN Guidelines Panel Disclosures ¥ Patient advocacy Committee Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion NCCN Breast Cancer Panel Members Fertility and Birth Control (BINV-C) Summary of Guidelines Updates Considerations for Surgical Axillary Staging (BINV-D) Clinical Trials: NCCN Axillary Lymph Node Staging (BINV-E) believes that the best Recommendations for Lobular Carcinoma In Situ were removed Margin Status Recommendations After BCS for Invasive management for any patient from the NCCN Guidelines for Breast Cancer. See NCCN Cancers and DCIS (BINV-F) with cancer is in a clinical trial. Guidelines for Breast Cancer Screening and Diagnosis Special Considerations to Breast Conservation Therapy Participation in clinical trials is Noninvasive Breast Cancer Requiring RT (BINV-G) especially encouraged. Ductal Carcinoma In Situ (DCIS) Workup and Primary Treatment Principles of Breast Reconstruction Following (DCIS-1) Surgery (BINV-H) Find an NCCN Member DCIS Postsurgical Treatment and Surveillance/Follow-up (DCIS-2) Principles of Radiation Therapy (BINV-I) Institution: https://www.nccn. Special Considerations for Breast Cancer in Males org/home/member-institutions. Invasive Breast Cancer Clinical Stage, Workup (BINV-1) (Sex Assigned at Birth) (BINV-J) NCCN Categories of Adjuvant Endocrine Therapy (BINV-K) Locoregional Treatment of cT1-3,cN0 or N+,M0 Disease Evidence and Consensus: All • BCS followed by RT (BINV-2) Preoperative/Adjuvant Therapy Regimens (BINV-L) recommendations are category • Mastectomy Followed by RT (BINV-3) Principles of Preoperative Systemic Therapy (BINV-M) Gene Expression Assays for Consideration of Adjuvant 2A unless otherwise indicated. Systemic Adjuvant Treatment • HR-Positive HER2-Positive Disease (BINV-5) Systemic Therapy (BINV-N) See NCCN Categories of • HR-Positive HER2-Negative Disease: Definition of Menopause (BINV-O) Evidence and Consensus. Postmenopausal Patients (BINV-6) Systemic Therapy for ER- and/or PR-Positive Recurrent Premenopausal Patients with pT1-3, pN0 (BINV-7) Unresectable (Local or Regional) or Stage IV (M1) Premenopausal Patients with pT1-3, pN+ (BINV-8) Disease (BINV-P) NCCN Categories of • HR-Negative HER2-Positive Disease (BINV-9) Systemic Therapy Regimens for Recurrent Unresectable Preference: • HR-Negative HER2-Negative Disease (BINV-10) (Local or Regional) or Stage IV (M1) Disease (BINV-Q) All recommendations are • Favorable Histologies (BINV-11) Systemic Chemotherapy for HR-Positive or -Negative and considered appropriate. Workup Prior to Preoperative Systemic Therapy (BINV-12) HER-2 Negative (BINV-Q 5) Adjuvant Systemic Therapy After Preoperative Systemic Additional Targeted Therapies and Associated Biomarker See NCCN Categories of Therapy (BINV-16) Testing for Recurrent Unresectable (Local or Regional) Preference. Surveillance/Follow-up (BINV-17) or Stage IV (M1) Disease (BINV-Q 6) Recurrent/Stage IV (M1) Disease (BINV-18) Principles of Monitoring Metastatic Disease (BINV-R) Staging (ST-1) Treatment of Local and Regional Recurrence (BINV-19) Special Considerations Abbreviations (ABBR-1) Systemic Treatment of Recurrent Unresectable (Local or Phyllodes Tumor (PHYLL-1) Regional) or Stage IV (M1) Disease (BINV-20) Paget Disease (PAGET-1) Principles of Biomarker Testing (BINV-A) Breast Cancer During Pregnancy (PREG-1) Principles of Dedicated Breast MRI Testing (BINV-B) Inflammatory Breast Cancer (IBC-1) The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2023. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation. Updates in Version 5.2023 of the NCCN Guidelines for Breast Cancer from Version 4.2023 include: BINV-P • HER2-Negative and postmenopausal or premenopausal receiving ovarian ablation or suppression, Second- and Subsequent-Line Therapy, Preferred Regimens, Revised: For PIK3CA-mutated tumors or AKT1/PTEN-activating mutations, see additional targeted therapy options, see BINV-Q (6). BINV-Q (6 of 14) • Table for biomarkers associated with FDA-approved therapies, For patients with HR+/HER-negative tumors with PIK3CA/AKT1/PTEN activating mutations added: Capivasertib + fulvestrant as a category 1 preferred regimen. With footnote x: In adult patients with PIK3CA/AKT1/PTEN activating mutations after disease progression or recurrence after one or more prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor. BINV-Q (13 of 14) • Additional targeted therapies and associated biomarker testing for recurrent unresectable (local or regional) or stage IV (M1) disease: Dosing added for capivasertib + fulvestrant. BINV-Q (14 of 14) • Reference 2 added: Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med 2023; 388:2058-2070. Updates in Version 4.2023 of the NCCN Guidelines for Breast Cancer from Version 3.2023 include: BINV-1 • Workup 4th bullet, sub-bullet removed: Ki-67 test if considering adjuvant abemaciclib (see BINV-K) BINV-K • Footnote d revised: In patients with HR-positive/HER2-negative, high-risk breast cancer (ie, those with ≥4 positive lymph nodes (confirmed preoperatively and/or at surgery), or 1–3 positive lymph nodes with one or more of the following: grade 3 disease, tumor size ≥5 cm (on pre-operative imaging and/or at surgery), or a Ki-67 score of ≥20%) 2 years of adjuvant abemaciclib can be considered in combination with endocrine therapy (category 1). In patients eligible for both adjuvant olaparib and abemaciclib, the optimal sequence is not known. Updates in Version 3.2023 of the NCCN Guidelines for Breast Cancer from Version 2.2023 include: BINV-12 • Additional workup, clarified "additional tests to consider" by adding "as clinically indicated" and removing footnote: Routine systemic staging is not indicated for non-metastatic (M0) cancer in the absence of signs or symptoms. If metastatic disease is suspected, see Workup on BINV-18. BINV-L (4 of 9) • Preoperative/adjuvant therapy regimens, HER2- Preferred Regimens: ◊ TC cycles modified: Cycled every 21 days for 4-6 cycles. ◊ Added reference: Nitz U, Gluz O, Clemens M, et al. West German Study PlanB Trial: Adjuvant four cycles of epirubicin and cyclophosphamide plus docetaxel versus six cycles of docetaxel and cyclophosphamide in HER2-negative early breast cancer. J Clin Oncol 2019;37:799-808. Continued Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. UPDATES Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Updates in Version 2.2023 of the NCCN Guidelines for Breast Cancer from Version 1.2023 include: BINV-P • HER2-Negative and postmenopausal or premenopausal receiving ovarian ablation or suppression, other recommended regimens, Revised header: First- and/or Subsequent-Line Therapy Added: For ESR1 mutated tumors, see BINV-Q (6). BINV-Q (6 of 14) • Table for biomarkers associated with FDA-approved therapies, added: Elacestrant • Footnote x added: For postmenopausal females or adult males with ER-positive, HER2-negative, ESR1-mutated disease after progression on one or two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor after progression on one prior line of endocrine therapy containing a CDK4/6 inhibitor.. Updates in Version 1.2023 of the NCCN Guidelines for Breast Cancer from Version 4.2022 include: DCIS-1 • Primary treatment, modified: Accelerated partial breast irradiation/partial breast radiation (APBI/PBI) • Footnote j, modified: Select patients with low-risk DCIS may be considered suitable for APBI/PBI if they meet all aspects of the definition of low-risk DCIS from the RTOG 9804 trial, including screen-detected DCIS, low to intermediate nuclear grade, tumor size ≤2.5 cm, and surgical resection with margins negative at >3 mm. DCIS-2 • DCIS postsurgical treatment, 1st bullet, 1st sub-bullet modified: Treated with BCS and RT (category 1), especially for patients with ER-positive DCIS. • Footnote n added: The use of a bisphosphonate (PO/IV) or denosumab is acceptable to maintain or improve bone mineral density and reduce risk of fractures in postmenopausal (natural or induced) patients receiving adjuvant aromatase inhibitor therapy. Optimal duration of either therapy has not been established. Benefits from duration beyond 3 years or optimal duration beyond 3 years is not known. Factors to consider for duration of anti- osteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture. There are case reports of spontaneous fractures after denosumab discontinuation. Patients treated with a bisphosphonate or denosumab should undergo a dental examination with preventive dentistry prior to the initiation of therapy, and should take supplemental calcium and vitamin D. BINV-2 • Locoregional treatment of cT1-3, cN0 or cN+, M0 Disease, modified: BCS with surgical axillary staging (category 1) ± oncoplastic reconstruction • Negative axillary nodes: • Modified: WBRT ± boosto to tumor bed, and consider comprehensive regional nodal irradiation (RNI) in patients with central/medial tumors, pT3 tumors, or pT2 tumors with <10 axillary nodes removed and one of the following high-risk features: grade 3, extensive lymphovascular invasion (LVI), or ER-negative. Modified: Consideration of APBI/PBI in selected low-risk patients (category 1) • Footnote m added: Includes techniques such as local tissue rearrangement, local flaps, regional flaps, breast reduction and mastopexy to allow for greater volumes of resection while optimizing aesthetic outcomes in patients undergoing BCS. BINV-3 • Footnote t modified: Postmastectomy RT may be considered for patients with multiple high-risk recurrence factors, including central/medial tumors or tumors ≥2 cm with <10 axillary nodes removed and at least one of the following: grade 3, ER-negative, or LVI. Continued Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. UPDATES Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Updates in Version 1.2023 of the NCCN Guidelines for Breast Cancer from Version 4.2022 include: DCIS-1 • Primary treatment, modified: Accelerated partial breast irradiation/partial breast radiation (APBI/PBI) • Footnote j, modified: Select patients with low-risk DCIS may be considered suitable for APBI/PBI if they meet all aspects of the definition of low-risk DCIS from the RTOG 9804 trial, including screen-detected DCIS, low to intermediate nuclear grade, tumor size ≤2.5 cm, and surgical resection with margins negative at >3 mm. DCIS-2 • DCIS postsurgical treatment, 1st bullet, 1st sub-bullet modified: Treated with BCS and RT (category 1), especially for patients with ER-positive DCIS. • Footnote n added: The use of a bisphosphonate (PO/IV) or denosumab is acceptable to maintain or improve bone mineral density and reduce risk of fractures in postmenopausal (natural or induced) patients receiving adjuvant aromatase inhibitor therapy. Optimal duration of either therapy has not been established. Benefits from duration beyond 3 years or optimal duration beyond 3 years is not known. Factors to consider for duration of anti- osteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture. There are case reports of spontaneous fractures after denosumab discontinuation. Patients treated with a bisphosphonate or denosumab should undergo a dental examination with preventive dentistry prior to the initiation of therapy, and should take supplemental calcium and vitamin D. BINV-2 • Locoregional treatment of cT1-3, cN0 or cN+, M0 Disease, modified: BCS with surgical axillary staging (category 1) ± oncoplastic reconstruction • Negative axillary nodes: • Modified: WBRT ± boosto to tumor bed, and consider comprehensive regional nodal irradiation (RNI) in patients with central/medial tumors, pT3 tumors, or pT2 tumors with <10 axillary nodes removed and one of the following high-risk features: grade 3, extensive lymphovascular invasion (LVI), or ER- negative. Modified: Consideration of APBI/PBI in selected low-risk patients (category 1) • Footnote m added: Includes techniques such as local tissue rearrangement, local flaps, regional flaps, breast reduction and mastopexy to allow for greater volumes of resection while optimizing aesthetic outcomes in patients undergoing BCS. BINV-3 • Footnote t modified: Postmastectomy RT may be considered for patients with multiple high-risk recurrence factors, including central/medial tumors or tumors ≥2 cm with <10 axillary nodes removed and at least one of the following: grade 3, ER-negative, or LVI. BINV-5 • pN+ ((≥1 ipsilateral metastases >2 mm), modified: Adjuvant chemotherapy with trastuzumab + pertuzumab (category 1, preferred) and endocrine therapy. • Footnote hh added: Updated results from the adjuvant APHINITY trial in HER2-positive early breast cancer, with a median follow-up of 8.4 years, have confirmed the benefit of adding pertuzumab to trastuzumab plus chemotherapy in preventing invasive disease recurrences. (Also on BINV-9) Continued Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. UPDATES Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Updates in Version 1.2023 of the NCCN Guidelines for Breast Cancer from Version 4.2022 include: BINV-9 • pN+ (≥1 ipsilateral metastases >2 mm), modified: Adjuvant chemotherapy with trastuzumab + pertuzumab (category 1) BINV-12 • Additional workup, additional tests to consider, 4th bullet modified: FDG PET/CT (optional) (useful in certain circumstances) • Footnote removed: Bone scan or sodium fluoride PET/CT may not be needed if FDG PET/CT is performed and clearly indicates bone metastasis, on both the PET and CT component. • Footnote removed: FDG PET/CT may be performed at the same time as diagnostic CT, and may be helpful in situations where standard staging studies are equivocal or suspicious. FDG PET/CT may also be helpful in identifying unsuspected regional nodal disease and/or distant metastases when used in addition to standard staging studies. • Footnote added: FDG PET/CT is most beneficial and accurate for advanced disease (stage III) and invasive ductal (compared to lobular) histology, but may be useful in selected circumstances of earlier stage disease (stage IIA disease: T1N1, T2N0) such as: equivocal CT+ bone scan results; suspicion of undetected nodal and/or distant disease; and treatment response assessment. An FDG-PET/CT may be utilized as an adjunct to, or in lieu of, initial standard staging and may be performed simultaneously with diagnostic CT. Conversely, a bone scan or sodium fluoride PET/CT may not be needed if an upfront FDG PET/CT clearly indicates consistent findings on both PET and CT components. BINV-14 • BCS possible, modified: BCS with surgical axillary staging ± oncoplastic reconstruction • Footnote m added: Includes techniques such as local tissue rearrangement, local flaps, regional flaps, breast reduction and mastopexy to allow for greater volumes of resection while optimizing aesthetic outcomes in patients undergoing BCS. • Footnote vv modified: The accurate assessment of in-breast tumor or regional lymph node response to preoperative systemic therapy is difficult, and should include physical examination and performance of imaging studies (mammogram and/or breast ultrasound and/or breast MRI) that were abnormal at the time of initial tumor staging. Selection of imaging methods prior to surgery should be determined by the multidisciplinary team. MRI is more accurate than mammography for assessing tumor response to adjuvant therapy.(Also on BINV-15) BINV-15 • Locoregional treatment, modified: Consider additional systemic chemotherapy and/or preoperative radiation • Footnote xx modified: Complete planned chemotherapy systemic therapy regimen course, if not completed preoperatively. BINV-16 • HR-negative/HER2-positive, ypT1-4,N0 or ypN≥1, modified: If ado-trastuzumab emtansine discontinued for toxicity, then trastuzumab (category 1) ± pertuzumab to complete 1 year of therapy complete (up to) 1 year of HER2-directed therapy with trastuzumab +/- pertuzumab. If node positive at initial staging, trastuzumab + pertuzumab (category 1) • HR-positive/HER2-positive, ypT0N0 or pCR, modified: Endocrine therapy (category 1) + complete up to one year of HER2-targeted therapy with trastuzumab (category 1) ± pertuzumab complete (up to) 1 year of HER2-directed therapy with trastuzumab +/- pertuzumab. If node positive at initial staging, trastuzumab + pertuzumab (category 1) • Footnote ccc modified: There are no data on sequencing or to guide selection of an adjuvant therapy. There are no data on sequencing or combining adjuvant capecitabine, pembrolizumab and/or olaparib in patients who meet criteria for treatment with one or more of these agents. However, their sequential/combined use may be considered in certain patients with high-risk of recurrence. Continued Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. UPDATES Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Updates in Version 1.2023 of the NCCN Guidelines for Breast Cancer from Version 4.2022 include: BINV-17 • Imaging, 3rd bullet added: For patients with germline mutations or family history of breast cancer, please refer to See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic • Added: Post treatment monitoring 1st bullet added: Cardiotoxicity monitoring for patients who received left-sided radiation therapy, anthracyclines, or HER2-targeted therapy. See NCCN Guidelines for Survivorship 2nd bullet added: Provide guidance on risk of comorbidities Footnote eee modified: Benefits of duration beyond 3 years or optimal duration beyond 3 years is not known... BINV-18 • Workup, 5th bullet, 6th sub-bullet added: Useful in certain circumstances • Sub-bullet added: FDG PET/CT (consider FES PET for ER-positive disease) • Footnote iii added: Tissue or plasma-based assays may be used. Tissue-based assays have greater sensitivity, but circulating tumor DNA (ctDNA) may reflect tumor heterogeneity more accurately. BINV-19 • Footnote mmm added: In selected patients who decline mastectomy and otherwise meet consensus criteria for radiotherapy omission or partial breast irradiation (APBI/PBI), repeat BCS +/- adjuvant APBI/PBI may be considered. There are limited data for a repeat BCS in this setting. BINV-20 • Footnote rrr modified: Denosumab, zoledronic acid, or pamidronate (all with calcium and vitamin D supplementation) should be given (category 1) in addition to chemotherapy systemic therapy or endocrine therapy if bone metastasis is present, expected survival is ≥3 months, and renal function is adequate. BINV-21 • Footnote ttt added: According to the 5th ESO-ESMO international consensus guidelines for advanced breast cancer visceral crisis is defined as: “severe organ dysfunction, as assessed by signs and symptoms, laboratory studies and rapid progression of disease. Visceral crisis is not the mere presence of visceral metastases but implies important organ compromise leading to a clinical indication for the most rapidly efficacious therapy.” • Footnote yyy added: It is acceptable to switch to endocrine-based therapy after disease stabilizes or response is observed. (See BINV-P). BINV-22 • Footnote zzz modified: The potential side effects of additional chemotherapy systemic therapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient preference must be taken into account. (Also on BINV-26) BINV-A (1 of 2) • Footnote d added: The distinction between HER2 IHC 0 and 1+ is currently clinically relevant in in the metastatic setting since metastatic patients with HER2 1+ or 2+/ISH negative results (on primary or metastatic samples) may be eligible for treatment targeting non-amplified levels of HER2 expression. BINV-B • Clinical indications and applications, 5th bullet modified and subsequent bullets added: The utility of MRI in follow-up screening of patients with prior breast cancer is undefined. It should generally be considered for: 1) Patients with dense breasts in the BCS + RT 2) Those diagnosed before the age of 50 • References have been updated. Continued Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. UPDATES Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Updates in Version 1.2023 of the NCCN Guidelines for Breast Cancer from Version 4.2022 include: BINV-F (2 of 2) • 2nd bullet modified: These margin recommendations cannot be applied directly to patients undergoing APBI/PBI,1 where data regarding local recurrence are more limited... BINV-H (7 of 7) • Nipple-sparing mastectomy, 1st sub-bullet modified: Historically, the NAC has been sacrificed with skin-sparing mastectomy for cancer therapy. However, NAC-sparing procedures may be an option in cancer patients who are carefully selected by experienced multidisciplinary teams. 3rd sub-bullet added: Topical 2% nitroglycerine (45 mg total dose) used prophylactically has been shown to reduce mastectomy skin flap necrosis in both skin sparing mastectomy and nipple sparing mastectomy in one randomized control trial. BINV-I (1 of 3) • Optimizing delivery of individual therapy, 1st bullet: 1st sub-bullet modified: 3-D CT-based treatment planning should be routinely utilized to delineate target volumes and adjacent organs at risk. CT- based treatment planning should routinely be utilized to delineate target volumes & organs at risk, and assess dose distribution across the entire treatment volume. 3rd sub-bullet modified: Improved homogeneity of the target dose and sparing of normal tissues can be accomplished using compensators such as wedges, forward planning using segments, and intensity-modulated RT (IMRT). Treatment planning should be optimized to maximally improve homogeneity across the target volume while minimizing dose to organs at risk 5th sub-bullet modified: Verification of treatment setup consistency is done with weekly imaging. When using certain techniques (ie, prone breast), more frequent imaging may be appropriate. Standard utilization of daily imaging is not recommended. At a minimum, weekly imaging to verify treatment setup should be utilized. More frequent imaging may be needed for selected cases with inconsistent reproducibility. IGRT may be utilized with DIBH to reduce normal tissue exposure of the heart, lung or liver. 6th sub-bullet modified: When treating the internal mammary nodes, Dose-volume histograms (DVHs) should be used to evaluate dose constraints, dose and constraints to normal tissues (ie, heart, lung), and planning target volumes (PTVs). • Whole Breast Radiation 3rd bullet, 1st sub-bullet modified: Ultra-hypofractionated WBRT of 28.5 Gy delivered as 5 (once-a-week) fractions may be considered in select patients aged >50 years following BCS with pTis/T1/T2/N0, though the optimal fractionation for the boost delivery is unknown for this regimen. Ultra-hypofractionated WBRT of 28.5 Gy in 5 (once-a-week) fractions may be considered for selected pts over 50 yrs following BCS with early- stage, node negative disease, particularly those in whom a boost is not intended. 4th bullet modified: 3-D planning to minimize inhomogeneity and exposure to heart and lung is essential when using this regimen. 3D treatment planning should be optimized as described in the section above. Continued Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. UPDATES Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Updates in Version 1.2023 of the NCCN Guidelines for Breast Cancer from Version 4.2022 include: BINV-I (2 of 3) • Chest wall radiation (including breast reconstruction), RT dosing: 1st bullet and subsequent bullets added: Chest wall RT dose is 45-50.4 Gy at 1.8-2 Gy/fx; in 25-28 fractions patients not undergoing breast reconstruction may alternatively receive 40 Gy at 2.67 Gy/fx or 42.5 Gy at 2.66 Gy/fx ◊ 45-50.4 Gy at 1.8-2.0 Gy/fx total 25-28 fractions. ◊ 40 Gy at 2.67 Gy/fx or 42.5 Gy at 266 Gy/fx total 15-16 fractions. ◊ Boost: 10-16 Gy at 1.8 to 2.0 Gy/fx total 5-8 fractions. 2nd bullet added: Chest wall scar boost of 10-16 Gy/fx may be delivered with or without bolus using electrons or photons. ◊ Sub-bullet removed: Dose is 45–50.4 Gy in 25–28 fractions to the chest wall ± scar boost, at 1.8–2 Gy per fraction, to a total dose of approximately 60–66 Gy. • Regional Nodal Radiation, RT dosing: Bullet removed: Dose is 45–50.4 Gy in 25–28 fractions to the regional nodal fields. 1st bullet added: Regional node dose is 45-50.4 Gy at 1.8-2 Gy/fx; patients not undergoing breast reconstruction may alternatively receive 40 Gy at 2.67 Gy/fx or 42.5 Gy at 2.66 Gy/fx 2nd bullet added: A supplemental boost of RT can be delivered to grossly involved or enlarged lymph nodes (i.e. internal mammary or supraclavicular) that have not been surgically addressed. • RT with preoperative or adjuvant systemic therapy Sequencing of RT with systemic therapy: ◊ 1st bullet, 2nd sub-bullet modified: Capecitabine should be is typically given after completion of RT. ◊ 2nd bullet modified: Available data suggest that sequential or concurrent endocrine therapy with RT is acceptable. Due to compounding side effects, initiating endocrine therapy at the completion of RT may be preferred. Endocrine therapy may be delivered concurrently with RT or started after the completion of RT. Emerging data on toxicities of RT when given currently with CDK 4/6 inhibitors. BINV-I (3 of 3) • Accelerated Partial Breast Irradiation (APBI) modified: Accelerated Partial Breast Irradiation/Partial Breast Irradiation (APBI/PBI) Bullet removed: Studies of APBI suggest that rates of local control in selected low-risk patients with early-stage breast cancer are comparable to those treated with standard WBRT. However, compared to standard WBRT, several studies document an inferior cosmetic outcome with external beam delivery methods of APBI. Follow-up is limited and studies are ongoing. Bullet added: ABPI/PBI offers comparable local control to WBRT in selected low-risk patients with early-stage breast cancer. However, the optimal external beam-APBI/PBI technique/fractionation for minimizing long-term cosmesis effects has not been determined. BINV-K • Footnote g added: Safety data support administration of GnRH agonists before or with chemotherapy, especially if there is a goal to enhance fertility preservation. They can also be initiated after chemotherapy in patients who remain premenopausal. • Footnote i modified: A balanced discussion of the risks and benefits associated with ovarian suppression therapy is critical, including the potential side effects of premature menopause. Aromatase inhibitor or tamoxifen for 5 y plus ovarian suppression should be considered, based on SOFT and TEXT clinical trial outcomes, for premenopausal patients at higher risk of recurrence (ie, young age, high-grade tumor, lymph node involvement). Coadministration of strong inhibitors of CYP2D6 should be used with caution. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. UPDATES Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Updates in Version 1.2023 of the NCCN Guidelines for Breast Cancer from Version 4.2022 include: BINV-L (1 of 9) • Preoperative/adjuvant therapy regimens, HER2-Negative: • Preferred regimens: • 1st regimen modified: Dose-dense AC (doxorubicin/cyclophosphamide) followed or preceded by paclitaxel every 2 weeks • 2nd regimen modified: Dose-dense AC (doxorubicin/cyclophosphamide) followed or preceded by weekly paclitaxel • Footnote g modified: The use of platinum agents in the adjuvant setting is not recommended. If platinum agents are included in an anthracycline-based regimen, the optimal sequence of chemotherapy and choice of taxane agent is not established. Carboplatin may be used as part of the pembrolizumab regimen. BINV-L (4 of 9) • Preoperative/adjuvant therapy regimens, HER2- Preferred Regimens: Preoperative pembrolizumab + chemotherapy followed by adjuvant pembrolizumab ◊ Preoperative – Modified: Carboplatin AUC 5 IV Day 1 Or Carboplatin AUC 1.5 IV Days 1, 8, 15 • Footnote removed: There is also a capsule formulation available. However, do not substitute the capsules for the tablets on a mg-per-mg basis due to differences in dosing and bioavailability. BINV-L (5 of 9) • Preoperative/adjuvant therapy regimens, HER2- Negative Regimens: Useful in certain circumstances, CMF chemotherapy: ◊ 1st bullet modified: Cyclophosphamide 100 mg/m² PO days 1–14 (IV acceptable) ◊ Added: – Or – Cyclophosphamide 600 mg/m2 IV day 1 – Methotrexate 40 mg/ m2 IV day 1 – 5-fluorouracil 600 mg/m2 IV day 1 – Cycled every 21 days for 8 cycles BINV-L (9 of 9) • Preoperative/adjuvant therapy regimens, HER2-Positive, Useful in certain circumstances: Paclitaxel + trastuzumab + pertuzumab ◊ Added: – Followed by: – Trastuzumab 6 mg/kg IV; – Pertuzumab 420 mg IV day 1; ▪ Cycled every 21 days to complete 1 y of therapy • References have been updated. BINV-N (3 of 5) • Footnote c added: Postmenopausal patients with UltraLow risk in the Stockholm Tamoxifen trial had a 20-year breast cancer specific survival of 97% with 2-5 years of Tamoxifen (Esserman LJ, et al. JAMA Oncology 2017;3:1503-1510). Patients with an ultralow-risk in the MINDACT trial have shown 8-year breast cancer specific survival above 99%. (Lopes Cardozo JMN, et al. J Clin Oncol 2022;40:1335-1345). Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. UPDATES Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Updates in Version 1.2023 of the NCCN Guidelines for Breast Cancer from Version 4.2022 include: BINV-N (4 of 5) • Title of page modified: Gene expression assays for consideration of extended adjuvant systemic therapy. BINV-P • Systemic therapy for ER- and/or PR-positive Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease: This page has been extensively revised. BINV-Q • Systemic therapy for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease: This section has been extensively revised. BINV-Q (10 of 14) • Title of page modified: Dosing: Systemic Therapy Regimens for recurrent unresectable (local or regional)... (Also on BINV-R 2 and BINV-R 3) • BINV-R (3 of 3) • HER2-Positive Regimens (continued), added: Neratinib ◊ 120 mg PO daily on days 1–7; followed by ◊ 160 mg PO daily on days 8–14; followed by ◊ 240 mg PO daily on days 15–21 Capecitabine 750 mg/m² PO twice daily on days 1–14 ◊ Cycled every 21 days x 1 cycle ◊ Followed by Neratinib 240 mg PO daily on days 1 – 21 Capecitabine 750 mg/m² PO twice daily on days 1–14 ◊ Cycled every 21 days beginning with cycle 2 BINV-Q (13 of 14) • Additional targeted therapies and associated biomarker testing for recurrent unresectable (local or regional) or stage IV (M1) disease: This page has been extensively revised. BINV-Q (14 of 14) • References have been updated. PREG-1 • Footnote d modified: There are limited data on the use of taxanes during pregnancy. The optimal schedule is unclear. If used, the NCCN Panel recommends weekly administration of paclitaxel after the first trimester if clinically indicated by disease status. The use of anti-HER2 therapy is contraindicated during pregnancy. IBC-1 • Workup Removed: Preoperative systemic therapy, anthracycline + taxane (preferred). If tumor HER2-positive, HER2-targeted therapy. Added: See Preoperative/Adjuvant Therapy Regimens (BINV-L) • Footnote removed: See Preoperative/Adjuvant Therapy Regimens (BINV-L) ABBR-1 • A new section has been added: Abbreviations Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. UPDATES Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Ductal Carcinoma In Situ (DCIS) Discussion DIAGNOSIS WORKUP PRIMARY TREATMENT Whole breast radiation therapy (WBRT) (category 1) with or • History and physical exam without boost to tumor bedg,h,i,j Breast-conserving • Diagnostic bilateral or See Postsurgical surgerye (BCS) without mammogram Accelerated partial breast Treatment (DCIS-2) lymph node surgeryf • Pathology reviewa irradiation/partial breast • Determination of tumor radiation (APBI/PBI)g,h,i,j DCIS or estrogen receptor (ER) Tis,N0,M0 No RTg,h,i,j (category 2B) status • Genetic counseling for patients at riskb of Total mastectomy with or without sentinel lymph node See Postsurgical hereditary breast cancer biopsy (SLNB)f,h + reconstruction (optional)k Treatment (DCIS-2) • Breast MRIc,d as indicated a The panel endorses the College of American Pathologists Protocol for pathology reporting for all invasive and noninvasive carcinomas of the breast. http://www.cap.org. b For risk criteria, See NCCN Guidelines for Genetic/Familial High-Risk Assessment: g See Principles of Radiation Therapy (BINV-I). Breast, Ovarian, and Pancreatic. c See Principles of Dedicated Breast MRI Testing (BINV-B). h Patients found to have invasive disease at total mastectomy or re-excision d The use of MRI has not been shown to increase likelihood of negative margins or should be managed as having clinical stage l or stage ll disease (See ST- decrease conversion to mastectomy. Data to support improved long-term outcomes 1), including lymph node staging. i See Special Considerations to Breast-Conservation Therapy Requiring are lacking. e Re-resection(s) may be performed in an effort to obtain negative margins in patients Radiation Therapy (BINV-G). j WBRT following BCS reduces ipsilateral breast tumor recurrence rates desiring breast-conservation therapy. Patients in whom adequate surgical margins cannot be achieved with BCS should undergo a total mastectomy. For definition in DCIS by about 50%–70%. Approximately half of the recurrences are of adequate surgical margins, see Margin Status Recommendations After BCS for invasive and half are DCIS. A number of factors determine local recurrence Invasive Cancers and DCIS (BINV-F). risk: palpable mass, larger size, higher grade, close or involved margins, f Complete axillary lymph node dissection should not be performed in the absence of and age <50 years. If the patient and physician view the individual risk as evidence of invasive cancer or proven axillary metastatic disease in patients with “low,” some patients may be treated by excision alone, particularly if they apparent pure DCIS. However, a small proportion of patients with apparent pure DCIS are ER-positive and will be receiving endocrine therapy. Select patients will be found to have invasive cancer at the time of their definitive surgical procedure. with low-risk DCIS may be considered suitable for APBI/PBI if they meet Therefore, the performance of a sentinel lymph node (SLN) procedure should be all aspects of the definition of low-risk DCIS from the RTOG 9804 trial, considered if the patient with apparent pure DCIS is to be treated with mastectomy or including screen-detected DCIS, low to intermediate nuclear grade, tumor with excision in an anatomic location compromising the performance of a future SLN size ≤2.5 cm, and surgical resection with margins negative at >3 mm. k See Principles of Breast Reconstruction Following Surgery (BINV-H). procedure. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. DCIS-1 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Ductal Carcinoma In Situ (DCIS) Discussion DCIS POSTSURGICAL TREATMENT SURVEILLANCE/FOLLOW-UP Risk reduction therapy for ipsilateral breast following BCS: • Consider endocrine therapy for 5 years for patients with ER- positive DCIS, if: Treated with BCS and RTm (category 1) Treated with excision alonel • Interval history and physical exam every 6–12 mo for 5 y, • Endocrine therapy:n then annually Tamoxifenm,o for premenopausal patients • Mammogram every 12 mo (first mammogram 6–12 mo, after Tamoxifenm,o or aromatase inhibitor for postmenopausal breast-conservation therapy, category 2B) patients with some advantage for aromatase inhibitor therapy in patients <60 years or with concerns for thromboembolism Risk reduction therapy for contralateral breast: • Counseling regarding risk reduction l Available data suggest endocrine therapy provides risk reduction in the ipsilateral breast treated with breast conservation and in the contralateral breast in patients with mastectomy or breast conservation with ER-positive primary tumors. Since a survival advantage has not been demonstrated, individual consideration of risks and benefits is important. m CYP2D6 genotype testing is not recommended for patients considering tamoxifen. n The use of a bisphosphonate (PO/IV) or denosumab is acceptable to maintain or improve bone mineral density and reduce risk of fractures in postmenopausal (natural or induced) patients receiving adjuvant aromatase inhibitor therapy. Optimal duration of either therapy has not been established. Benefits from duration beyond 3 years or optimal duration beyond 3 years is not known. Factors to consider for duration of anti-osteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture. There are case reports of spontaneous fractures after denosumab discontinuation. Patients treated with a bisphosphonate or denosumab should undergo a dental examination with preventive dentistry prior to the initiation of therapy, and should take supplemental calcium and vitamin D. o The standard dose of tamoxifen is 20 mg/day for 5 years. Low-dose tamoxifen (5 mg/day for 3 years) is an option only if patient is symptomatic on the 20-mg dose or if patient is unwilling or unable to take standard-dose tamoxifen. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. DCIS-2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion DIAGNOSIS WORKUPa CLINICAL STAGE • History and physical exam • Imaging: Diagnostic bilateral mammogram Ultrasound as necessary Breast MRIb (optional), with special consideration for mammographically occult tumors See NCCN Guidelines cT0,cN+,M0 • Pathology reviewc for Occult Primary • Determination of tumor estrogen/ progesterone receptor (ER/PR) status and Locoregional treatmenti Non-metastatic HER2 statusd Not • See BCS Followed by (M0) invasive • Genetic counseling and testing if patient is at considering RT (BINV-2) breast cancer riske for hereditary breast cancer, has triple- preoperative See or negative breast cancer (TNBC) (at any age), or systemic criteria for • See Mastectomy is a candidate for adjuvant olaparib therapy cT1–T3, preoperative Followed by RT (BINV-3) • Address fertility and sexual health concerns as appropriatef ≥cN0,M0 systemic • Pregnancy test in all patients of childbearing therapy Considering See Additional potentialf (If pregnant, see PREG-1) (BINV-M) preoperative Workup Prior to • Assess for distressg systemic Preoperative Systemic • Consider additional imaging studies only in the presence of signs and symptoms of therapy Therapy (BINV-12) metastatic diseaseh (see BINV-18) Stage IV (M1) or See Workup for Recurrent or Metastatic (M1) invasive breast cancer Recurrent disease Stage IV (M1) Disease (BINV-18) Clinical pathologic diagnosis of inflammatory breast cancer (IBC) See Workup for IBC (IBC-1) a For tools to aid optimal assessment and management of older f For Fertility and Birth Control, see BINV-C. The general considerations for fertility and sexual adults, see NCCN Guidelines for Older Adult Oncology. health/function outlined for specific populations in NCCN Guidelines for Adolescent and Young b Breast MRI may be useful for characterizing axillary and/or Adult (AYA) Oncology and NCCN Guidelines for Survivorship are applicable to all patients internal mammary nodal disease. See Principles of Dedicated diagnosed with breast cancer. Breast MRI Testing (BINV-B). g See NCCN Guidelines for Distress Management. c The panel endorses the College of American Pathologists h Routine systemic staging is not indicated for non-metastatic (M0) cancer in the absence of Protocol for pathology reporting for all invasive and noninvasive systemic symptoms. If metastatic disease is suspected, see Workup on BINV-18. carcinomas of the breast. http://www.cap.org. i Patients with a known or suspected genetic predisposition to breast cancer may have an increased d See Principles of Biomarker Testing (BINV-A). risk of ipsilateral breast recurrence or contralateral breast cancer with breast-conservation therapy. e For risk criteria, see NCCN Guidelines for Genetic/Familial High- These patients may be considered for prophylactic bilateral mastectomy for risk reduction. See Risk Assessment: Breast, Ovarian, and Pancreatic. NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-1 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion LOCOREGIONAL TREATMENT OF cT1–3, cN0 or cN+, M0 DISEASE:a BREAST-CONSERVING SURGERY (BCS) FOLLOWED BY RT RT AFTER COMPLETION OF BCS AND AXILLARY STAGING WBRT ± boosto to tumor bed, and consider comprehensive regional nodal irradiation (RNI) in patients with central/medial tumors, pT3 tumors, or pT2 tumors and one of the following high-risk features: grade 3, extensive lymphovascular Negative invasion (LVI), or ER-negative. or axillary nodes Consider APBI/PBI in selected low-risk patients (category 1)o,p or Consider omitting breast irradiation in patients ≥70 y of age with ER-positive, cN0, pT1 tumors who receive adjuvant endocrine therapy (category 1) WBRT ± boost (use of comprehensive RNI with or Yes to Meets ALL of the following without intentional inclusion of See all BCS with surgical criteria: axilla is at the discretion of the BINV-4 axillary staging • cT1–T2, cN0 radiation oncologist) (category 1) 1–3 positive (category 1)i,j,k,l • No preoperative chemotherapy axillary nodes • 1–2 positive sentinel lymph WBRT with inclusion of any ± oncoplastic reconstructionm node (SLNs) portion of the undissected axilla • WBRT planned No at risk ± boosto to tumor bed (category 1). Strongly consider comprehensive RNI. ≥4 positiven WBRT ± boosto to tumor bed (category 1) + comprehensive RNI with axillary nodes inclusion of any portion of the undissected axilla at risk (category 1) l See Special Considerations to Breast-Conservation Therapy a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Requiring Radiation Therapy (BINV-G). m Includes techniques such as local tissue rearrangement, local Older Adult Oncology. flaps, regional flaps, breast reduction and mastopexy to allow for i Patients with a known or suspected genetic predisposition to breast cancer may have an increased greater volumes of resection while optimizing aesthetic outcomes risk of ipsilateral breast recurrence or contralateral breast cancer with breast-conservation therapy. in patients undergoing BCS These patients may be considered for prophylactic bilateral mastectomy for risk reduction. See n Consider imaging for systemic staging, including chest/abdominal NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. ± pelvic diagnostic CT with contrast, bone scan, and optional FDG j See Considerations for Surgical Axillary Staging (BINV-D). k See Axillary Lymph Node Staging (BINV-E) and Margin Status Recommendations After BCS for PET/CT. o See Principles of Radiation Therapy (BINV-I). Invasive Cancers and DCIS (BINV-F). p APBI/PBI may be administered prior to chemotherapy. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion LOCOREGIONAL TREATMENT OF cT1–3, cN0 or cN+, M0 DISEASE:a,r MASTECTOMY FOLLOWED BY RT RT AFTER COMPLETION OF MASTECTOMY AND AXILLARY STAGING Negative axillary nodes and tumor ≤5 cm and No RTt margins ≥1 mm Negative axillary Consider RTo to chest wall. For patients with additional high-risk nodes and tumor features,t consider addition of comprehensive RNI (including any ≤5 cm and negative portion of the undissected axilla at risk). margins but <1 mm Total mastectomy with surgical Negative axillary nodes Consider RTo to chest wall ± comprehensive RNI (including any See axillary stagingi,j,k and tumor >5 cm portion of the undissected axilla at risk). BINV-4 (category 1) ± reconstructionq 1–3 positive Strongly consider RTo to chest wall + comprehensive RNI (including axillary nodess any portion of the undissected axilla at risk). ≥4 positive RTo to chest wall + comprehensive RNI (including any portion of the axillary nodesn undissected axilla at risk) (category 1) Re-excision to negative margins is preferred. If not feasible, then Margins positive strongly consider RTo to chest wall ± comprehensive RNI (including any portion of the undissected axilla at risk). a For tools to aid optimal assessment and management of older adults, see n Consider imaging for systemic staging, including chest/abdominal ± pelvic diagnostic CT NCCN Guidelines for Older Adult Oncology. with contrast, bone scan, and optional FDG PET/CT. i Patients with a known or suspected genetic predisposition to breast cancer may o See Principles of Radiation Therapy (BINV-I). have an increased risk of ipsilateral breast recurrence or contralateral breast q See Principles of Breast Reconstruction Following Surgery (BINV-H). cancer with breast-conservation therapy. These patients may be considered for r See Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). prophylactic bilateral mastectomy for risk reduction. See NCCN Guidelines for s In the case of a micrometastasis (>0.2 to ≤2.0 mm), and no axillary dissection, evaluate Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. other patient risk factors when considering RT. j See Considerations for Surgical Axillary Staging (BINV-D). t Postmastectomy  RT may be considered for patients with multiple high-risk recurrence k See Axillary Lymph Node Staging (BINV-E) and Margin Status factors, including central/medial tumors or tumors ≥2 cm and at least one of the Recommendations After BCS for Invasive Cancers and DCIS (BINV-F). following: grade 3, ER-negative, or LVI. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-3 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion HISTOLOGY HR STATUS HER2 STATUS SYSTEMIC ADJUVANT TREATMENT HER2-positivey See BINV-5 ER-positivey,z and/or Postmenopausalaa See BINV-6 PR-positivey,z • Ductal/NSTu HER2-negativey pT1–3 AND pN0 See BINV-7 • Lobular Premenopausalaa • Mixed pT1–3 AND pN+ See BINV-8 • Micropapillary • Metaplasticv HER2-positivey See BINV-9 ER-negative and PR-negativey,z HER2-negativey See BINV-10 Favorable histologic type:w • Pure tubular • Pure mucinous • Pure cribriform ER-positivez and/or PR-positivez • Encapsulated or solid See Favorable Histologies (BINV-11) or papillary carcinoma (SPC)x • Adenoid cystic and other ER-negative and PR-negative x Encapsulated papillary carcinoma (EPC) without associated conventional invasion salivary carcinomas is staged as pTis because behavior is similar to DCIS (per AJCC). SPC should • Secretory carcinoma be specified as in situ or invasive based on WHO criteria but both forms have • Rare low-grade forms of favorable outcomes. metaplastic carcinomav y Correlation of histology, hormone receptor (HR), and HER2 status should • Other rare forms always be done with awareness of unusual/discordant or borderline results. See u According to WHO, carcinoma of no special type (NST) encompasses Principles of Biomarker Testing (BINV-A). multiple patterns including medullary pattern, cancers with neuroendocrine z Although patients with cancers with 1%–100% ER immunohistochemistry (IHC) expression, and other rare patterns. staining are considered ER-positive and eligible for endocrine therapies, there are v There are rare subtypes of metaplastic carcinoma (eg, low-grade more limited data on the subgroup of cancers with ER-low–positive (1%–10%) adenosquamous and low-grade fibromatosis-like carcinoma) that are results. The ER-low–positive group is heterogeneous with reported biologic considered to have a favorable prognosis without adjuvant systemic therapies. behavior often similar to ER-negative cancers; thus, individualized consideration w To be associated with favorable prognosis, the favorable histologic type of risks versus benefits of endocrine therapy and additional adjuvant therapies should not be high grade, should be pure (>90% as classified on the surgical should be incorporated into decision-making. See Principles of Biomarker Testing excision, not core biopsy alone), and should be HER2 negative. If atypical (BINV-A). pathologic or clinical features are present, consider treating as ductal/NST. aa See Definition of Menopause (BINV-O). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-4 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE - HER2-POSITIVE DISEASEd,r,z Consider adjuvant endocrine therapybb ± pN0 adjuvant chemotherapya,bb,cc with trastuzumabdd,ee (category 2B) Tumor ≤0.5 cm Adjuvant endocrine therapybb,ff pT1, pT2, or pT3; pN1mi or and pN0 or pN1mi Adjuvant chemotherapya,bb,cc with Tumor 0.6–1.0 cm (≤2 mm axillary trastuzumabdd and endocrine therapybb,ff See node metastasis) Follow-Up • Ductal/NSTu Adjuvant chemotherapya,bb,cc with (BINV-17) Tumor >1 cm • Lobular trastuzumab (category 1) and endocrine therapybb,ff • Mixed • Micropapillary Adjuvant chemotherapya,bb,cc with trastuzumabdd pN+ (≥1 ipsilateral (category 1) and endocrine therapybb,ff,gg metastases >2 mm) or Adjuvant chemotherapya,bb,cc with trastuzumabdd a For tools to aid optimal assessment and management of older adults, see NCCN + pertuzumabhh (category 1, preferred) and Guidelines for Older Adult Oncology. endocrine therapybb,ff,gg d See Principles of Biomarker Testing (BINV-A). r See Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). u According to WHO, carcinoma of NST encompasses multiple patterns including ee Adjuvant chemotherapy with weekly paclitaxel and trastuzumab can be considered medullary pattern, cancers with neuroendocrine expression, and other rare patterns. for pT1,N0,M0, HER2-positive cancers, particularly if the primary cancer is HR- z Although patients with cancers with 1%–100% ER IHC staining are considered negative. The absolute benefit of HER2-based systemic chemotherapy is likely ER-positive and eligible for endocrine therapies, there are more limited data on the negligible in patients with HR-positive cancers and tumor size bordering on T1mic subgroup of cancers with ER-low–positive (1%–10%) results. The ER-low–positive (<1 mm), when the estimated recurrence risk is less than 5% and endocrine group is heterogeneous with reported biologic behavior often similar to ER-negative therapy remains a viable option for systemic treatment. cancers; thus, individualized consideration of risks versus benefits of endocrine ff Consider  adjuvant bisphosphonate therapy for risk reduction of distant metastasis therapy and additional adjuvant therapies should be incorporated into decision- for 3–5 years in postmenopausal patients (natural or induced) with high-risk node- making. See Principles of Biomarker Testing (BINV-A). negative or node-positive tumors. bb See Adjuvant Endocrine Therapy (BINV-K). gg Consider extended adjuvant neratinib following adjuvant trastuzumab-containing cc See  Preoperative/Adjuvant Therapy Regimens (BINV-L). dd The prognosis of patients with pT1a and pT1b tumors that are pN0 is uncertain therapy for patients with HR-positive, HER2-positive disease with a perceived high risk of recurrence. The benefit or toxicities associated with extended neratinib in even when HER2 is amplified or overexpressed. This is a population of breast patients who have received pertuzumab is unknown. cancer patients that was not studied in the available randomized trials. The hh Updated results from the adjuvant APHINITY trial in HER2-positive early breast decision for use of trastuzumab therapy in this cohort of patients must balance the known toxicities of trastuzumab, such as cardiac toxicity, and the uncertain, cancer, with a median follow-up of 8.4 years, have confirmed the benefit of adding absolute benefits that may exist with trastuzumab therapy. pertuzumab to trastuzumab plus chemotherapy in preventing recurrences. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-5 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE - HER2-NEGATIVE DISEASEd,r,z POSTMENOPAUSALaa PATIENTS with pT1–3 AND pN0 or pN+ TUMORS Tumor ≤0.5 cm Consider adjuvant endocrine and therapy (category 2B)bb pN0 Adjuvant chemotherapya,cc followed by endocrine Not done therapybb,ff (category 1) Strongly or Tumor >0.5 cm Adjuvant endocrine therapybb,ff See • Ductal/NSTu consider or Follow-Up • Lobular 21-gene RT- pN1mi (≤2 mm axillary Recurrence Adjuvant endocrine therapy (BINV-17) PCR assay if • Mixed node metastases) score <26 (category 1)bb,ff • Micropapillary candidate for or chemotherapy Adjuvant chemotherapya,cc,bb pN1 (1–3 positive nodes) (category 1)jj,kk Recurrence followed by score ≥26 endocrine therapybb,ff (category 1) Adjuvant chemotherapya,bb,cc,ll pN2/pN3 (≥4 ipsilateral followed by metastases >2 mm)ii endocrine therapybb,ff (category 1) a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology. d See Principles of Biomarker Testing (BINV-A). r See Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). cc See Preoperative/Adjuvant Therapy Regimens (BINV-L). u According to WHO, carcinoma of NST encompasses multiple ff Consider  adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3–5 years patterns including medullary pattern, cancers with neuroendocrine in postmenopausal patients (natural or induced) with high-risk node-negative or node-positive expression, and other rare patterns. tumors. z Although patients with cancers with 1%–100% ER IHC staining are ii There are few data regarding the role of gene expression assays in those with ≥4 ipsilateral considered ER-positive and eligible for endocrine therapies, there are axillary lymph nodes. Decisions to administer adjuvant chemotherapy for this group should be more limited data on the subgroup of cancers with ER-low–positive based on clinical factors. (1%–10%) results. The ER-low–positive group is heterogeneous with jj Other prognostic gene expression assays may be considered to help assess risk of recurrence reported biologic behavior often similar to ER-negative cancers; thus but have not been validated to predict response to chemotherapy. See Gene Expression individualized consideration of risks versus benefits of endocrine Assays for Consideration of Adjuvant Systemic Therapy (BINV-N). therapy and additional adjuvant therapies should be incorporated into kk Patients  with T1b tumors with low-grade histology and no LVI should be treated with endocrine decision-making. See Principles of Biomarker Testing (BINV-A). monotherapy as the TAILORx trial did not include patients with such tumors. aa See Definition of Menopause (BINV-O). ll Addition of 1 year of adjuvant olaparib is an option for select patients with germline BRCA1/2 bb See Adjuvant Endocrine Therapy (BINV-K). mutation after completion of adjuvant chemotherapy. See BINV-L. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-6 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE - HER2-NEGATIVE DISEASEd,r,z PREMENOPAUSALaa PATIENTS with pT1–3 AND pN0 TUMORS Consider adjuvant endocrine Tumor ≤0.5 cm and pN0 therapy (category 2B)bb Adjuvant chemotherapycc followed by endocrine therapybb,ff (category 1) • Ductal/NSTu Not done or • Lobular Adjuvant endocrine therapybb,ff ± • Mixed ovarian suppression/ablationbb,ff • Micropapillary See Follow-Up Recurrence Adjuvant endocrine therapybb,ff ± (BINV-17) Strongly consider score ≤15 ovarian suppression/ablationbb,ff,mm Tumor >0.5 cm 21-gene RT-PCR and assay if candidate Adjuvant endocrine therapybb,ff ± pN0 for chemotherapy ovarian suppression/ablationbb,ff,mm Recurrence or (category 1)jj,kk score 16–25 Adjuvant chemotherapycc followed by endocrine therapybb,ff,mm Recurrence Adjuvant chemotherapycc followed by score ≥26 endocrine therapybb,ff d See Principles of Biomarker Testing (BINV-A). q See Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). u According to WHO, carcinoma of NST encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns. ff Consider  adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3–5 z Although patients with cancers with 1%–100% ER IHC staining are years in postmenopausal patients (natural or induced) with high-risk node-negative or considered ER-positive and eligible for endocrine therapies, there are node-positive tumors. more limited data on the subgroup of cancers with ER-low–positive jj Other prognostic gene expression assays may be considered to help assess risk of (1%–10%) results. The ER-low–positive group is heterogeneous with recurrence but have not been validated to predict response to chemotherapy. See Gene reported biologic behavior often similar to ER-negative cancers; thus Expression Assays for Consideration of Adjuvant Systemic Therapy (BINV-N). individualized consideration of risks versus benefits of endocrine kk Patients  with T1b tumors with low-grade histology and no LVI should be treated with therapy and additional adjuvant therapies should be incorporated into endocrine monotherapy as the TAILORx trial did not include patients with such tumors. decision-making. See Principles of Biomarker Testing (BINV-A). mm In premenopausal patients with recurrence score <26, the addition of chemotherapy to aa See Definition of Menopause (BINV-O). endocrine therapy was associated with a lower rate of distant recurrence compared with bb See Adjuvant Endocrine Therapy (BINV-K). endocrine monotherapy, but it is unclear if the benefit was due to the ovarian suppression cc See  Preoperative/Adjuvant Therapy Regimens (BINV-L). effects promoted by chemotherapy. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-7 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE - HER2-NEGATIVE DISEASEd,r,z PREMENOPAUSALaa PATIENTS with pT1–3 AND pN+ TUMORS Not a candidate Adjuvant endocrine therapy + pN1mi (≤2 mm for chemotherapy ovarian suppression/ablationbb,ff,mm axillary node Assess to metastasis) determine if or candidate for pN1 (1–3 chemotherapy If candidate for Adjuvant chemotherapybb,cc positive nodes) chemotherapy consider followed by endocrine See gene expression therapybb,ff,mm or Follow-Up • Ductal/NSTu assay to assess Adjuvant endocrine therapy + (BINV-17) • Lobular prognosismm,oo • Mixed ovarian suppression/ablationbb,ff,mm • Micropapillary pN2/pN3 (≥4 ipsilateral Adjuvant chemotherapybb,cc metastases >2 mm)nn followed by endocrine therapybb,ff,ll (category 1) d See Principles of Biomarker Testing (BINV-A). ff Consider  adjuvant bisphosphonate therapy for risk reduction of distant q See Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) metastasis for 3–5 years in postmenopausal patients (natural or induced) (BINV-J). with high-risk node-negative or node-positive tumors. u According to WHO, carcinoma of NST encompasses multiple patterns including ll Addition of 1 year of adjuvant olaparib is an option for select patients with medullary pattern, cancers with neuroendocrine expression, and other rare patterns. germline BRCA1/2 mutation after completion of adjuvant chemotherapy. z Although patients with cancers with 1%–100% ER IHC staining are considered See BINV-L. ER-positive and eligible for endocrine therapies, there are more limited data on the mm In premenopausal patients with RS <26, the addition of chemotherapy to subgroup of cancers with ER-low–positive (1%–10%) results. The ER-low–positive endocrine therapy was associated with a lower rate of distant recurrence group is heterogeneous with reported biologic behavior often similar to ER-negative compared with endocrine monotherapy, but it is unclear if the benefit was cancers; thus individualized consideration of risks versus benefits of endocrine due to the ovarian suppression effects promoted by chemotherapy. therapy and additional adjuvant therapies should be incorporated into decision- nn There are few data regarding the role of gene expression assays in those making. See Principles of Biomarker Testing (BINV-A). with ≥4 ipsilateral axillary lymph nodes. Decisions to administer adjuvant aa See Definition of Menopause (BINV-O). chemotherapy for this group should be based on clinical factors. bb See Adjuvant Endocrine Therapy (BINV-K). oo See Gene Expression Assays for Consideration of Adjuvant Systemic cc See Preoperative/Adjuvant Therapy Regimens (BINV-L). Therapy (BINV-N). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-8 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC ADJUVANT TREATMENT: HR-NEGATIVE - HER2-POSITIVE DISEASEd,r,z Consider adjuvant chemotherapya,pp pN0 with trastuzumabdd,ee (category 2B) Tumor ≤0.5 cm Consider adjuvant chemotherapya,pp pN1mi with trastuzumabdd,ee,ff pT1, pT2, or pT3; and Consider adjuvant chemotherapya,pp pN0 or pN1mi (≤2 mm Tumor 0.6–1.0 cm with trastuzumabdd,ee,ff axillary node metastasis) See Follow-Up • Ductal/NSTu Adjuvant chemotherapya,pp (BINV-17) • Lobular Tumor >1 cm with trastuzumabff (category 1) • Mixed • Micropapillary Adjuvant chemotherapya,pp with trastuzumabff (category 1) or pN+ (≥1 ipsilateral metastases >2 mm) Adjuvant chemotherapya,pp with trastuzumabff + pertuzumabhh (category 1, preferred) a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology. d See Principles of Biomarker Testing (BINV-A). r See Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). u According to WHO, carcinoma of NST encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns. z Although patients with cancers with 1%–100% ER IHC staining are considered ER-positive and eligible for endocrine therapies, there are more limited data on the subgroup of cancers with ER-low–positive (1%–10%) results. The ER-low–positive group is heterogeneous with reported biologic behavior often similar to ER-negative cancers; thus, individualized consideration of risks versus benefits of endocrine therapy and additional adjuvant therapies should be incorporated into decision-making. See Principles of Biomarker Testing (BINV-A). dd The prognosis of patients with T1a and T1b tumors that are node negative is uncertain even when HER2 is amplified or overexpressed. This is a population of breast cancer patients that was not studied in the available randomized trials. The decision for use of trastuzumab therapy in this cohort of patients must balance the known toxicities of trastuzumab, such as cardiac toxicity, and the uncertain, absolute benefits that may exist with trastuzumab therapy. ee Adjuvant chemotherapy with weekly paclitaxel and trastuzumab can be considered for pT1,N0,M0, HER2-positive cancers, particularly if the primary cancer is HR- negative. The absolute benefit of HER2-based systemic chemotherapy is likely negligible in patients with HR-positive cancers and tumor size bordering on T1mic (<1 mm), when the estimated recurrence risk is less than 5% and endocrine therapy remains a viable option for systemic treatment. ff C  onsider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3–5 years in postmenopausal patients (natural or induced) with high-risk node- negative or node-positive tumors. hh Updated results from the adjuvant APHINITY trial in HER2-positive early breast cancer, with a median follow-up of 8.4 years, have confirmed the benefit of adding pertuzumab to trastuzumab plus chemotherapy in preventing recurrences. pp See Preoperative/Adjuvant Therapy Regimens (BINV-L). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-9 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC ADJUVANT TREATMENT: HR-NEGATIVE - HER2-NEGATIVE DISEASEd,r,z pN0 No adjuvant therapyqq Tumor ≤0.5 cm pN1mi Consider adjuvant chemotherapya,cc,ff,ll pT1, pT2, or pT3; and pN0 or pN1mi (≤2 mm axillary node Tumor 0.6–1.0 cm Consider adjuvant chemotherapya,cc,ff,ll metastasis) See Follow-Up • Ductal/NSTu Tumor >1 cm Adjuvant chemotherapya,cc,ff,ll (category 1) (BINV-17) • Lobular • Mixed • Micropapillary • Metaplasticv pN+ (≥1 ipsilateral metastases >2 mm) Adjuvant chemotherapya,cc,ff,ll (category 1) a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology. d See Principles of Biomarker Testing (BINV-A). r See Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). u According to WHO, carcinoma of NST encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns. cc See Preoperative/Adjuvant Therapy Regimens (BINV-L). v There are rare subtypes of metaplastic carcinoma (eg, low-grade adenosquamous and ff Consider  adjuvant bisphosphonate therapy for risk reduction of low-grade fibromatosis-like carcinoma) that are considered to have a favorable prognosis distant metastasis for 3–5 years in postmenopausal patients (natural without adjuvant systemic therapies. or induced) with high-risk node-negative or node-positive tumors. z Although patients with cancers with 1%–100% ER IHC staining are considered ER-positive ll Addition of 1 year of adjuvant olaparib is an option for select patients and eligible for endocrine therapies, there are more limited data on the subgroup of cancers with germline BRCA1/2 mutation after completion of adjuvant with ER-low–positive (1%–10%) results. The ER-low–positive group is heterogeneous chemotherapy. See BINV-L. with reported biologic behavior often similar to ER-negative cancers; thus, individualized qq In select patients with high-risk features (eg, young patients with consideration of risks versus benefits of endocrine therapy and additional adjuvant therapies high-grade histology), adjuvant chemotherapy may be considered should be incorporated into decision-making. See Principles of Biomarker Testing (BINV-A). (category 2B). See BINV-L. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-10 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC ADJUVANT TREATMENT: FAVORABLE HISTOLOGIESr,w Consider adjuvant endocrine <1 cm therapybb for risk reduction pT1, pT2, or pT3; and pN0 or pN1mi Consider adjuvant endocrine 1–2.9 cm (≤2 mm axillary therapybb • Pure tubular node metastasis) • Pure mucinous ER-positive • Pure cribriform and/or ≥3 cm Adjuvant endocrine therapybb,ff • Encapsulated or PR-positive, See solid papillary HER2-negativey Follow-Up carcinomax pN+ (≥1 ipsilateral Adjuvant endocrine therapybb,ff (BINV-17) metastases >2 mm) ± adjuvant chemotherapya,bb,cc • Adenoid cystic and other salivary carcinomas ER-negative • Secretory Limited available data support local therapy and carcinoma only with consideration for systemic/targeted PR-negative, • Rare low- therapies only in pN+ disease HER2-negativey grade forms of metaplastic carcinomav a For tools to aid optimal assessment and management of older adults, see NCCN x EPC without associated conventional invasion is staged as pTis because Guidelines for Older Adult Oncology. behavior is similar to DCIS (per AJCC). SPC should be specified as in situ or r See Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) invasive based on WHO criteria but both forms have favorable outcomes. (BINV-J). y Correlation of histology, HR, and HER2 status should always be done with v There are rare subtypes of metaplastic carcinoma (eg, low-grade awareness of unusual/discordant or borderline results. See Principles of adenosquamous and low-grade fibromatosis-like carcinoma) that are considered Biomarker Testing (BINV-A). to have a favorable prognosis without adjuvant systemic therapies. bb See Adjuvant Endocrine Therapy (BINV-K). w To be associated with favorable prognosis, the favorable histologic type should cc See Preoperative/Adjuvant Therapy Regimens (BINV-L). not be high grade, should be pure (>90% as classified on the surgical excision, ff Consider  adjuvant bisphosphonate therapy for risk reduction of distant metastasis not core biopsy alone), and should be HER2 negative. If atypical pathologic or for 3–5 years in postmenopausal patients (natural or induced) with high-risk clinical features are present, consider treating as ductal/NST. node-negative or node-positive tumors. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-11 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion WORKUP PRIOR TO PREOPERATIVE SYSTEMIC THERAPY CLINICAL STAGE ADDITIONAL WORKUPa For operable breast • Axillary assessment with exam cancers: See Breast and Consider ultrasound Axillary Evaluation Prior c≥T2tt or cN+ and M0 Percutaneous biopsy of suspicious nodesss to Preoperative Systemic or • CBC Therapy (BINV-13) cT1c, cN0 HER2-positive • Comprehensive metabolic panel, including liver function tests and disease alkaline phosphatase or Additional tests to consider as clinically indicated cT1c, cN0 TNBC • Chest diagnostic CT ± contrast (For preoperative • Abdominal ± pelvic diagnostic CT with contrast or MRI with contrast systemic therapy criteria, • Bone scan or sodium fluoride PET/CT (category 2B) For inoperable see BINV-M 1)rr • FDG PET/CT (useful in certain circumstances)uu breast cancers: See • Breast MRIb (optional), with special consideration for Preoperative Systemic mammographically occult tumors, if not previously done Therapy (BINV-15) tt If considering preoperative therapy, consider use of a gene expression assay during workup for postmenopausal patients with cN0, operable ER-positive, HER2-negative disease (Iwata H, et al. Breast Cancer Res Treat 2019;173,123-133; Pease AM, et al. Ann Surg Oncol 2019;26:366-371). uu FDG PET/CT is most beneficial and accurate for advanced disease (stage III) a For tools to aid optimal assessment and management of older adults, see and invasive ductal (compared to lobular) histology, but may be useful in selected NCCN Guidelines for Older Adult Oncology. circumstances of earlier stage disease (stage IIA disease: T1N1, T2N0) such as: b Breast MRI may be useful for characterizing axillary and/or internal mammary equivocal CT+ bone scan results; suspicion of undetected nodal and/or distant nodal disease. See Principles of Dedicated Breast MRI Testing (BINV-B). disease; and treatment response assessment. An FDG-PET/CT may be utilized as an rr See Principles of Preoperative Systemic Therapy (BINV-M). adjunct to, or in lieu of, initial standard staging and may be performed simultaneously ss At the time of axillary node sampling, a clip or tattoo should be placed to with diagnostic CT. Conversely, a bone scan or sodium fluoride PET/CT may not be permit verification that the biopsy-positive lymph node has been removed at needed if an upfront FDG PET/CT clearly indicates consistent findings on both PET the time of definitive surgery. and CT components. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-12 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion OPERABLE DISEASE: BREAST AND AXILLARY EVALUATION PRIOR TO PREOPERATIVE SYSTEMIC THERAPY Prior to preoperative systemic therapy, perform: • Core biopsy of breast with placement of image- detectable clips or marker(s), if not previously performed, should be performed prior to preoperative therapy to demarcate the tumor bed Preoperative systemic See Surgical Treatment and Adjuvant • Axillary imaging with ultrasound or MRI (if not therapy based on HR and Therapy After Preoperative Systemic previously done) HER2 statuscc,rr Therapy (BINV-14) and • Biopsy + clip placement recommended of suspicious and/or clinically positive axillary lymph nodes, if not previously done cc See Preoperative/Adjuvant Therapy Regimens (BINV-L). rr See Principles of Preoperative Systemic Therapy (BINV-M). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-13 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion OPERABLE DISEASE: SURGICAL TREATMENT AND ADJUVANT THERAPY AFTER PREOPERATIVE SYSTEMIC TREATMENTvv SURGICAL TREATMENT ADJUVANT THERAPY Adjuvant systemic therapyrr,xx (see BINV-16) + post-lumpectomy adjuvant RTo • cN+ and ypN0: Adjuvant RT to the whole breast ± boost to the tumor bed;yy BCS with surgical and strongly consider comprehensive RNI with inclusion of any portion of the axillary stagingj (see undissected axilla at risk. BINV-D) ± oncoplastic • Any ypN+: Adjuvant RT to the whole breast ± boost to the tumor bed;yy and reconstructionm comprehensive RNI with inclusion of any portion of the undissected axilla at risk. • Any cN0, ypN0: Adjuvant RT to whole breast ± boost to tumor bed BCS possible Adjuvant systemic therapyrr,xx (see BINV-16) + post-mastectomy adjuvant RTo • cN+ and ypN0: Strongly consider RT to the chest wall and comprehensive RNI with inclusion of any portion of the undissected axilla at risk. Mastectomy and surgical • Any ypN+: RT is indicated to the chest wall + comprehensive RNI with axillary stagingj (see BINV-D) inclusion of any portion of the undissected axilla at risk. + reconstruction (optional)q BCS not possible or Adjuvant systemic therapyrr,ww (see BINV-16) without adjuvant RT for any cN0,ypN0 if axilla was assessed by SLNB or axillary node dissectionj j See Considerations for Surgical Axillary Staging (BINV-D). q See Principles of Breast Reconstruction Following Surgery (BINV-H). m Includes techniques such as local tissue rearrangement, local flaps, regional flaps, breast reduction and mastopexy to allow for greater volumes of resection while optimizing aesthetic outcomes in patients undergoing BCS. o See Principles of Radiation Therapy (BINV-I). rr See Principles of Preoperative Systemic Therapy (BINV-M). vv The  accurate assessment of in-breast tumor or regional lymph node response to preoperative systemic therapy is difficult, and should include physical examination and performance of imaging studies (mammogram and/or breast ultrasound and/or breast MRI) that were abnormal at the time of initial tumor staging. Selection of imaging methods prior to surgery should be determined by the multidisciplinary team. MRI is more accurate than mammography for assessing tumor response to adjuvant therapy. xx Complete planned systemic therapy regimen course if not completed preoperatively. yy Strongly consider RT boost for high-risk features (eg, high-grade disease, age <50 years). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion INOPERABLE OR LOCALLY ADVANCED DISEASE (NON-INFLAMMATORY): PREOPERATIVE SYSTEMIC THERAPY AND SUBSEQUENT TREATMENT RESPONSEyy LOCOREGIONAL TREATMENT Mastectomy and surgical axillary stagingj Adjuvant systemic therapyxx (see BINV-16) Response to + reconstruction (optional)q and preoperative or Adjuvant RTo to the whole breast or chest systemic therapyvv BCS with surgical axillary wall and comprehensive RNI with inclusion of and tumor is operable stagingj,zz ± oncoplastic any portion of the undissected axilla at risk. reconstructionm Preoperative systemic therapyqq Response to preoperative Follow pathway systemic therapyvv above No response to and tumor is operable Consider additional systemic preoperative systemic therapy and/or preoperative therapyvv and/or tumor radiationo remains inoperable No response to preoperative systemic Individualize therapyvv and tumor treatment is inoperable j See Considerations for Surgical Axillary Staging (BINV-D). q See Principles of Breast Reconstruction Following Surgery (BINV-H). o See Principles of Radiation Therapy (BINV-I). m Includes techniques such as local tissue rearrangement, local flaps, regional flaps, breast reduction and mastopexy to allow for greater volumes of resection while optimizing aesthetic outcomes in patients undergoing BCS. xx Complete  planned systemic therapy regimen course, if not completed qq See Principles of Preoperative Systemic Therapy (BINV-M). preoperatively. vv The  accurate assessment of in-breast tumor or regional lymph node response zz For  patients with skin and/or chest wall involvement (T4 non-inflammatory) to preoperative systemic therapy is difficult, and should include physical prior to preoperative systemic therapy, breast conservation may be performed examination and performance of imaging studies (mammogram and/or breast in carefully selected patients based on a multidisciplinary assessment of local ultrasound and/or breast MRI) that were abnormal at the time of initial tumor recurrence risk. In addition to standard contraindications to breast conservation staging. Selection of imaging methods prior to surgery should be determined (see BINV-G), exclusion criteria for breast conservation include: inflammatory by the multidisciplinary team. MRI is more accurate than mammography for (T4d) disease before preoperative systemic therapy and incomplete resolution of assessing tumor response to adjuvant therapy. skin involvement after preoperative systemic therapy. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-15 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion ADJUVANT SYSTEMIC THERAPY AFTER PREOPERATIVE SYSTEMIC THERAPYff RESPONSE/PATHOLOGIC STAGE ADJUVANT SYSTEMIC THERAPYbb,cc,ff,gg AFTER PREOPERATIVE THERAPY ypT0N0 or pCR Adjuvant endocrine therapy (category 1) HR-positive/ or + adjuvant olaparib if germline BRCA1/2 mutation CPS+EG score ≥3, and ypT1–4,N0 HER2-negative or residual disease. Select patients may be eligible for adjuvant abemaciclib, ypN≥1 see BINV-K for eligibility criteria. Complete up to 1 year of HER2-targeted therapy with trastuzumab (category 1) ypT0N0 or pCR ± pertuzumab HR-negative/ Ado-trastuzumab emtansine (category 1) alone for 14 cycles.aaa HER2-positive If ado-trastuzumab emtansine discontinued for toxicity, then complete ypT1–4,N0 (up to) 1 year of HER2-directed therapy with trastuzumab (category 1) ± or pertuzumab. If node positive at initial staging, trastuzumab + pertuzumabhh ypN≥1 (category 1) and See HR-positive/ If HR-positive, adjuvant endocrine therapygg (category 1) HER2-positive Follow-Up Endocrine therapy (category 1) + complete (up to) 1 year of HER2-directed (BINV-17) ypT0N0 or pCR therapy with trastuzumab ± pertuzumab. If node positive at initial staging, trastuzumab + pertuzumab (category 1) For high-risk:bbb Adjuvant pembrolizumab (if pembrolizumab-containing ypT0N0 or pCR regimen was given preoperatively) HR-negative/ Adjuvant pembrolizumab (if pembrolizumab-containing regimen was given HER2-negative ypT1–4,N0 preoperatively)ccc or or Adjuvant capecitabine (6–8 cycles)aaa,ccc ypN≥1 or bb See Adjuvant Endocrine Therapy (BINV-K). Adjuvant olaparib for 1 year if germline BRCA1/2 mutationccc hh Updated results from the adjuvant APHINITY trial in HER2-positive early breast cancer, cc See Preoperative/Adjuvant Therapy Regimens (BINV-L). ff Consider  with a median follow-up of 8.4 years, have confirmed the benefit of adding pertuzumab to adjuvant bisphosphonate therapy for risk reduction of distant trastuzumab plus chemotherapy in preventing recurrences. metastasis for 3–5 years in postmenopausal patients (natural or induced) aaa Recommendations do not apply to residual DCIS (ypTis). with high-risk node-negative or node-positive tumors. bbb High-risk criteria include stage II–III TNBC. The use of adjuvant pembrolizumab (category gg Consider extended adjuvant neratinib following adjuvant trastuzumab- 2A) may be individualized. containing therapy for patients with HR-positive, HER2-positive disease ccc There are no data on sequencing or combining adjuvant capecitabine, pembrolizumab with a perceived high risk of recurrence. The benefit or toxicities and/or olaparib in patients who meet criteria for treatment with one or more of these agents. associated with extended neratinib in patients who have received However, their sequential/combined use may be considered in certain patients with high-risk of pertuzumab or ado-trastuzumab emtansine is unknown. recurrence. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-16 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SURVEILLANCE/FOLLOW-UP Exam: • History and physical exam 1–4 times per year as clinically Endocrine therapy: appropriate for 5 y, then annually • Assess and encourage adherence to adjuvant endocrine Genetic screening: therapy • Periodic screening for changes in family history and genetic • Patients on tamoxifen: testing indications and referral to genetic counseling as indicated, Age-appropriate gynecologic screening see NCCN Guidelines for Genetic/Familial High-Risk Assessment: Routine annual pelvic ultrasound is not recommended Breast, Ovarian, and Pancreatic • Patients on an aromatase inhibitor or who experience Post surgical management: ovarian failure secondary to treatment should have • Educate, monitor, and refer for lymphedema management, see monitoring of bone health with a bone mineral density NCCN Guidelines for Survivorship: Lymphedema. determination at baseline and periodically thereaftereee Imaging: Lifestyle: • Mammography every 12 moddd • Evidence suggests that active lifestyle, healthy diet, See • Routine imaging of reconstructed breast is not indicated limited alcohol intake, and achieving and maintaining an Recurrent • For patients with germline mutations or family history of breast ideal body weight (20–25 BMI) may lead to optimal breast Disease cancer, please refer to See NCCN Guidelines for Genetic/Familial cancer outcomes (BINV-18) High-Risk Assessment: Breast, Ovarian, and Pancreatic Communication: • For patients receiving anthracycline-based therapy, see NCCN • Coordination of care between the primary care provider Guidelines for Survivorship for echocardiogram recommendations. and specialists is encouraged. Additionally, a personalized Screening for metastases: survivorship treatment plan including personalized • In the absence of clinical signs and symptoms suggestive of treatment summary of possible long-term toxicity and recurrent disease, there is no indication for laboratory or imaging clear follow-up recommendations is recommended. See studies for metastases screening. NCCN Guidelines for Survivorship Post treatment monitoring: Engagement: • Cardiotoxicity monitoring for patients who received left-sided • Patients frequently require follow-up encouragement in radiation therapy, anthracyclines, or HER2-targeted therapy. order to improve adherence to ongoing screening and For anthracycline-induced toxicity, See NCCN Guidelines for medication adherence Survivorship • Provide guidance on risk of comorbidities ddd Studies indicate that annual mammograms are the appropriate frequency for surveillance of breast cancer patients who have had BCS and RT with no clear advantage to shorter interval imaging. Patients should wait 6 to 12 months after the completion of RT to begin their annual mammogram surveillance. Suspicious findings on physical examination or surveillance imaging might warrant a shorter interval between mammograms.  eee The use of estrogen, progesterone, or selective ER modulators to treat osteoporosis or osteopenia in patients with breast cancer is discouraged. The use of a bisphosphonate (oral/IV) or denosumab is acceptable to maintain or to improve bone mineral density and reduce risk of fractures in postmenopausal (natural or induced) patients receiving adjuvant aromatase inhibitor therapy. Optimal duration of either therapy has not been established. Benefits of duration beyond 3 years or optimal duration beyond 3 years is not known. Factors to consider for duration of anti-osteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture. There are case reports of spontaneous fractures after denosumab discontinuation. Patients treated with a bisphosphonate or denosumab should undergo a dental examination with preventive dentistry prior to the initiation of therapy, and should take supplemental calcium and vitamin D. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-17 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion RECURRENT/STAGE IV (M1) DISEASE CLINICAL WORKUPa STAGE • History and physical exam • Discuss goals of therapy, adopt shared decision-making, and document course of care • CBC See Treatment • Comprehensive metabolic panel, including liver function tests and alkaline phosphatase of Local and • Imaging for systemic staging: Regional Recurrence Chest diagnostic CT ± contrast (BINV-19) Abdominal ± pelvic diagnostic CT with contrast or MRI with contrast and Brain MRI with contrast if suspicious CNS symptoms Supportive carehhh Spine MRI with contrast if back pain or symptoms of cord compression Stage IV (M1) Bone scan or sodium fluoride PET/CT (category 2B) or Useful in certain circumstances: Recurrent ◊ FDG PET/CT (consider FES PET/CT for ER-positive disease) X-rays of symptomatic bones and long and weight-bearing bones abnormal on bone scan See Systemic • Biomarker testing: Treatment of Recurrent Biopsy of at least first recurrence of disease (consider re-biopsy if progression) Unresectable (local or Evaluation of ER/PR and HER2 statusd,fff,ggg regional) or Stage IV Comprehensive germline and somatic profiling to identify candidates for additional (M1) (BINV-20)iii targeted therapies,iii see Additional Targeted Therapies and Associated Biomarker and Testing for Recurrent or Stage IV (M1) Disease (BINV-Q 6) Supportive carejjj • Genetic counseling if patient is at riske for hereditary breast cancer • Assess for distressg fff False-negative ER and/or PR determinations occur, and there may be discordance between the ER and/or PR determination between the primary and metastatic tumor(s). Therefore, endocrine therapy with its low attendant toxicity may be considered in patients with non-visceral or asymptomatic visceral tumors, especially in patients with clinical characteristics predicting for an HR-positive tumor (eg, long disease-free interval, limited sites of recurrence, indolent disease, older age). ggg In clinical situations where a biopsy cannot safely be obtained but the clinical evidence is strongly supportive of recurrence, treatment may commence based on the ER/PR/HER2 status of the primary tumor. Since ER/PR and HER2 status can change with treatment and metastatic progression, it may be appropriate to consider repeat testing on new samples in these scenarios if management will change. a For tools to aid optimal assessment and management of older adults, see NCCN hhh See NCCN Guidelines for Palliative Care and NCCN Guidelines for Supportive Care. Guidelines for Older Adult Oncology. iii Tissue or plasma-based circulating tumor DNA (ctDNA) assays may be used. Tissue- d See Principles of Biomarker Testing (BINV-A). based assays have greater sensitivity, but ctDNA may reflect tumor heterogeneity more e For risk criteria, see NCCN Guidelines for Genetic/Familial High-Risk Assessment: accurately. Breast, Ovarian, and Pancreatic. jjj For the treatment of brain metastases, see NCCN Guidelines for Central Nervous g See NCCN Guidelines for Distress Management. System Cancers. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-18 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion TREATMENT OF LOCAL AND REGIONAL RECURRENCE Total mastectomy + axillary Consider systemic lymph node staging if level l/ll therapyppp Initial treatment with BCS + RTo axillary dissection not previously See donelll,mmm Adjuvant Endocrine Therapy (BINV-K) Local only Initial treatment with mastectomy + level l/ll recurrencekkk axillary dissection and prior RT Surgical resection if possiblennn,ooo Preoperative/Adjuvant Chemotherapy (BINV-L) Initial treatment with mastectomy Surgical resection if Systemic Therapy and no prior RT possiblennn + RTo,ooo for ER- and/or PR- Positive Recurrent Unresectable (local or Surgical resection if possiblennn regional) or Stage IV Axillary recurrence + RT if possibleo,ooo (M1) Disease (BINV-P) Regional only or Chemotherapy Local and Supraclavicular recurrence RT if possibleo,ooo Regimens regional for Recurrent recurrencekkk Unresectable (local or Internal mammary node recurrence RT if possibleo,ooo regional) or Stage IV (M1) Disease (BINV-Q) mmm In selected patients who decline mastectomy and otherwise meet consensus o See Principles of Radiation Therapy (BINV-I). criteria for radiotherapy omission or APBI/PBI, repeat BCS +/- adjuvant APBI/PBI kkk Multidisciplinary  approach is especially important in the management of may be considered. There are limited data for a repeat BCS in this setting. breast cancer recurrence to consider all potential treatment options for optimal nnn If not technically resectable, consider systemic therapy to best response, then outcomes. resect if possible. lll In patients with a local breast recurrence after BCS who had a prior SLNB, ooo The decision to use RT to treat locoregional recurrence must factor in any prior a repeat SLNB may be considered although the accuracy of repeat SLNB is radiation to the area and the risk of late normal tissue toxicity from the sum of unproven. After mastectomy, repeat SLNB may be considered although there are the prior and planned radiation courses. limited data in this setting. ppp See the Discussion for additional information. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-19 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE ER- and/or PR-positive; HER2-negatived,z,sss See BINV-21 Add denosumab, zoledronic acid, Bone disease present or pamidronaterrr ER- and/or PR-positive; HER2-positived,z,sss See BINV-23 Recurrent unresectable (local or regional) or stage IV (M1) diseaseqqq ER- and PR-negative; HER2-positived,z See BINV-25 Bone disease not present ER- and PR-negative; HER2-negatived,z See BINV-26 d See Principles of Biomarker Testing (BINV-A). z Although patients with cancers with 1%–100% ER IHC staining are considered ER-positive and eligible for endocrine therapies, there are more limited data on the subgroup of cancers with ER-low–positive (1%–10%) results. The ER-low–positive group is heterogeneous with reported biologic behavior often similar to ER-negative rrr Denosumab, zoledronic acid, or pamidronate (all with calcium and vitamin D cancers; thus, individualized consideration of risks and benefits of endocrine therapy supplementation) should be given (category 1) in addition to systemic therapy and additional adjuvant therapies should be incorporated into decision-making. See or endocrine therapy if bone metastasis is present, expected survival is ≥3 Principles of Biomarker Testing (BINV-A). months, and renal function is adequate. Patients should undergo a dental qqq Routine surgical resection of the primary breast tumor is generally not indicated in examination with preventive dentistry prior to initiation of this therapy. The the management of patients presenting with de novo stage IV (M1) disease. Although optimal schedule for zoledronic acid is every 12 weeks. there is no survival benefit, it may be considered for local control of the primary sss Baseline assessment of bone density recommended for patients receiving tumor. Discussion regarding management of the primary tumor in this setting must be an aromatase inhibitor who are at risk of osteoporosis (eg, age >65, family individualized. history, chronic steroids). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-20 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE: ER- AND/OR PR-POSITIVE; HER2-NEGATIVEd Continue therapy until Progression Visceral crisisttt Consider initial systemic therapyuuu progressionxxx See BINV-22 or unacceptable toxicityyyy Premenopausalaa Ovarian ablation or suppression + systemic therapyvvv,www No visceral crisis and Prior endocrine therapy within 1 y Postmenopausalaa Systemic therapyvvv,www Continue endocrine therapy until Progression Ovarian ablation or suppression + systemic therapyvvv progressionxxx See BINV-22 Premenopausalaa or or unacceptable Selective ER modulatorsvvv toxicity No visceral crisis and No prior endocrine therapy within 1 y Postmenopausalaa Systemic therapyvvv d See Principles of Biomarker Testing (BINV-A). aa See Definition of Menopause (BINV-O). ttt According to the 5th ESO-ESMO international consensus guidelines (Cardoso F, et al. Ann Oncol 2020;31:1625) for advanced breast cancer visceral crisis is defined as: “severe organ dysfunction, as assessed by signs and symptoms, laboratory studies and rapid progression of disease. Visceral crisis is not the mere presence of visceral metastases but implies important organ compromise leading to a clinical indication for the most rapidly efficacious therapy.” uuu See Systemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q). vvv See  Systemic Therapy for ER- and/or PR-Positive Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-P). www If progression on initial endocrine therapy, switch to a different endocrine therapy option. xxx See Principles of Monitoring Metastatic Disease (BINV-T). yyy It is acceptable to switch to endocrine-based therapy (see BINV-P) after disease stabilizes or response is observed Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-21 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE: ER- AND/OR PR-POSITIVE; HER2-NEGATIVEd,r If not endocrine therapy refractory, consider: No clinical benefit after up to 3 sequential Alternate endocrine therapyfff endocrine therapy regimensxxx Systemic therapyuuu,xxx ± targeted therapy or Progressionxxx (see second-line therapy Symptomatic visceral disease or unacceptable options on BINV-P) toxicity on first-line endocrine therapy or Most patients will be candidates for multiple lines of systemic therapy to Systemic therapyuuu Consider no further palliate advanced breast cancer. At cytotoxic therapyzzz each reassessment clinicians should and assess value of ongoing treatment, For those with Continue supportive care the risks and benefits of an additional visceral crisis: (See NCCN Guidelines for Palliative line of systemic therapy, patient Progressionxxx Alternate systemic Care and NCCN Guidelines for performance status, and patient or unacceptable therapyuuu Supportive Care) preferences through a shared decision- toxicity on first-line making process. systemic therapy d See Principles of Biomarker Testing (BINV-A). r See Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). uuu See Systemic Therapy Regimens for Recurrent Unresectable (Local or fff False-negative  ER and/or PR determinations occur, and there may be Regional) or Stage IV (M1) Disease (BINV-Q). discordance between the ER and/or PR determination between the primary vvv See  Systemic Therapy for ER- and/or PR-Positive Recurrent Unresectable and metastatic tumor(s). Therefore, endocrine therapy with its low attendant (Local or Regional) or Stage IV (M1) Disease (BINV-P). toxicity may be considered in patients with non-visceral or asymptomatic visceral xxx See Principles of Monitoring Metastatic Disease (BINV-T). tumors, especially in patients with clinical characteristics predicting for a HR- zzz The  potential side effects of additional line of therapy may outweigh any clinical positive tumor (eg, long disease-free interval, limited sites of recurrence, indolent benefit in a patient who has a compromised performance status. Patient disease, older age). preference must be taken into account. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-22 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE: ER- and/or PR-POSITIVE; HER2-POSITIVEd Systemic therapy + HER2-targeted therapyuuu,vvv or Continue therapy until Progression Endocrine therapyaaaa ± HER2-targeted therapy progressionxxx See BINV-24 (if premenopausal,aa consider ovarian ablation or unacceptable toxicity or suppression)vvv,bbbb vvv See  Systemic Therapy for ER- and/or PR-Positive Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-P). d See Principles of Biomarker Testing (BINV-A). xxx See Principles of Monitoring Metastatic Disease (BINV-T). aa See Definition of Menopause (BINV-O). aaaa If prior endocrine therapy within 1 y, consider a different endocrine therapy. uuu See Systemic Therapy Regimens for Recurrent Unresectable (local or regional) or bbbb For premenopausal patients, tamoxifen alone (without ovarian ablation/ Stage IV (M1) Disease (BINV-Q). suppression) + HER2-targeted therapy is also an option. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-23 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE: ER- and/or PR-POSITIVE; HER2-POSITIVEd No clinical Most patients will benefit after up be candidates for Consider alternate multiple lines of to 3 sequential Progressionxxx endocrine therapy, Systemic therapy systemic therapy to endocrine therapy on first-line if not endocrine + HER2-targeted palliate advanced regimens ± HER2- Consider no further endocrine refractoryfff,vvv therapy until breast cancer. At targeted therapyxxx HER2-targeted therapy ± HER2-targeted progressionuuu,vvv,xxx each reassessment therapyuuu or therapyzzz and Symptomatic clinicians should continue supportive visceral disease assess value of care ongoing treatment, See NCCN Guidelines the risks and benefits for Palliative Care Progressionxxx of an additional line Alternate and on systemic of systemic therapy, systemic therapy Continue HER2-targeted therapy NCCN Guidelines for therapy patient performance + HER2-targeted until progressionxxx,cccc Supportive Care + HER2-targeted status, and patient therapyuuu preferences through therapy a shared decision- making process. d See Principles of Biomarker Testing (BINV-A). fff False-negative  ER and/or PR determinations occur, and there may be vvv See  Systemic Therapy for ER- and/or PR-Positive Recurrent Unresectable discordance between the ER and/or PR determination between the primary (Local or Regional) or Stage IV (M1) Disease (BINV-P). and metastatic tumor(s). Therefore, endocrine therapy with its low attendant xxx See Principles of Monitoring Metastatic Disease (BINV-T). toxicity may be considered in patients with non-visceral or asymptomatic zzz The  potential side effects of additional line of therapy may outweigh any clinical visceral tumors, especially in patients with clinical characteristics predicting for benefit in a patient who has a compromised performance status. Patient a HR-positive tumor (eg, long disease-free interval, limited sites of recurrence, preference must be taken into account. indolent disease, older age). cccc Continue  HER2-targeted therapy following progression on first-line HER2- uuu See Systemic Therapy Regimens for Recurrent Unresectable (Local or targeted chemotherapy for metastatic breast cancer. The optimal duration of Regional) or Stage IV (M1) Disease (BINV-Q). trastuzumab in patients with long-term control of disease is unknown. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-24 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE: ER- and/or PR-NEGATIVE; HER2-POSITIVEd Most patients will be candidates Consider no further for multiple lines of systemic HER2-targeted therapy to palliate advanced breast therapyzzz and Continue cancer. At each reassessment continue supportive Alternate Systemic therapy therapy until clinicians should assess value care systemic therapy + HER2-targeted progressionxxx Progressionxxx of ongoing treatment, the risks See NCCN + HER2-targeted therapyuuu or unacceptable and benefits of an additional Guidelines for therapyuuu,xxx,cccc toxicity line of systemic therapy, patient Palliative Care performance status, and patient and preferences through a shared NCCN Guidelines for decision-making process. Supportive Care d See Principles of Biomarker Testing (BINV-A). uuu See Systemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q). xxx See Principles of Monitoring Metastatic Disease (BINV-T). zzz The potential side effects of additional line of therapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient preference must be taken into account. cccc Continue HER2-targeted therapy following progression on first-line HER2-targeted chemotherapy for metastatic breast cancer. The optimal duration of trastuzumab in patients with long-term control of disease is unknown. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-25 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE: ER- AND/OR PR-NEGATIVE; HER2-NEGATIVEd Most patients will be candidates for multiple lines of systemic therapy to palliate advanced Consider no further cytotoxic breast cancer. At each therapyzzz and continue Continue reassessment clinicians supportive care therapy until should assess value Alternative systemic See NCCN Guidelines for Systemic therapy uuu,ffff progressionxxx of ongoing treatment, therapyuuu,dddd Palliative Care or unacceptable the risks and benefits and toxicity of an additional line of NCCN Guidelines for systemic therapy, patient Supportive Care performance status, and patient preferences through a shared decision-making process. d See Principles of Biomarker Testing (BINV-A). xx See  Systemic Therapy Regimens for Recurrent Unresectable (local or regional) or Stage IV (M1) Disease (BINV-Q). xxx See Principles of Monitoring Metastatic Disease (BINV-T). zzz The potential side effects of additional line of therapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient preference must be taken into account. dddd See  Additional Targeted Therapies and Associated Biomarker Testing for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease BINV-Q (6). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-26 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF BIOMARKER TESTING HER2 TESTINGa,b • HER2 testing should be performed on all new primary or newly metastatic breast cancers using methodology outlined in the ASCO/CAP HER2 testing guideline.a • A re-review of the pathology with consideration for repeat or consultative HER2 testing should be made if a Grade 1 (any histologic type), pure mucinous, pure tubular, or pure cribriform carcinoma tests HER2-positive.a • After a negative HER2 test result on initial biopsy sample, consider retesting on subsequent surgical or other additional sample if the initial sample was suboptimal (eg, minimal invasive cancer was present, cold ischemic time or fixation was suboptimal), testing error is expected, additional samples contain higher grade morphologically distinct cancer from the biopsy, to rule out heterogeneity in a high grade cancer, or if it will otherwise aid in clinical decision- making.a IHC 0,1+d HER2 (-) Must reflex test with ISH (if same specimen), HER2 testing Equivocal result or order new test with IHC or dual probe ISH (if IHC 2+ by validated new specimen available). immunohistochemistry IHC 3+ HER2 (+) b,c (IHC) assay HER2-Negative: • (Group 5) HER2/CEP17 ratio <2.0 AND average HER2 copy number <4.0 signals/cell HER2-Negativef (Determined by concurrent IHC and ISH results): • (Group 2) HER2/CEP17 ratio ≥2.0 AND average HER2 copy number <4.0 signals/cell and concurrent IHC 0-1+ or 2+ • (Group 3) HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥6.0 signals/cell and concurrent IHC 0-1+ • (Group 4) HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥4.0 and <6.0 signals/cell and concurrent IHC 0-1+ or 2+ HER2 testing by validated dual-probee ISH assayb,c HER2-Positivef (Determined by concurrent IHC and ISH results): • (Group 2) HER2/CEP17 ratio ≥2.0 AND average HER2 copy number <4.0 signals/cell and concurrent IHC 3+ • (Group 3) HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥6.0 signals/cell and concurrent IHC 2+ or 3+ • (Group 4) HER2/CEP17 ratio <2.0 AND average HER2 copy number ≥4.0 and <6.0 signals/cell and concurrent IHC 3+ HER2-Positive: • (Group 1) HER2/CEP17 ratio ≥2.0 AND average HER2 copy number ≥ 4.0 signals/cell d The distinction between HER2 IHC 0 and 1+ is currently clinically relevant in a NCCN endorses the ASCO/CAP HER2 testing guideline. “Principles of HER2 Testing” the metastatic setting since patients with HER2 1+ or 2+/ISH negative results (on primary or metastatic samples) may be eligible for treatment targeting modified with permission from Wolff AC, Hammond MEH, Allison KH, et al. Human non-amplified levels of HER2 expression. Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of e Single-probe ISH assays are not preferentially recommended but if used, Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused cases with average HER2 copy number ≥4.0 and <6.0 signals/cell should Update. J Clin Oncol 2018;36:2105-2122. base final results on concurrent IHC and if 2+ reflexed to dual probe ISH b Laboratory must participate in a quality assurance accreditation program for HER2 testing. testing. Otherwise, tissue specimen should be sent to an accredited laboratory for testing. f For ISH Groups 2–4 final ISH results are based on review of concurrent IHC, Health care systems and providers must cooperate to ensure the highest quality testing. with recounting of the ISH test by a second reviewer if IHC is 2+ (per 2018 c Evidence from trastuzumab adjuvant trials show that HER2 testing by ISH or IHC have CAP/ASCO Update recommendations). Additional report comments are similar utility to predict clinical benefit from HER2-targeted therapy. recommended for negative final results in these ISH groups. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-A Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 1 OF 2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF BIOMARKER TESTING HR TESTING • HR testing (ER and PR) by IHC should be performed on any new primary • Laboratories should have standard operating procedures to maximize or newly metastatic breast cancer using methodology outlined in the accuracy and reproducibility of results for cases with <10% ER staining latest ASCO/CAP HR testing guideline.g DCIS should be tested for ER or weak intensity staining (to avoid false negatives). The status of (PR not required). controls should be reported for cases with these results. • ER testing should be used to determine if a patient is a candidate for • PR testing by IHC on invasive cancers can aid in the prognostic endocrine therapies. classification of cancers and serve as a control for possible false- Cancers with 1%–100% of cells positive for ER expression are negative ER results. Patients with ER-negative, PR-positive cancers may considered ER-positive. Patients with these results are considered be considered for endocrine therapies, but the data on this group are eligible for endocrine therapies (applies to DCIS and invasive cancers). noted to be limited. The same overall interpretation principles apply but Invasive cancers with between 1%–10% ER positivity are considered PR should be interpreted as either positive (if 1%–100% of cells have ER-low–positive. There are more limited data on the benefit of nuclear staining) or negative (if <1% or 0% of cells have nuclear staining). endocrine therapies in this group, but they suggest possible benefit • Interpretation of any ER result by pathology should include evaluation from endocrine treatment, so patients are considered eligible for this of the concordance with the histologic findings of each case. Clinicians treatment (as above). However, this group is noted to be heterogeneous should be aware of when results are unusual and work with pathologists and the biologic behavior of ER-low–positive cancers may be more to attempt to resolve (eg, repeat testing, consultative review) or explain similar to ER-negative cancers. This should be considered in decision- atypical reported findings. See table below. making for other adjuvant therapy and overall treatment pathway. Cancers with <1% staining are considered ER-negative. Patients with cancers with these results have not been shown to benefit from endocrine therapies. Summary of ER IHC Scoring/Interpretation Correlation of ER and Histology: Highly Unusual Results Results Interpretation/ Highly Unusual ER-Negative Results Highly Unusual ER-Positive Results (following ER testing by Report As: Low-grade invasive carcinomas of no Metaplastic carcinomas of all subtypes validated IHC assay) special type (also known as invasive ductal carcinoma) 0% – <1% of nuclei stain ER-negative Lobular carcinomas (classic type) Adenoid cystic carcinomas and other ER-low–positive salivary gland-like carcinomas of the breast 1%–10% of nuclei 1%–100% of stain (with recommended comment) Pure tubular, cribriform, or mucinous Secretory carcinoma nuclei stain carcinomas >10% of nuclei stain ER-positive Encapsulated papillary and solid Carcinomas with apocrine differentiation papillary carcinomas g Allison KH, Hammond MEH, Dowsett M, et al. Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update. J Clin Oncol 2020;38:1346-1366; Arch Pathol Lab Med 2020;144:545-563. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-A Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 2 OF 2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF DEDICATED BREAST MRI TESTING See NCCN Guidelines for Breast Cancer Screening and Diagnosis for indications for screening MRI in patients at increased breast cancer risk. Personnel, Facility, and Equipment Clinical Indications and Applications • Breast MRI examinations are performed with IV contrast and should • May be used for staging evaluation to define extent of cancer or be performed and interpreted by an expert breast imaging team presence of multifocal or multicentric cancer in the ipsilateral working in concert with the multidisciplinary treatment team. breast, or as screening of the contralateral breast cancer at time • Breast MRI examinations require a dedicated breast coil and breast of initial diagnosis (category 2B). There are no high-level data to imaging radiologists familiar with the optimal timing sequences and demonstrate that the use of MRI to facilitate local therapy decision- other technical details for image interpretation. The imaging center making improves local recurrence or survival.1 should have the ability to perform MRI-guided needle sampling and/ • May be helpful for breast cancer evaluation before and after or image-guided localization of MRI-detected findings. preoperative systemic therapy to define extent of disease, response to treatment, and potential for breast-conservation therapy. • May be useful in identifying otherwise clinically occult disease in patients presenting with axillary nodal metastases (cT0, cN+), with Paget disease, or with invasive lobular carcinoma poorly (or inadequately) defined on mammography, ultrasound, or physical examination. • False-positive findings on breast MRI are common. Surgical decisions should not be based solely on the MRI findings. Additional tissue sampling of areas of concern identified by breast MRI is recommended. • The utility of MRI in follow-up screening of patients with prior breast cancer is undefined. It should generally be considered for: 1) Patients with dense breasts treated with BCS + RT 2) Those diagnosed before the age of 50 3) Whose lifetime risk of a second primary breast cancer is >20% based on models largely dependent on family history, such as in those with the risk associated with inherited susceptibility to breast cancer.2 1 Houssami N, Ciatto S, Macaskill P, et al. Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. J Clin Oncol 2008;26:3248-3258. 2 Monticciolo DL, Newell MS, Moy L, et al. Breast cancer screening in women at higher-than-average risk: Recommendations from the ACR. J Am Coll Radiol 2018;15:408-414. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-B Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion FERTILITY AND BIRTH CONTROL See NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology • All premenopausal patients should be informed about the potential • Although data are limited, hormone-based birth control is impact of chemotherapy on fertility and asked about their desire discouraged regardless of the HR status of the patient's cancer. for potential future pregnancies. Patients who may desire future • Alternative methods of birth control include intrauterine devices pregnancies should be referred to fertility specialists before (IUDs), barrier methods, or, for patients with no intent of future chemotherapy and/or endocrine therapy to discuss the options pregnancies, tubal ligation or vasectomy for the partner. based on patient specifics, disease stage, and biology (which • Randomized trials have shown that ovarian suppression with determine the urgency, type, and sequence of treatment). Timing GnRH agonist therapy administered during adjuvant chemotherapy and duration allowed for fertility preservation, options inclusive in premenopausal patients with breast tumors (regardless of HR of oocyte and embryo cryopreservation as well as evolving status) may preserve ovarian function and diminish the likelihood of technologies, and the probability of successful pregnancies chemotherapy-induced amenorrhea. subsequent to completion of breast cancer therapy are also to be • Smaller historical experiences in patients with ER-positive disease discussed. have reported conflicting results with regard to the protective effect • Although amenorrhea frequently occurs during or after of GnRH agonist therapy on fertility. chemotherapy, it appears that the majority of patients <35 years • Breastfeeding following breast-conservation cancer treatment is resume menses within 2 years of finishing adjuvant chemotherapy. not contraindicated. However, the quantity and quality of breast • Menses and fertility are not necessarily linked. Absence of regular milk produced by the conserved breast may not be sufficient or menses, particularly if the patient is taking tamoxifen, does not may be lacking some of the nutrients needed. Breastfeeding is necessarily imply infertility. Conversely, the presence of menses not recommended during active treatment with chemotherapy and does not guarantee fertility. There are limited data regarding endocrine therapy or within 6 months of completing trastuzumab or continued fertility after chemotherapy. pertuzumab. • Patients should not become pregnant during treatment with RT, chemotherapy, endocrine therapy, or during or within 6 months of completing trastuzumab or pertuzumab. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-C Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion CONSIDERATIONS FOR SURGICAL AXILLARY STAGING SLN not identified Axillary dissection level I/IIf No palpable lymph node at diagnosis SLN negativec No further axillary surgery (category 1) or ≤2 suspicious Axillary SLN lymph nodes on Meets ALL of the following criteria:g No dissection level mapping and • cT1–T2, cN0 imaging or ≤2 I/IIf positive lymph excisionb,c • No preoperative chemotherapy nodes confirmed Breast- • 1–2 positive SLNs conserving • WBRT planned Yes by needle biopsy surgery to all No further ± clip placementa SLN positivec Micrometastases seen in SLN axillary surgery Clinically Axillary suspicious Mastectomye Meets ALL of the following criteria:h • cT1–T2, cN0 No dissection level (palpable) lymph FNA or • No preoperative chemotherapy I/IIf nodes or core • 1–2 positive SLNsi biopsy • Adjuvant RT planned with intentional Consider no ≥3 suspicious Yes inclusion of undissected axilla at risk further axillary lymph nodes on negatived to all US-guided FNA surgeryk imaging or or core biopsy If no preoperative Preoperative + clip placement FNA or Axillary dissection level I/IIf chemotherapy was given systemic therapy recommendeda core being considered biopsy Axillary dissection level I/IIf for residual disease by exam or imaging and suspicious positive If preoperative or lymph nodes chemotherapy was given SLNB (SLN biopsy) in selected cases when nodes clinically at diagnosis on negative after neoadjuvant therapy (category 2B)j exam or imaging f See Axillary Lymph Node Staging (BINV-E). a If a positive lymph node is clipped at biopsy, every effort should be made g ACOSOG Z0011: Giuliano AE, et al. JAMA 2017;318:918-926. to remove the clipped node at the time of surgery. h EORTC AMAROS: Donker M, et al. Lancet Oncol 2014;15:1303-10; Rutgers E, et al. b SLN mapping injections may be peritumoral, subareolar, or subdermal. Cancer Research 2019;79 GS4-01-GS04-01. c Sentinel node involvement is defined by multilevel node sectioning with i Limited data exist for ≥3 positive SLNs. hematoxylin and eosin (H&E) staining. Cytokeratin IHC may be used j Among patients shown to be N+ prior to preoperative systemic therapy, SLNB has a for equivocal cases on H&E. Routine cytokeratin IHC to define node >10% false-negative rate when performed after preoperative systemic therapy. This involvement is not recommended in clinical decision-making. rate can be improved by marking biopsied lymph nodes to document their removal, d If clinically negative axilla before chemotherapy and then have a positive using dual tracer, and by removing ≥3 sentinel nodes (targeted axillary lymph node sentinel node after chemotherapy, consider completion axillary lymph node dissection). (Caudle AS, et al. J Clin Oncol 2016;34:1072-1078.) dissection or multidisciplinary tumor board discussion on appropriateness k In the mastectomy setting, in patients who were initially cN0, who have positive of radiation of axilla without further surgery. nodes on SLNB, and have no axillary dissection, RT to the chest wall should include e Limited data exist for mastectomy patients. undissected axilla at risk ± RNI. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-D Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion AXILLARY LYMPH NODE STAGING SLNB should be performed and is the preferred method of axillary lymph node staging if the patient is an appropriate SLNB candidate (See BINV-D). In the absence of definitive data demonstrating superior survival, the performance of axillary staging may be considered optional in patients who have particularly favorable tumors, patients for whom the selection of adjuvant systemic and/or RT is unlikely to be affected, the elderly, or those with serious comorbid conditions. Level III dissection to the thoracic inlet should be performed only in cases with gross disease in level II and/or lll. In the absence of gross disease in level II nodes, lymph node dissection should include tissue inferior to the axillary vein from the latissimus dorsi muscle laterally to the medial border of the pectoralis minor muscle (level I/II). Lymphedema is a potential side effect after the treatment of axillary lymph node surgery resulting from damage to the lymphatic system. Early detection/diagnosis of lymphedema is key for optimal management. Consider pretreatment measurement of both arms as a baseline for patients with risk factors for lymphedema. See NCCN Guidelines for Survivorship: Lymphedema (SLYMPH-1). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-E Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion MARGIN STATUS RECOMMENDATIONS AFTER BREAST-CONSERVING SURGERY (BCS) FOR INVASIVE CANCERS AND DCIS • Margins should be evaluated on all surgical specimens from BCS. Requirements for optimal margin evaluation include: Orientation of the surgical specimens Description of the gross and microscopic margin status Reporting of the distance, orientation, and type of tumor (invasive or DCIS) in relation to the closest margin. • For mammographically detected DCIS with microcalcifications, complete resection should be documented by analysis of margins and specimen radiography. Post-excision mammography can be considered if there is uncertainty. • The NCCN Panel accepts the definitions of negative margins after breast-conservation therapy from the 2014 SSO/ASTRO Margins Guideline1 for Stage I/II Invasive Cancers and the 2016 SSO/ASTRO/ASCO Guideline for DCIS.2 For patients with stage I or II invasive cancers after BCS, a positive margin is defined as “ink on tumor” (any invasive cancer or DCIS cells on ink). These patients generally require further surgery—either a re-excision to achieve a negative margin or a mastectomy. If re-excision is technically feasible to allow for BCS to achieve “no ink on tumor,” this can be done with resection of the involved margin guided by the orientation of the initial resection specimen or re- excision of the entire original excision cavity. There may be select patients with stage III invasive cancers who may be eligible for BCS. For these patients, the margins status would be accessed with similar definitions. DCIS • For patients with pure DCIS treated by BCS and WBRT, a quantitative description of any tumor close to margin resection width of at least 2 mm is associated with a reduced risk of ipsilateral breast tumor recurrence (IBTR) relative to narrower negative margin widths, while the routine practice of obtaining margins greater than 2 mm to further improve outcomes is not supported by the evidence. When there is only minimal or focal DCIS involvement near the margin, clinical judgment should be utilized to weigh the risks of re-excision with risk of recurrence for an individual patient. • For patients with DCIS treated with excision alone (no WBRT), regardless of margin width, there is a substantially higher rate of IBTR than treatment with excision and WBRT, even in predefined, low-risk patients. Although the optimal margin width for treatment with excision alone is unknown, it should be at least 2 mm, with some evidence suggesting improved IBTR rates with margin widths wider than 2 mm. • DCIS with microinvasion (DCIS-M), defined as an invasive focus ≤1 mm in size, should refer to the DCIS margin definition when considering the optimal margin width (>2 mm), given that the majority of DCIS-M is comprised of DCIS and systemic therapy utilization for this lesion more closely reflects the treatment pattern for DCIS than for invasive carcinoma. Continued 1 Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for BCS with whole-breast irradiation in stages I and II invasive breast cancer. J Clin Oncol 2014;32:1507-1515. 2 Morrow M, Van Zee KJ, Solin LJ, et al. Society of Surgical Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology Consensus Guideline on Margins for BCS With Whole-Breast Irradiation in Ductal Carcinoma In Situ. J Clin Oncol 2016;34:4040-4046. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-F Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 1 OF 2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion MARGIN STATUS RECOMMENDATIONS AFTER BCS FOR INVASIVE CANCERS AND DCIS Invasive Breast Cancer • For invasive breast cancers that have a component of DCIS, regardless of the extent of DCIS, the negative margin definition of “no ink on tumor” should be based on the invasive margin guideline. In this setting, “no ink on tumor” is recommended for either DCIS or invasive cancer cells, primarily because the natural history, treatment, and outcomes of these lesions are more similar to invasive cancer than DCIS. For specifically challenging cases, clinical judgment and discussion with the patient should precede routine re-excision. • These margin recommendations cannot be applied directly to patients undergoing APBI/PBI,1 where data regarding local recurrence are more limited. Furthermore, individualized clinical judgment should be utilized on a case-by-case basis, using postoperative mammography to identify residual calcifications and clinical-pathologic factors such as quantitative extent of disease near margin, presence of extensive intraductal component (EIC),3 young age, or multiple close margins to assist in identifying patients who may have an increased risk of IBTR and therefore may be selected to benefit from re-excision. • For patients with invasive breast cancer after BCS, with microscopically focally positive margins (in the absence of an EIC),3 the use of a higher radiation boost dose to the tumor bed may be considered, since generally a boost to the tumor bed is recommended for patients at higher risk of recurrence. See BINV-I. No margin No ink on tumor 2-mm margin necessary Invasive breast cancer X Invasive breast cancer + DCIS X Invasive breast cancer + extensive DCIS X Pure DCIS X DCIS with microinvasion X Pure LCIS* at surgical margin X Atypia at surgical margin X *For pleomorphic Lobular Carcinoma In Situ (LCIS), the optimal width of margins is not known. 1 Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for BCS with whole- breast irradiation in stages I and II invasive breast cancer. J Clin Oncol 2014;32:1507-1515. 3 EIC is defined as an infiltrating ductal cancer where >25% of the tumor volume is DCIS and DCIS extends beyond the invasive cancer into surrounding normal breast parenchyma. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-F Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 2 OF 2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SPECIAL CONSIDERATIONS TO BREAST-CONSERVATION THERAPY REQUIRING RT Contraindications for breast-conservation therapy requiring RT include: Absolute • RT during pregnancy • Diffuse suspicious or malignant-appearing microcalcifications • Widespread disease that cannot be incorporated by local excision of a single region or segment of breast tissue that achieves negative margins with a satisfactory cosmetic result • Diffusely positive pathologic marginsa • Homozygous (biallelic inactivation) for ATM mutation (category 2B) Relative • Prior RT to the chest wall or breast; knowledge of doses and volumes prescribed is essential • Active connective tissue disease involving the skin (especially scleroderma and lupus) • Persistently positive pathologic margina • Patients with a known or suspected genetic predisposition to breast cancer: May have an increased risk of ipsilateral breast recurrence or contralateral breast cancer with breast-conservation therapy May be considered for prophylactic bilateral mastectomy for risk reduction (See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic) May have known or suspected Li-Fraumeni syndrome (category 2B) a See Margin Status Recommendations After BCS for Invasive Cancers and DCIS (BINV-F). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-G Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY No reconstruction required if ratio of tumor to breast volume is small and Breast-conserving minimal cosmetic deformity will result surgeryc or Delayed fat grafting (mark cavity with Consider oncoplastic reduction or clips for subsequent mastopexy and simultaneous or delayed Delayed flap for correction RT planning, contralateral matching procedure RT or of contour defects particularly in cases of oncoplastic tissue Consider bilateral breast reduction if symptoms warrant breast reduction Contralateral reduction/mastopexy rearrangement/ for symmetry reduction)d or Local tissue rearrangement, regional flap (LD, partial LD, TDAP) See Reconstruction Based on Planned Adjuvant RT (BINV-H 2) History of RT or adjuvant RT needed or Carcinoma See Reconstruction Based on in situa,b History of RT (BINV-H 3) or Mastectomye No history of RT/no adjuvant RT needed Implant, autologous, or combination reconstruction Invasive carcinoma See Reconstruction Based on Unknown Unknown RT history or need for RT History of RT or Unknown Need for Postmastectomy RT (BINV-H 4) IBC Delayed reconstruction (See Special Cases, BINV-H 7) a See General Principles of Breast Reconstruction (BINV-H 5). b See Patient Factors Affecting Choice of Reconstruction (BINV-H 6). c An evaluation of the likely cosmetic outcome of BCS should be performed prior to surgery. Oncoplastic techniques for breast conservation can extend breast-conserving surgical options in situations where the resection by itself would likely yield an unacceptable cosmetic outcome. d Consider staged partial mastectomy reconstruction (oncoplastic Application of these oncoplastic techniques may reduce the need for mastectomy and decrease approaches) if preoperative margin status is unclear (lobular, the need for a secondary surgery to minimize breast deformity. Patients should be informed of multifocal/centric). the possibility of positive margins and potential need for secondary surgery, which could include e As with any mastectomy, there is a risk of locoregional cancer either segmental re-excision, or mastectomy with or without loss of the nipple. Systematic recurrence, and evidence suggests skin-sparing or skin- and oncoplastic reduction specimen orientation as well as highly specific operative documentation nipple-sparing mastectomy is probably equivalent to standard regarding tissue rearrangement should be conducted. Enhanced communication between the mastectomy in this regard. Post-mastectomy RT should still be radiation oncology team and reconstructive team will be necessary for boost cavity localization applied in cases treated by skin-sparing mastectomy following for RT treatment planning (Shah C, et al. Ann Surg Oncol 2018;25:2509-2511). the same selection criteria as for standard mastectomy. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-H Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 1 OF 7 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY RECONSTRUCTION BASED ON PLANNED ADJUVANT RTa,b Expansion followed by exchange to implant prior to the initiation of RTk 2 stage: tissue expander followed by permanent implant (prepectoral, partial submuscular, or total submuscular tissue expander) Implant-based Expansion followed by RT and delayed exchange to implantj,k reconstruction plannedf 1 stage: direct to implanth Immediate autologous reconstructioni Autologous reconstruction Delayed reconstruction after the completion of RTi plannedg Place tissue expander at the time of surgery, followed by expansion, RT, and delayed autologous reconstructioni,j a See General Principles of Breast Reconstruction (BINV-H 5). b See Patient Factors Affecting Choice of Reconstruction (BINV-H 6). f In the setting of RT, implants are at a statistically significant increased risk of capsular contracture, aesthetic deformity, malposition, implant exposure, infection, and reconstructive failure. i Consider delaying autologous reconstruction until after RT is completed, as RT to g Common donor sites for autologous tissue include the abdomen (ie, DIEP, MS- a flap may cause loss of cosmesis and/or fat necrosis. TRAM, SIEA, free TRAM, pedicled TRAM), gluteal region (ie, SGAP, IGAP), thigh j Consultation with radiation oncology may be necessary to determine if volume of (ie, TUG, VUG, DUG, PAP), or the back (ie, LD, TDAP). contralateral tissue expander will affect RT treatment plan, because cases may h Determined by preoperative size and ptosis, patient desire of postoperative size, require contralateral deflation. Radiation oncology consultation should also be and assessment intraoperatively of skin and soft tissue quality and perfusion, with requested in cases of an anticipated close or positive deep margin, as this may consideration for patient-specific relative contraindications (eg, smoking, obesity) impact the optimal placement of the expander (pre- vs. subpectoral). to single-stage vs. two-stage approaches. Healing issues may occur and delay k Exchange of tissue expander to implant should be timed to avoid any delay in initiation of RT. adjuvant RT. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-H Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 2 OF 7 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY RECONSTRUCTION BASED ON HISTORY OF RTa,b Autologous (preferred) or combination Adequatem 1 stage: direct to implant Recurrent 2 stage: tissue expander carcinoma after Assess soft tissue preoperatively followed by implant breast conservation and intraoperativelyl including RT Inadequatem Autologous (preferred) or combinationn,o Autologous (preferred) or combinationn,o Adequatem 2 stage: tissue expander followed by Delayed implant or autologous tissue reconstruction after Assess soft tissue preoperatively mastectomy and RT and intraoperativelyl Inadequatem Autologous (preferred) or combinationn,o a See General Principles of Breast Reconstruction (BINV-H 5). b See Patient Factors Affecting Choice of Reconstruction (BINV-H 6). n Addition of latissimus flap to prosthetics in the previously irradiated patient l Assessment includes clinical examination and may also include intraoperative mitigates many of the above effects. technologies to assess perfusion. o In the delayed reconstruction patient, there is often limited soft tissue even with m In patients with a history of RT to the breast, implant-based reconstruction the addition of a latissimus flap. Therefore, latissimus flap + tissue expander carries a significantly increased risk of capsular contracture, aesthetic deformity, placement may be required if a permanent implant cannot be accommodated malposition, implant exposure, infection, and reconstructive failure. under the latissimus flap. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-H Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 3 OF 7 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY RECONSTRUCTION BASED ON NO OR UNKNOWN HISTORY OF RT OR UNKNOWN NEED FOR POSTMASTECOMY RTa,b Exchange tissue expander to implant No RT planned or Tissue Convert to autologous tissue reconstruction Adjuvant expansion chemotherapy planned during Exchange tissue expander to permanent implantf,j Immediate placement chemotherapy (prior to initiation of RT or after RT) of tissue expander at RT planned or the time of mastectomy Conversion to autologous tissue reconstruction after RT (prepectoral, partial submuscular, total Tissue expansion followed by exchange to permanent submuscular tissue No RT planned implant or autologous tissue reconstruction expander placement)f No adjuvant chemotherapy Tissue expansion (prior to RT), followed by exchange planned to permanent implantf,j after RT (can be considered prior to RT if no delay to initiation of treatment) RT planned or Tissue expansion followed by RT, and conversion to 1 stage: direct to implanth autologous tissue reconstructionj or Consider revisional surgeries Immediate autologous to the ipsilateral or contralateral reconstruction or latissimus dorsi breast after RT if needed with implant at time of mastectomyi RT not required Reconstruction with implant, autologous tissue, or a combination Delayed reconstruction RT required See Reconstruction Based on History of RT (BINV-H 3) a See General Principles of Breast Reconstruction (BINV-H 5). b See Patient Factors Affecting Choice of Reconstruction (BINV-H 6). i Consider delaying autologous reconstruction until after RT is completed, f In the setting of RT, implants are at a statistically significant increased risk of capsular as RT to a flap may cause loss of cosmesis and/or fat necrosis. contracture, aesthetic deformity, malposition, implant exposure, infection, and j Consultation with radiation oncology may be necessary to determine if reconstructive failure. volume of contralateral tissue expander will affect RT treatment plan, h Determined by preoperative size and ptosis, patient desire of postoperative size, because cases may require contralateral deflation. Radiation oncology and assessment intraoperatively of skin and soft tissue quality and perfusion, with consultation should also be requested in cases of an anticipated close consideration for patient-specific relative contraindications (eg, smoking, obesity) to single- or positive deep margin, as this may impact the optimal placement of stage vs. two-stage approaches. Healing issues may occur and delay initiation of RT. the expander (pre- vs. subpectoral). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-H Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 4 OF 7 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY General Principles of Breast Reconstruction • Breast reconstruction may be an option for any patient receiving surgical treatment for breast cancer. All patients undergoing breast cancer treatment should be educated about breast reconstructive options as adapted to their individual clinical situation. However, breast reconstruction should not interfere with the appropriate surgical management of the cancer or the scope of appropriate surgical treatment for this disease. Coordinating consultation and surgical treatment with a reconstructive surgeon should be executed within a reasonable time frame. The process of breast reconstruction should not govern the timing or the scope of appropriate surgical treatment for this disease. The availability of or the practicality of breast reconstruction should not result in the delay or refusal of appropriate surgical intervention. • Some patients may choose not to have reconstruction after mastectomy. The option to undergo mastectomy alone with a surgically optimized closure should be offered to all patients as part of a comprehensive discussion of reconstructive options. Achieving the optimal result in this scenario may require additional procedures beyond the initial mastectomy. See BINV-H (6) for patient factors influencing choice of reconstruction. • Selection of reconstruction option is based on an assessment of cancer treatment, patient body habits, obesity, smoking history, comorbidities, and patient concerns. Smoking and obesity (WHO Class 2 and 3) increase the risk of preoperative complications for all types of breast reconstruction, whether with implant or flap prosthetic or autologous. Patients with these risk factors should be counseled about their increased risk for complications following breast reconstruction, including donor site complications/hernias and bulges of the abdominal wall, delayed healing, mastectomy skin flap necrosis, total flap failure (obesity), and implant failure (smoking). • Nipple areolar reconstruction should be offered to patients if the nipple-areolar complex (NAC) has been removed as part of their cancer treatment. Various techniques are available for nipple reconstruction. Three-dimensional (3-D) tattooing can be offered to patients as an option for NAC reconstruction. • Additionally, patients who are not satisfied with the cosmetic outcome following completion of breast cancer treatment should be offered reconstructive surgery consultation. • Patients known to harbor genetic mutations that increase the risk of breast cancer may opt to undergo bilateral prophylactic mastectomies with reconstruction. Reconstruction can be performed with prosthetic, autologous tissue, or a combination of implant with autologous tissue. • Skin-sparing mastectomy should be performed by an experienced breast surgery team that works in a coordinated, multidisciplinary fashion to guide proper patient selection for skin-sparing mastectomy, determine optimal sequencing of the reconstructive procedure(s) in relation to adjuvant therapies, and perform a resection that achieves appropriate surgical margins. • Revisional surgery may be necessary after breast reconstruction. This may include procedures such as fat grafting, mastopexy, direct excision/suction-assisted lipectomy, contralateral procedures (in cases of unilateral reconstruction), and others. Patients should be informed before reconstruction that revision surgery may be necessary. Continued Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-H Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 5 OF 7 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY Patient Factors Influencing Breast Reconstruction • Breast reconstruction is elective and patients may choose to not have breast reconstruction. Individual patients present preoperatively with a variety of factors that may impact the choice of reconstruction, the risk of complications, donor site morbidity, and aesthetic result. Each of these factors must be taken into account, along with patient desire, to choose the optimal method of reconstruction. • Patient desire The patient may have a strong feeling towards one form of reconstruction after being given the options. Breast reconstruction should be a shared decision. • Medical comorbidities Medical comorbidities may preclude longer reconstructive procedures such as autologous tissue reconstruction in some patients. The selection of the reconstructive method of choice should take into consideration patient comorbidities. Poorly controlled diabetes is a risk factor for postoperative complications in both implant and autologous tissue reconstruction. Patients should be screened for personal or familial thrombophilia. Thrombophilia may result in reconstructive failure of microsurgical reconstruction or thromboembolic events. • Tobacco use Smoking has been associated with increased risk of delayed wound healing, mastectomy flap necrosis, NAC necrosis in the setting of nipple-sparing mastectomy, infection, and failure of implant-based reconstruction. In free flap reconstruction, smoking increases the risk of donor complications. Patients should be encouraged to stop smoking prior to reconstruction. Smoking has not definitively been shown to increase the risk of microvascular thrombosis in free flap breast reconstruction. • Breast size/shape If patient has significant macromastia or ptosis, consideration can be given to a reduction pattern mastectomy with either implant-based or autologous tissue reconstruction, or oncoplastic reduction techniques. The volume limitations of implants may preclude an acceptable reconstruction in patients with macromastia if preservation of volume is a priority. • BMI Patients with a markedly elevated BMI may be at increased risk of infectious complications and seromas as well as donor site complications from autologous reconstruction, including delayed healing and hernia formation. Immediate reconstruction can be performed, but delayed reconstruction can be considered if the patient is motivated to lose weight. Oncoplastic reduction techniques can be considered if the breast is large/ptotic. • Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) There exists an association between certain types of textured breast implants and BIA-ALCL. The risk appears to vary based on the method of texturing. Patients with a past or current history of textured implants should follow up with their reconstructive surgeon. See NCCN Guidelines for T-Cell Lymphomas. Continued Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-H Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 6 OF 7 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY Special Cases • Nipple-sparing mastectomy NAC-sparing procedures may be an option in cancer patients who are carefully selected by experienced multidisciplinary teams. Retrospective data support the use of NAC-sparing procedures for early-stage breast cancer, DCIS, risk-reduction procedures, and in some locally advanced invasive cancers (ie, with complete clinical response to preoperative chemotherapy and no nipple involvement with cancer). Preoperative clinical or radiographic evidence of nipple involvement, including Paget disease, bloody nipple discharge associated with malignancy, IBC, and/or imaging findings suggesting malignant involvement of the nipple or subareolar tissues contraindicates nipple preservation. Nipple margin assessment is mandatory, and the nipple margin should be clearly designated. Preoperative breast size, shape, and nipple position should also be considered in the decision to perform NAC-sparing mastectomy. Patients with small to moderate breast volume with good nipple position are ideal candidates. In patients with large or significantly ptotic breasts, NAC-sparing mastectomies may be offered in select cases by using various reduction patterns or delay techniques to augment the NAC perfusion, either in an immediate or delayed fashion, as long as it does not delay oncologic care. Intraoperative assessment of the NAC perfusion should also guide the decision to preserve the NAC or remove it. Patients should be counseled on the risk of delayed healing, nipple necrosis, loss of pigmentation, loss of sensation, loss of projection, and need for subsequent removal of the NAC. Topical 2% nitroglycerine (45 mg total dose) used prophylactically has been shown to reduce mastectomy skin flap necrosis in both skin- sparing mastectomy and nipple sparing mastectomy in one randomized control trial. • Inflammatory breast cancer Delayed reconstruction after mastectomy for IBC remains the clinical standard, for several reasons. The need to resect involved skin negates the benefit of skin-sparing mastectomy for immediate reconstruction, and high rates of local and distant recurrence warrant comprehensive, RNI in a timely fashion, which may be technically more challenging or subject to delay after immediate reconstruction. Advances in multimodal therapy have improved 5-year survival in IBC patients, justifying clinical studies to see if immediate reconstruction may be appropriate for certain patients with IBC, but neither the outcomes nor the clinical features to predict such outcomes are known at this time. In the uncommon clinical circumstance that the extent of skin excision at the time of mastectomy precludes primary or local closure, reconstruction of the chest wall defect with autologous tissue is necessary, and concomitant immediate reconstruction may be accomplished. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-H Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 7 OF 7 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF RADIATION THERAPY Optimizing Delivery of Individual Therapy • It is important to individualize RT planning and delivery. 3-D CT-based treatment planning should routinely be utilized to delineate target volumes & organs at risk, and assess dose distribution across the entire treatment volume. Radiation to the breast/chest wall and nodal regions is generally delivered with single energy or mixed energy photons ± electrons. Treatment planning should be optimized to maximally improve homogeneity across the target volume while minimizing dose to organs at risk. Additional techniques such as respiratory control (deep inspiration breath-hold), prone positioning, and cardiac blocks may also be used to try to further reduce dose to heart, lung, and adjacent normal tissue. At a minimum, weekly imaging to verify treatment setup should be utilized. More frequent imaging may be needed for selected cases with inconsistent reproducibility. Image-guided radiation therapy (IGRT) may be utilized with deep inspiration breath-hold (DIBH) technique to reduce normal tissue exposure of the heart, lung or liver. Dose-volume histograms (DVHs) should be used to evaluate, dose and constraints to normal tissues (ie, heart, lung), and planning target volumes (PTVs). • It is common for RT to follow chemotherapy when chemotherapy is indicated. Whole Breast Radiation • Target definition is the breast tissue at risk. • RT dosing: The whole breast should receive a hypofractionated dose of 40–42.5 Gy in 15–16 fractions; in selected cases 45–50.4 Gy in 25–28 fractions may be considered. A boost to the tumor bed is recommended in patients at higher risk for recurrence. Typical boost doses are 10–16 Gy in 4–8 fractions. • Lumpectomy cavity boost can be delivered using enface electrons, photons, or brachytherapy. Ultra-hypofraction ated WBRT of 28.5 Gy in 5 (once-a-week) fractions may be considered for selected pts over 50 yrs following BCS with early-stage, node-negative disease, particularly those in whom a boost is not intended.a,b a Alternatively, 26 Gy in 5 daily fractions over one week may be considered, though data beyond 5 years for local relapse or toxicity are not yet available for this regimen. [Murray Brunt A, Haviland JS, Wheatley DA, et al. Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial. Lancet 2020;395:1613-1626.] b Brunt AM, Haviland JS, Sydenham M, et al. Ten-year results of FAST: A randomized controlled trial of 5-fraction whole-breast radiotherapy for early breast cancer. J Clin Oncol 2020;38:3261-3272. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-I Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 1 OF 3 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF RADIATION THERAPY Chest Wall Radiation (including breast reconstruction) • The target includes the ipsilateral chest wall, mastectomy scar, and drain sites when indicated. Depending on whether or not the patient has had breast reconstruction, several techniques using photons and/or electrons are appropriate. Special consideration should be given to the use of bolus material to ensure that the skin dose is adequate, particularly in the case of IBC. • RT dosing: Chest wall RT dose is 45-50.4 Gy at 1.8-2 Gy/fx; in 25-28 fractions patients not undergoing breast reconstruction may alternatively receive 40 Gy at 2.67 Gy/fx or 42.5 Gy at 2.66 Gy/fx ◊ Boost: 10-16 Gy at 1.8 to 2.0 Gy/fx total 5-8 fractions. Chest wall scar boost of 10-16 Gy/fx may be delivered with or without bolus using electrons or photons. Chest wall scar boost may be delivered with or without bolus using electrons or photons. Regional Nodal Radiation • For paraclavicular and axillary nodes, prescription depth varies based on the patient anatomy. • Regional nodes should be contoured when considering regional nodal RT. Refer to breast atlases for contouring guidelines.c,d • RT dosing: Regional node dose is 45-50.4 Gy at 1.8-2 Gy/fx; patients not undergoing breast reconstruction may alternatively receive 40 Gy at 2.67 Gy/fx or 42.5 Gy at 2.66 Gy/fx A supplemental boost of RT can be delivered to grossly involved or enlarged lymph nodes (i.e. internal mammary or supraclavicular) that have not been surgically addressed. ◊ A supplemental boost of RT can be delivered to grossly involved or enlarged lymph nodes (ie, internal mammary or clavicular) that have not been surgically addressed. RT with Preoperative or Adjuvant Systemic Therapy • In patients treated with preoperative systemic therapy, adjuvant RT is based on the maximal disease stage (ie, clinical stage, pathologic stage, tumor characteristics) at diagnosis (before preoperative systemic therapy) and pathology results after preoperative systemic therapy. • Sequencing of RT with systemic therapy: ◊ It is common for RT to follow chemotherapy when chemotherapy is indicated. However, – CMF (cyclophosphamide/methotrexate/fluorouracil) and RT may be given concurrently, or CMF may be given first. – Capecitabine is typically given after completion of RT. – Olaparib should be given after completion of RT. ◊ Available data suggest that sequential or concurrent endocrine therapy with RT is acceptable. Due to compounding side effects, initiating endocrine therapy at the completion of RT may be preferred. Endocrine therapy may be delivered concurrently with RT or started after the completion of RT. ◊ Adjuvant HER2-targeted therapy ± endocrine therapy may be delivered concurrently with RT. c Offersen BV, Boersma LJ, Kirkove C, et al. ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer. Radiother Oncol 2015;114:3-10. d Gentile MS, Usman AA, Neuschler EI, et al. Contouring guidelines for the axillary lymph nodes for the delivery of radiation therapy in breast cancer: Evaluation of the RTOG Breast Cancer Atlas. Int J Radiat Oncol Biol Phys 2015;93:257-265. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-I Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 2 OF 3 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF RADIATION THERAPY Accelerated Partial Breast Irradiation (APBI)/Partial Breast Irradiation (PBI) • APBI/PBI offers comparable local control to WBRT in selected low-risk patients with early-stage breast cancer. However, the optimal external beam-APBI/PBI technique/fractionation for minimizing long-term cosmesis effects has not been determined. Patients are encouraged to participate in clinical trials. The NCCN Panel recommends APBI/PBI for any patient who is BRCA negative and meets the 2016 ASTRO criteria. The 2016 ASTRO criteria define patients aged ≥50 years to be considered "suitable" for APBI/PBI if: ◊ Invasive ductal carcinoma measuring ≤2 cm (pT1 disease) with negative margin widths of ≥2 mm, no LVI, and ER-positive or ◊ Low/intermediate nuclear grade, screening-detected DCIS measuring size ≤2.5 cm with negative margin widths of ≥3 mm. • RT dosing: Regimen Method Reference 30 Gy/5 fractions QOD External Livi L, Meattini I, Marrazzo L, et al. Accelerated partial breast irradiation using intensity-modulated radiotherapy (preferred) beam RT versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial. Eur J Cancer (EBRT)e 2015;51:451-463. Meattini I, Marrazzo L, Saieva C, et al. Accelerated partial-breast irradiation compared with whole-breast irradiation for early breast cancer: Long-term results of the randomized phase III APBI-IMRT-Florence Trial. J Clin Oncol 2020;38:4175-4183. 40 Gy/15 fractions EBRT Coles CE, Griffin CL, Kirby AM, et al. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet 2017;390:1048-1060. 34 Gy/10 fractions BID Balloon/ Vicini FA, Cecchini RS, White JR, et al. Long-term primary results of accelerated partial breast irradiation after Interstitial BCS for early-stage breast cancer: a randomised, phase 3, equivalence trial. Lancet 2019;394:2155-2164. 38.5 Gy/10 fractions BID EBRT Whelan TJ, Julian JA, Berrang TS, et al. External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial. Lancet 2019;394:2165-2172. e The protocol mandated IMRT. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-I Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 3 OF 3 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SPECIAL CONSIDERATIONS FOR BREAST CANCER IN MALES (SEX ASSIGNED AT BIRTH) NCCN recommendations have been developed to be inclusive of individuals of all sexual and gender identities to the greatest extent possible. On this page, the terms males and females refer to sex assigned at birth. • Few males have been included in breast cancer trials.1 Therefore, recommendations regarding management of breast cancer in males are generally extrapolated from findings of clinical trials focusing on breast cancer in females. • Although there are some biologic and clinical differences between breast cancer in males and females, management of breast cancer in males is similar overall to management of breast cancer in females, with the following special considerations pertinent to male patients:2 Genetics: The NCCN Panel recommends consideration of genetic testing for all males with breast cancer (See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic). Breast surgery: Historically, males with breast cancer have undergone mastectomy more often than BCS. However, breast-conservation therapy is increasingly being performed in males and evolving data indicate that breast conservation in males is associated with equivalent outcomes to mastectomy and that it is safe and feasible. Decisions about breast conservation versus mastectomy in males should be made according to similar criteria as for females.2-9 Axillary lymph node surgery: As in females, SLNB should be performed in the setting of male breast cancer with a clinically node-negative axilla.2,4 RT: Indications for radiation after breast surgery in males with breast cancer are the same as for females with breast cancer.2,5,10,11 Use of molecular assays: Data are limited regarding the use of molecular assays to assess prognosis and to predict benefit from chemotherapy in males with breast cancer.2 Available data suggest the 21-gene assay recurrence score provides prognostic information in males with breast cancer.12,13 Preoperative/adjuvant systemic therapy: Chemotherapy with/without HER2-targeted therapy should be recommended for males with breast cancer according to guidelines for females with breast cancer.2 Options for adjuvant endocrine therapy for males with breast cancer include tamoxifen for 5–10 years or, if tamoxifen is contraindicated, a GnRH analog plus an aromatase inhibitor. In males, single- agent adjuvant treatment with an aromatase inhibitor has been associated with inferior outcomes compared to tamoxifen alone, likely due to inadequate estradiol suppression, and is not recommended.2,14-17 Follow-up after treatment for early-stage disease: There are only limited data to support screening for breast cancer in males.2 The NCCN Panel recommends that bone density be assessed at baseline and every 2 years in males with breast cancer who receive adjuvant GnRH analog therapy. Low bone density should be managed according to standard guidelines.18 Systemic therapy for advanced disease: Management of advanced breast cancer in males is similar to that in females; however, it is preferred that when an aromatase inhibitor is used, a GnRH analog should be given concurrently.2 Available data suggest single-agent fulvestrant has similar efficacy in males as in females.19 Newer agents such as CDK4/6 inhibitors in combination with an aromatase inhibitor or fulvestrant, mTOR inhibitors, and PIK3CA inhibitors have not been systematically evaluated in clinical trials in males with breast cancer. However, available real-world data suggest comparable efficacy and safety profiles and it is reasonable to recommend these agents to males based on extrapolation of data from studies comprised largely of female participants with advanced breast cancer. Indications for and recommendations regarding chemotherapy, HER2-targeted therapy, immunotherapy, and PARP inhibitors for advanced breast cancer in males are similar to those for advanced breast cancer in females.1 References Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-J Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 1 OF 2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SPECIAL CONSIDERATIONS FOR BREAST CANCER IN MALES (SEX ASSIGNED AT BIRTH) REFERENCES 1 Duma N, Hoversten KP, Ruddy KJ. Exclusion of male patients in breast cancer clinical trials. JNCI Cancer Spectr 2018;2:pky018. 2 Gao Y, Goldberg JE, Young TK, et al. Breast cancer screening in high-risk men: A 12-year longitudinal observational study of male breast imaging utilization and outcomes. Radiology 2019;293:282-291. 3 Cardoso F, Bartlett JMS, Slaets L, et al. Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program. Ann Oncol 2018;29:405-417. 4 Cloyd JM, Hernandez-Boussard T, Wapnir IL. Outcomes of partial mastectomy in male breast cancer patients: analysis of SEER, 1983-2009. Ann Surg Oncol 2013;20:1545-1550. 5 Bateni SB, Davidson AJ, Arora M, et al. Is breast-conserving therapy appropriate for male breast cancer patients? A National Cancer Database analysis. Ann Surg Oncol 2019;26:2144-2153. 6 Zaenger D, Rabatic BM, Dasher B, Mourad WF. Is breast conserving therapy a safe modality for early-stage male breast cancer? Clin Breast Cancer 2016;16:101-104. 7 Leone J, Zwenger AO, Leone BA, et al. Overall survival of men and women with breast cancer according to tumor subtype: A population-based study. Am J Clin Oncol 2019;42:215-220. 8 Elmi M, Sequeira S, Azin A, et al. Evolving surgical treatment decisions for male breast cancer: an analysis of the National Surgical Quality Improvement Program (NSQIP) database. Breast Cancer Res Treat 2018;171:427-434. 9 Fields EC, DeWitt P, Fisher CM, Rabinovitch R. Management of male breast cancer in the United States: a surveillance, epidemiology and end results analysis. Int J Radiat Oncol Biol Phys 2013;87:747-752. 10 Flynn LW, Park J, Patil SM, et al. Sentinel lymph node biopsy is successful and accurate in male breast carcinoma. J Am Coll Surg 2008;206:616-621. 11 Jardel P, Vignot S, Cutuli B, et al. Should adjuvant radiation therapy be systematically proposed for male breast cancer? A systematic review. Anticancer research. 2018;38:23-31. 12 Massarweh SA, Sledge GW, Miller DP, et al. Molecular characterization and mortality from breast cancer in men. J Clin Oncol 2018;36:1396-1404. 13 Grenader T, Yerushalmi R, Tokar M, et al. The 21-gene recurrence score assay (Oncotype DX) in estrogen receptor-positive male breast cancer: experience in an Israeli cohort. Oncology 2014;87:1-6. 14 Hayes FJ, Seminara SB, Decruz S, et al. Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback. J Clin Endocrinol Metab 2000;85:3027-3035. 15 Mauras N, O'Brien KO, Klein KO, Hayes V. Estrogen suppression in males: metabolic effects. J Clin Endocrinol Metab 2000;85:2370-2377. 16 Eggemann H, Ignatov A, Smith BJ, et al. Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients. Breast Cancer Res Treat 2013;137:465-4670. 17 Harlan LC, Zujewski JA, Goodman MT, Stevens JL. Breast cancer in men in the United States: a population-based study of diagnosis, treatment, and survival. Cancer 2010;116:3558-3568. 18 Gralow JR, Biermann JS, Farooki A, et al. NCCN Task Force Report: Bone Health In Cancer Care. J Natl Compr Canc Netw 2013;11 Suppl 3:S1-50; quiz S51. 19 Zagouri F, Sergentanis TN, Chrysikos D, et al: Fulvestrant and male breast cancer: a case series. Ann Oncol 2013;24:265-266. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-J Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 2 OF 2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion ADJUVANT ENDOCRINE THERAPYa,b,c,d Aromatase inhibitor for 5 yj (category 1) Postmenopausale or Tamoxifenh for 5 y (category 1) Consider tamoxifenh for an additional 5 y to complete 10 y ± ovarian suppression or ablationf,i (category 1) Consider tamoxifenh for an additional 5 y to complete 10 y Premenopausal Premenopausale,g or at diagnosise,f,g or No further endocrine therapy Aromatase inhibitor for 5 yj + ovarian suppression or ablationf,i (category 1) Consider aromatase inhibitor for an additional 3–5 yj Aromatase inhibitorj for 5 y (category 1) or Aromatase inhibitorj for 2–3 y (category 1) Tamoxifeng to complete 5 y of endocrine therapy (category 1) or Aromatase inhibitor to complete 5 yj of endocrine therapy (category 1) Tamoxifenh for 2–3 y or Up to 5 y of an aromatase inhibitorj (category 2B) Postmenopausal Aromatase inhibitor for 5 yj (category 1) Tamoxifenh for 4.5–6 y or at diagnosise Consider tamoxifenh for an additional 5 y to complete 10 y Patients with a contraindication to aromatase Tamoxifenh for 5 y (category 1) inhibitors, who decline aromatase inhibitors, or or who are intolerant to aromatase inhibitors Consider tamoxifenh for up to 10 y g Safety data support administration of GnRH agonists before or with chemotherapy, a If patient is not postmenopausal, sequential evaluation of hormonal status is especially if there is a goal to enhance fertility preservation. They can also be initiated recommended to consider an alternative endocrine agent. after chemotherapy in patients who remain premenopausal. b Baseline assessment of bone density recommended for patients receiving an h Some SSRIs like fluoxetine and paroxetine decrease the formation of endoxifen, 4-OH aromatase inhibitor who are at risk of osteoporosis (eg, age >65, family history, chronic tamoxifen, and active metabolites of tamoxifen, and may impact its efficacy. Caution steroids). is advised about coadministration of these drugs with tamoxifen. However, SNRIs c The use of a bisphosphonate (oral/IV) or denosumab is acceptable to maintain or to (citalopram and venlafaxine) appear to have minimal impact on tamoxifen metabolism. At improve bone mineral density and reduce risk of fractures in postmenopausal (natural this time, based on current data the panel recommends against CYP2D6 gene testing for or induced) patients receiving adjuvant aromatase inhibitor therapy. patients being considered for tamoxifen therapy. d In patients with HR-positive/HER2-negative, high-risk breast cancer (ie, those with i A balanced discussion of the risks and benefits associated with ovarian suppression ≥4 positive lymph nodes (confirmed preoperatively and/or at surgery), or 1–3 positive therapy is critical, including the potential side effects of premature menopause. Aromatase lymph nodes with one or more of the following: grade 3 disease, tumor size ≥5 cm inhibitor or tamoxifen for 5 y plus ovarian suppression should be considered, based on (on pre-operative imaging and/or at surgery) 2 years of adjuvant abemaciclib can be SOFT and TEXT clinical trial outcomes, for premenopausal patients at higher risk of considered in combination with endocrine therapy (category 1). In patients eligible for recurrence (ie, young age, high-grade tumor, lymph node involvement). both adjuvant olaparib and abemaciclib, the optimal sequence is not known. j The three selective aromatase inhibitors (ie, anastrozole, letrozole, exemestane) have e See Definition of Menopause (BINV-O). f Evidence  shown similar anti-tumor efficacy and toxicity profiles in randomized studies in the suggests that the magnitude of benefit from surgical or radiation ovarian adjuvant and preoperative settings. The optimal duration of aromatase inhibitors in ablation in premenopausal patients with HR-positive breast cancer is similar to that adjuvant therapy is uncertain. Patients with lymph node involvement may benefit from achieved with CMF alone. extended aromatase inhibitor duration (7.5–10 years total). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-K Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PREOPERATIVE/ADJUVANT THERAPY REGIMENSa HER2-Negativeb Preferred Regimens: • Dose-dense AC (doxorubicin/cyclophosphamide) followed or preceded by paclitaxel every 2 weeksc • Dose-dense AC (doxorubicin/cyclophosphamide) followed or preceded by weekly paclitaxelc • TC (docetaxel and cyclophosphamide) • Olaparib, if germline BRCA1/2 mutationsd,e • High-riskf TNBC: Preoperative pembrolizumab + carboplatin + paclitaxel, followed by preoperative pembrolizumab + cyclophosphamide + doxorubicin or epirubicin, followed by adjuvant pembrolizumab • TNBC and residual disease after preoperative therapy with taxane-, alkylator-, and anthracycline-based chemotherapy:e Capecitabine Useful in Certain Circumstances: Other Recommended Regimens: • Dose-dense AC (doxorubicin/cyclophosphamide) • AC followed by docetaxel every 3 weeksc • AC (doxorubicin/cyclophosphamide) every 3 weeks (category 2B) • EC (epirubicin/cyclophosphamide) • CMF (cyclophosphamide/methotrexate/fluorouracil) • TAC (docetaxel/doxorubicin/cyclophosphamide) • AC followed by weekly paclitaxelc • Select patients with TNBC:g,1 • Capecitabine (maintenance therapy for TNBC after adjuvant Paclitaxel + carboplatin (various schedules) chemotherapy) Docetaxel + carboplating,1 (preoperative setting only) See Additional Considerations for Those Receiving Preoperative/Adjuvant Therapy (BINV-L, 3) e Patients in the OlympiA trial did not receive capecitabine; thus, there are a Alternative taxanes (ie, docetaxel, paclitaxel, albumin-bound paclitaxel) may be substituted for select patients due to medical necessity (ie, hypersensitivity reaction). If substituted for no data on sequencing or to guide selection of one agent over the other. f High-risk criteria include stage II–III TNBC. The use of adjuvant weekly paclitaxel or docetaxel, then the weekly dose of albumin-bound paclitaxel should not exceed 125 mg/m2. pembrolizumab (category 2A) may be individualized. b The regimens listed in the table for HER2-negative disease are all category 1 (except where g The inclusion of platinum agents as neoadjuvant chemotherapy for indicated) when used in the adjuvant setting. TNBC remains controversial. Several studies have shown improved c It is acceptable to change the administration sequence to taxane (with or without HER2- pCR rates with incorporation of platinum. However, long-term outcomes targeted therapy) followed by AC. remain unknown. The routine use of platinum agents as part of d Consider  addition of adjuvant olaparib for 1 y for those with germline BRCA1/2 mutations neoadjuvant therapy for TNBC is not recommended for most patients and: (including BRCA mutation carriers), but it may be considered in select • TNBC, if 1) ≥pT2 or ≥pN1 disease after adjuvant chemotherapy, or 2) residual disease patients (such as those for whom achieving better local control is after preoperative chemotherapy • HR-positive, HER2-negative tumors, if 1) ≥4 positive lymph nodes after adjuvant necessary). The use of platinum agents in the adjuvant setting is not chemotherapy (category 2A), or 2) residual disease after preoperative therapy and recommended. If platinum agents are included in an anthracycline- a clinical stage, pathologic stage, ER status, and tumor grade (CPS+EG) score ≥3 based regimen, the optimal sequence of chemotherapy and choice of (category 2A). taxane agent is not established. Carboplatin may be used as part of the Adjuvant olaparib can be used concurrently with endocrine therapy. pembrolizumab regimen. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-L Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 1 OF 9 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PREOPERATIVE/ADJUVANT THERAPY REGIMENSa HER2-Positive Preferred Regimens: • Paclitaxel + trastuzumabh • TCH (docetaxel/carboplatin/trastuzumab) • TCHP (docetaxel/carboplatin/trastuzumab/pertuzumab) • If no residual disease after preoperative therapy or no preoperative therapy: Complete up to one year of HER2-targeted therapy with trastuzumabj (category 1) ± pertuzumab. • If residual disease after preoperative therapy: Ado-trastuzumab emtansine (category 1) alone. If ado-trastuzumab emtansine discontinued for toxicity, then trastuzumab (category 1) ± pertuzumab to complete one year of therapy.i,j If node positive at initial staging, trastuzumab + pertuzumab (category 1)k Useful in Certain Circumstances: Other Recommended Regimens: • Docetaxel + cyclophosphamide + trastuzumab • AC followed by docetaxelc + trastuzumabj (doxorubicin/ c j • AC followed by T + trastuzumab (doxorubicin/cyclophosphamide cyclophosphamide followed by docetaxel + trastuzumab) followed by paclitaxel plus trastuzumab, various schedules) • AC followed by docetaxelc + trastuzumab + pertuzumabj • AC followed by Tc + trastuzumab + pertuzumabj (doxorubicin/ (doxorubicin/cyclophosphamide followed by docetaxel + cyclophosphamide followed by paclitaxel plus trastuzumab plus trastuzumab + pertuzumab) pertuzumab, various schedules) • Neratinibi (adjuvant setting only) • Paclitaxel + trastuzumab + pertuzumabj • Ado-trastuzumab emtansine (TDM-1) (adjuvant setting only) See Additional Considerations for Those Receiving Preoperative/Adjuvant Therapy (BINV-L, 3) i Consider extended adjuvant neratinib following adjuvant trastuzumab-containing therapy for patients with HR-positive, HER2-positive disease with a perceived high a Alternative taxanes (ie, docetaxel, paclitaxel, albumin-bound paclitaxel) may risk of recurrence. The benefit or toxicities associated with extended neratinib in be substituted for select patients due to medical necessity (ie, hypersensitivity patients who have received pertuzumab or ado-trastuzumab emtansine is unknown. reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly j Trastuzumab given in combination with an anthracycline is associated with dose of albumin-bound paclitaxel should not exceed 125 mg/m2. significant cardiac toxicity. Concurrent use of trastuzumab and pertuzumab with an c It is acceptable to change the administration sequence to taxane (with or anthracycline should be avoided. without HER2-targeted therapy) followed by AC. k Updated results from the adjuvant APHINITY trial in HER2-positive early breast h Paclitaxel  + trastuzumab may be considered for patients with low-risk cancer, with a median follow-up of 8.4 years, have confirmed the benefit of adding T1,N0,M0, HER2-positive disease, particularly those not eligible for other pertuzumab to trastuzumab plus chemotherapy in preventing recurrences in those standard adjuvant regimens due to comorbidities. with node positive disease. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-L Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 2 OF 9 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PREOPERATIVE/ADJUVANT THERAPY REGIMENS Additional Considerations for Those Receiving Preoperative/Adjuvant Therapy • Consider scalp cooling to reduce incidence of chemotherapy-induced alopecia for patients receiving neoadjuvant/adjuvant chemotherapy. Results may be less effective with anthracycline-containing regimens. • Sequence of therapies in the adjuvant setting: Chemotherapy and endocrine therapy should be given sequentially, with endocrine therapy given after chemotherapy. Adjuvant olaparib can be given concurrently with endocrine therapy. For sequencing of RT with systemic therapy, see BINV-I (2). • Considerations for HER2-positive disease: An FDA-approved biosimilar is an appropriate substitute for trastuzumab. Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for trastuzumab. It has different dosage and administration instructions compared to intravenous trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or with ado- trastuzumab emtansine. Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use may be substituted anywhere that the combination of intravenous pertuzumab and intravenous trastuzumab are given as part of systemic therapy. Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different dosing and administration instructions compared to the intravenous products. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-L Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 3 OF 9 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS HER2-Negative Preferred Regimens • Dose-dense AC followed by paclitaxel2 • Preoperative pembrolizumab + chemotherapy followed by adjuvant Doxorubicin 60 mg/m2 IV day 1 pembrolizumab4 Cyclophosphamide 600 mg/m2 IV day 1 Preoperative: ◊ Cycled every 14 days for 4 cycles.l ◊ Pembrolizumab 200 mg IV Day 1 ◊ Followed by: ◊ Paclitaxel 80 mg/m2 IV Days 1, 8, 15 Paclitaxel 175 mg/m2 by 3 h IV infusion day 1 ◊ Carboplatin AUC 5 IV Day 1 ◊ Cycled every 14 days for 4 cycles.l Or • Dose-dense AC followed by weekly paclitaxel2 ◊ Carboplatin AUC 1.5 IV Days 1, 8, 15 Doxorubicin 60 mg/m2 IV day 1 – Cycled every 21 days x 4 cycles (cycles 1–4) Cyclophosphamide 600 mg/m2 IV day 1 Followed by: ◊ Cycled every 14 days for 4 cycles.l ◊ Pembrolizumab 200 mg IV Day 1 ◊ Followed by: ◊ Doxorubicin 60 mg/m2 IV Day 1 or Epirubicin 90 mg/m2 IV Day 1 Paclitaxel 80 mg/m2 by 1 h IV infusion weekly for 12 weeks. ◊ Cyclophosphamide 600 mg/m2 IV Day 1 • TC3 – Cycled every 21 days x 4 cycles (cycles 5–8) Docetaxel 75 mg/m2 IV day 1 Followed by: Cyclophosphamide 600 mg/m2 IV day 1 Adjuvant pembrolizumab 200 mg IV Day 1 ◊ Cycled every 21 days for 4-6 cycles.l ◊ Cycled every 21 days x 9 cycles • Capecitabine5 1,000–1,250 mg/m2 PO twice daily on days 1–14 ◊ Cycled every 21 days for 6–8 cycles • Olaparib6 300 mg PO twice daily Cycled every 28 days for 1 y l All cycles are with myeloid growth factor support. See NCCN Guidelines for Hematopoietic Growth Factors. The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-L Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 4 OF 9 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS HER2-Negative HER2-Negative Other Recommended Regimens Useful in Certain Circumstances • AC followed by docetaxel every 3 weeks7 • Paclitaxel + carboplatin • Dose-dense AC2 Doxorubicin 60 mg/m² IV on day 1 Weekly paclitaxel + carboplatin1,10 Doxorubicin 60 mg/m² IV day 1 Cyclophosphamide 600 mg/m² IV day 1 (preoperative setting only) Cyclophosphamide 600 mg/m² IV day 1 ◊ Cycled every 21 days for 4 cycles. ◊ Paclitaxel 80 mg/m2 days 1, 8, and 15 ◊ Cycled every 14 days for 4 cycles.l ◊ Followed by: ◊ Carboplatin AUC 5 or 6 day 1; • AC15 Docetaxel 100 mg/m² IV on day 1 – Cycled every 21 days x 4 cycles Doxorubicin 60 mg/m² IV on day 1 ◊ Cycled every 21 days for 4 cycles. Weekly paclitaxel + weekly carboplatin11,12 Cyclophosphamide 600 mg/m² IV day 1 • EC chemotherapy8 ◊ Paclitaxel 80 mg/m2 days 1, 8, and 15 ◊ Cycled every 21 days for 4 cycles. Epirubicin 100 mg/m² IV day 1 ◊ Carboplatin AUC 1.5–2 days 1, 8, and 15 Cyclophosphamide 830 mg/m² IV day 1 • CMF chemotherapy16,17 – Cycled every 28 days x 6 cycles ◊ Cycled every 21 days for 8 cycles. Cyclophosphamide 100 mg/m² PO days 1–14 • Docetaxel + carboplatin (4–6 cycles) Methotrexate 40 mg/m² IV days 1 & 8 • TAC chemotherapy9 Docetaxel 75 mg/m² IV day 1 (preoperative setting only)1,13,14,l 5-fluorouracil 600 mg/m² IV days 1 & 8 Doxorubicin 50 mg/m² IV day 1 Docetaxel 75 mg/m2 day 1 ◊ Cycled every 28 days for 6 cycles. Cyclophosphamide 500 mg/m² IV day 1 Carboplatin AUC 6 day 1 Or ◊ Cycled every 21 days for 6 cycles.l ◊ Cycled every 21 days x 4–6 cycles. Cyclophosphamide 600 mg/m2 IV day 1 Methotrexate 40 mg/ m2 IV day 1 5-fluorouracil 600 mg/m2 IV day 1 ◊ Cycled every 21 days for 8 cycles • AC followed by weekly paclitaxel18 Doxorubicin 60 mg/m² IV day 1 Cyclophosphamide 600 mg/m² IV day 1 ◊ Cycled every 21 days for 4 cycles. ◊ Followed by Paclitaxel 80 mg/m² by 1 h IV infusion weekly for 12 weeks. • Capecitabine (maintenance therapy)19 650 mg/m2 PO twice daily on days 1–28 Cycled every 28 days for 1 year l All cycles are with myeloid growth factor support. See NCCN Guidelines for Hematopoietic Growth Factors. The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-L Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 5 OF 9 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS HER2-Positivem,n,o Preferred Regimens Paclitaxel + trastuzumab20 TCH21 TCH + pertuzumab22 Paclitaxel 80 mg/m2 IV weekly for 12 Docetaxel 75 mg/m IV day 1 2 Docetaxel 75 mg/m2 IV day 1 weeks Carboplatin AUC 6 IV day 1 Carboplatin AUC 6 IV day 1 ◊ With: ◊ Cycled every 21 days for 6 cycles ◊ Cycled every 21 days for 6 cycles Trastuzumab 4 mg/kg IV with first dose of ◊ With: With: paclitaxel Trastuzumab 4 mg/kg IV wk 1 Trastuzumab 8 mg/kg IV day 1 ◊ Followed by: ◊ Followed by: Pertuzumab 840 mg IV day 1 Trastuzumab 2 mg/kg IV weekly to Trastuzumab 2 mg/kg IV for 17 wks ◊ Followed by: complete 1 y of treatment. As an ◊ Followed by: Trastuzumab 6 mg/kg IV on day 1 alternative, trastuzumab 6 mg/kg IV Trastuzumab 6 mg/kg IV Pertuzumab 420 mg IV day 1 every 21 days may be used following the ◊ Cycled every 21 days to complete 1 y of ◊ Cycled every 21 days to complete 1 y of therapy.p p completion of paclitaxel, and given to therapy. complete 1 y of trastuzumab treatment. OR Trastuzumab 8 mg/kg IV wk 1 ◊ Followed by: Trastuzumab 6 mg/kg IV ◊ Cycled every 21 days to complete 1 y of therapy.p o Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use may be substituted anywhere that the combination of intravenous pertuzumab and intravenous trastuzumab are given as part of systemic therapy. Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different m An FDA-approved biosimilar is an appropriate substitute for trastuzumab. dosing and administration instructions compared to the intravenous products. n Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be p Evaluate left ventricular ejection fraction (LVEF) prior to and during treatment. substituted for trastuzumab. It has different dosage and administration instructions The optimal frequency of LVEF assessment during adjuvant trastuzumab therapy compared to intravenous trastuzumab. Do not substitute trastuzumab and is not known. The FDA label recommends LVEF measurements prior to initiation hyaluronidase-oysk for or with ado-trastuzumab emtansine. of trastuzumab and every 3 mo during therapy. The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-L Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 6 OF 9 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS HER2-Positivem,n,o Useful in Certain Circumstances AC followed by T + trastuzumab23 Dose-dense AC followed by AC or Dose-Dense AC followed by Docetaxel/cyclophosphamide + Doxorubicin 60 mg/m2 IV day 1 paclitaxel + trastuzumab24 T + trastuzumab + pertuzumab25 trastuzumab26 Cyclophosphamide 600 mg/m2 IV Doxorubicin 60 mg/m2 IV day 1 Doxorubicin 60 mg/m2 IV day 1 Docetaxel 75 mg/m2 IV day 1 day 1 Cyclophosphamide 600 mg/m2 IV Cyclophosphamide 600 mg/m2 IV Cyclophosphamide 600 mg/m2 IV ◊ Cycled every 21 days for 4 day 1 day 1 day 1 cycles. ◊ Cycled every 14 days for 4 ◊ Cycled every 21 days for 4 cycles ◊ Cycled every 21 days for 4 cycles ◊ Followed by: cycles. or ◊ With: Paclitaxel 80 mg/m2 by 1 h IV ◊ Followed by: For dose-dense: Cycle every 14 Trastuzumab 4 mg/kg IV wk 1 weekly for 12 wks Paclitaxel 175 mg/m2 by 3 h IV days for 4 cycles ◊ Followed by ◊ With: infusion day 1 ◊ Followed by: Trastuzumab 2 mg/kg IV weekly for Trastuzumab 4 mg/kg IV with first ◊ Cycled every 14 days for 4 Pertuzumab 840 mg IV day 1 11 wks dose of paclitaxel cycles.l followed by 420 mg IV ◊ Followed by ◊ Followed by: ◊ With: Trastuzumab 8 mg/kg IV day 1 Trastuzumab 6 mg/kg IV Trastuzumab 2 mg/kg IV weekly Trastuzumab 4 mg/kg IV with first followed by 6 mg/kg IV ◊ Cycled every 21 days to complete to complete 1 y of treatment. As dose of paclitaxel Paclitaxel 80 mg/m2 IV days 1, 8, 1 y of therapy of trastuzumab an alternative, trastuzumab 6 ◊ Followed by: and 15 therapy.p mg/kg IV every 21 days may be Trastuzumab 2 mg/kg IV weekly to ◊ Cycled every 21 days for 4 cycles OR used following the completion of complete 1 y of treatment. As an ◊ Followed by: Trastuzumab 8 mg/kg IV wk 1 paclitaxel, and given to complete 1 y alternative, trastuzumab Trastuzumab 6 mg/kg IV day 1 ◊ Followed by: of trastuzumab treatment.p 6 mg/kg IV every 21 days may be Pertuzumab 420 mg IV day 1 Trastuzumab 6 mg/kg IV every 21 used following the completion of ◊ Cycled every 21 days to complete days to complete 1 y of trastuzumab paclitaxel, and given to complete 1 y 1 y of therapyp therapyp of trastuzumab treatment.p o Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use may be substituted anywhere that the combination of intravenous pertuzumab l All cycles are with myeloid growth factor support. See NCCN Guidelines for and intravenous trastuzumab are given as part of systemic therapy. Pertuzumab, Hematopoietic Growth Factors. trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different m An FDA-approved biosimilar is an appropriate substitute for trastuzumab. dosing and administration instructions compared to the intravenous products. n Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may p Evaluate LVEF prior to and during treatment. The optimal frequency of LVEF be substituted for trastuzumab. It has different dosage and administration assessment during adjuvant trastuzumab therapy is not known. The FDA label instructions compared to intravenous trastuzumab. Do not substitute recommends LVEF measurements prior to initiation of trastuzumab and every 3 mo trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab emtansine. during therapy. The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-L Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 7 OF 9 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS HER2-Positivem,n,o Other Recommended Regimens AC followed by docetaxel + trastuzumab20,27 AC followed by docetaxel + trastuzumab + pertuzumab28 Doxorubicin 60 mg/m2 IV day 1 Doxorubicin 60 mg/m2 IV day 1 Cyclophosphamide 600 mg/m2 IV day 1 Cyclophosphamide 600 mg/m2 IV day 1 ◊ Cycled every 21 days for 4 cycles ◊ Cycled every 21 days for 4 cycles ◊ Followed by: ◊ Followed by: Docetaxel 100 mg/m2 IV day 1 Pertuzumab 840 mg IV day 1 followed by 420 mg IV ◊ Cycled every 21 days for 4 cycles Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV ◊ With: Docetaxel 75–100 mg/m2 IV day 1 Trastuzumab ◊ Cycled every 21 days for 4 cycles ◊ 4 mg/kg IV wk 1; Followed by: ◊ Followed by: ◊ 2 mg/kg IV weekly for 11 wks; Followed by: Trastuzumab 6 mg/kg IV ◊ 6 mg/kg IV Pertuzumab 420 mg IV day 1 ◊ Cycled every 21 days to complete 1 y of trastuzumab therapy.p ◊ Cycled every 21 days to complete 1 y of therapy.p HER2-Positivem,n,o Useful in Certain Circumstances Neratinib29 Paclitaxel + trastuzumab + pertuzumab30 Ado-trastuzumab emtansine (T-DM1)31 120 mg PO daily on days 1–7; Followed by: Paclitaxel 80 mg/m IV day 1 2 3.6 mg/kg IV day 1 160 mg PO daily on days 8–14; Followed by: ◊ Cycled every 7 days x 12 cycles ◊ Cycled every 21 days for 17 cycles 240 mg PO daily on days 15–28 Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV ◊ Cycled every 28 days x 1 cycle Pertuzumab 840 mg IV day 1 followed by 420 mg IV ◊ Followed by: ◊ Cycled every 21 days x 4 cycles 240 mg PO daily on days 1–28 ◊ Followed by: ◊ Cycled every 28 days x 12 cycles beginning with cycle 2 Trastuzumab 6 mg/kg IV; Pertuzumab 420 mg IV day 1; ◊ Cycled every 21 days to complete 1 y of therapyp m An FDA-approved biosimilar is an appropriate substitute for trastuzumab. n Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for trastuzumab. It has different dosage and administration instructions compared to intravenous trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab emtansine. o Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use may be substituted anywhere that the combination of intravenous pertuzumab and intravenous trastuzumab are given as part of systemic therapy. Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different dosing and administration instructions compared to the intravenous products. p Evaluate LVEF prior to and during treatment. The optimal frequency of LVEF assessment during adjuvant trastuzumab therapy is not known. The FDA label recommends LVEF measurements prior to initiation of trastuzumab and every 3 mo during therapy. The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-L Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 8 OF 9 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PREOPERATIVE/ADJUVANT THERAPY REGIMENS - REFERENCES 1 Gupta S, Nair NS, Hawaldar RW, et al. Addition of platinum to sequential taxane-anthracycline 16 Goldhirsch A, Colleoni M, Coates AS, et al: Adding adjuvant CMF chemotherapy to either radiotherapy or neoadjuvant chemotherapy in patients with triple-negative breast cancer: A phase III randomized tamoxifen: are all CMFs alike? The International Breast Cancer Study Group (IBCSG). Ann Oncol 1998;9:489- controlled trial. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 493. 2022; San Antonio, TX. Abstract GS5-01. 17 Jakesz R, Hausmaninger H, Kubista E, et al. Austrian Breast and Colorectal Cancer Study Group Trial 2 Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally 5. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with treatment of node-positive primary breast cancer: First report of intergroup trial C9741/cancer and hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol leukemia group B trial 9741. J Clin Oncol 2003;21:1431-1439. 2002;20:4621-4627. 3 Jones S, Holmes F, O’Shaughnessey J, et al. Docetaxel with cyclophosphamide is associated 18 Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in adjuvant treatment of breast cancer. N Engl J Med with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year 2008;258:1663-1671. follow-up of US Oncology Research trial 9735. J Clin Oncol 2009;27:1177-1183; Nitz U, Gluz 19 Wang X, Wang SS, Huang H, et al. Effect of capecitabine maintenance therapy using lower dosage and higher O, Clemens M, et al. West German Study PlanB Trial: Adjuvant four cycles of epirubicin and frequency vs observation on disease-free survival among patients with early-stage triple-negative breast cancer cyclophosphamide plus docetaxel versus six cycles of docetaxel and cyclophosphamide in HER2- who had received standard treatment: The SYSUCC-001 randomized clinical trial. JAMA 2021;325:50-58. negative early breast cancer. J Clin Oncol 2019;37:799-808. 20 Tolaney S, Barry W, Dang C, et al. Adjuvant paclitaxel and trastuzumab for node-negative HER2-positive 4 Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N breast cancer. N Engl J Med 2015;372:134-141. Engl J Med, 2020;382:810-821. 21 Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 5 Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative 2011;365:1273-1283. chemotherapy. N Engl J Med 2017;376:2147-2159. 22 Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard 6 Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant Olaparib for Patients with BRCA1- or BRCA2- neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with Mutated Breast Cancer. N Engl J Med 2021;384:2394-2405. 7 von Minckwitz G1, Raab G, Caputo A, et al. Doxorubicin with cyclophosphamide followed by HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013;24:2278-2284. docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative 23 Romond EH, Perez EZ, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2 positive treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin breast cancer. N Engl J Med 2005;353:1673-1684. Oncol 2005;23:2676-2685. 24 Dang C, Fornier M, Sugarman S, et al: The safety of dose-dense doxorubicin and cyclophosphamide 8 Piccart MJ, Di Leo A, Beauduin M, et al. Phase III trial comparing two dose levels of epirubicin followed by paclitaxel with trastuzumab in HER-2/neu over-expressed/amplified breast cancer. J Clin Oncol combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node- 2008;26:1216-1222. positive breast cancer. J Clin Oncol 2001;19:3103-3110. 25 Swain SM, Ewer MS, Viale G, et al. Pertuzumab, trastuzumab, and standard anthracycline- and taxane- 9 Martin, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005;352:22. based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer 10 Sharma P, Kimler BF, O'Dea A, et al. Randomized phase II trial of anthracycline-free and (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol 2018;29:646- anthracycline-containing neoadjuvant carboplatin chemotherapy regimens in stage I-III triple- 653. negative breast cancer (NeoSTOP). Clin Cancer Res 2021;27:975-982. 26 Jones SE, Collea R, Paul D, et al. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients 11 Yu KD, Ye FG, He M, et al. Effect of adjuvant paclitaxel and carboplatin on survival in women with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol with triple-negative breast cancer: A phase 3 randomized clinical trial. JAMA Oncol 2020;6:1390- 2013;14:1121-1128. 1396. 27 Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without 12 von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple- trastuzumab for breast cancer. N Engl J Med 2006;354:809-820. negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 28 Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in trial. Lancet Oncol 2014;15:747-756. women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised 13 Sharma P, Lopez-Tarruella S, Garcia-Saenz J, et al. Efficacy of neoadjuvant carboplatin plus multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32. docetaxel in triple-negative breast cancer: Combined analysis of two cohorts. Clin Cancer Res 29 Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with 2017;23:649-657. HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 14 Zhang L, Wu ZY, Li J, et al. Neoadjuvant docetaxel plus carboplatin versus epirubicin plus trial. Lancet Oncol 2016;17:367-377. cyclophosphamide followed by docetaxel in triple-negative, early-stage breast cancer (NeoCART): 30 Nitz UA, Gluz O, Christgen M, et al. De-escalation strategies in HER2-positive early breast cancer (EBC): final Results from a multicenter, randomized controlled, open-label phase II trial. Int J Cancer analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of 2022;150:654-662. neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel. Ann Oncol 2017;28:2768- 15 Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin-cyclophosphamide with and 2772. without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, 31 Tolaney SM, Tayob N, Dang C, et al. Adjuvant trastuzumab emtansine versus paclitaxel in 8combination and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: with trastuzumab for stage I HER2-positive breast cancer (ATEMPT): A randomized clinical trial. J Clin Oncol results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 2021;39:2375-2385. 1990;8:1483-1496. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-L Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 9 OF 9 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF PREOPERATIVE SYSTEMIC THERAPY Known Benefits of Preoperative Systemic Therapy Cautions • Facilitates breast conservation • Possible overtreatment with systemic therapy if clinical stage is • Can render inoperable tumors operable overestimated • Treatment response provides important prognostic information at an • Possible undertreatment locoregionally with radiotherapy if individual patient level, particularly in patients with TNBC or HER2- clinical stage is underestimated positive breast cancer • Possibility of disease progression during preoperative systemic • Identifies patients with residual disease at higher risk for relapse to therapy allow for the addition of supplemental adjuvant regimens, particularly in patients with TNBC or HER2-positive breast cancer. Candidates for Preoperative Systemic Therapy • Allows time for genetic testing • Patients with inoperable breast cancer: • Allows time to plan breast reconstruction in patients electing IBC mastectomy Bulky or matted cN2 axillary nodes • Allows time for delayed decision-making for definitive surgery cN3 nodal disease cT4 tumors Opportunities • In select patients with operable breast cancer • May allow SLNB alone if initial cN+ becomes cN0 after preoperative Preoperative systemic therapy is preferred for: therapy ◊ HER2-positive disease and TNBC, if ≥cT2 or ≥cN1 • May provide an opportunity to modify systemic treatment if no ◊ Large primary tumor relative to breast size in a patient who preoperative therapy response or progression of disease desires breast conservation • May allow for more limited radiation fields in patients with cN+ who ◊ cN+ disease likely to become cN0 with preoperative systemic become cN0/pN0 after preoperative therapy therapy • Provides excellent research platform to test novel therapies and Preoperative systemic therapy can be considered for cT1c, cN0 predictive biomarkers HER2-positive disease and TNBC • Patients in whom definitive surgery may be delayed. Non-candidates for Preoperative Systemic Therapy • Patients with extensive in situ disease when extent of invasive carcinoma is not well-defined • Patients with a poorly delineated extent of tumor • Patients whose tumors are not palpable or clinically assessable Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-M Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 1 OF 2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF PREOPERATIVE SYSTEMIC THERAPY • Randomized trials of chemotherapy demonstrate similar long-term outcomes when patients are given the same treatment preoperatively compared with postoperatively.a • Pathologic complete response (pCR) to preoperative systemic therapy is associated with an extremely favorable disease-free and overall survival (OS), particularly in situations in which all treatment is given preoperatively. The correlation between pathologic response and long- term outcome is strongest for TNBC, somewhat less so for HER2-positive disease, and least for ER-positive disease.b,c • A number of chemotherapy regimens have activity in the preoperative setting. In general, those chemotherapy regimens recommended in the adjuvant setting may be considered in the preoperative setting. See Preoperative/Adjuvant Therapy Regimens (BINV-L). • Preoperative endocrine therapy alone may be considered for patients with ER-positive disease based on comorbidities or low-risk luminal biology based on clinical characteristics and/or genomic signatures. • Patients with HER2-positive tumors should be treated with preoperative systemic therapy incorporating trastuzumab.d A pertuzumab- containing regimen may be administered preoperatively to patients with ≥ pT2 or ≥ pN1, HER2-positive early-stage breast cancer. See Preoperative/Adjuvant Therapy Regimens (BINV-L). • Some studies suggest an increased risk of locoregional recurrence following use of preoperative chemotherapy.e These trials delivered chemotherapy regimens that are no longer standard, did not include targeted therapies, did not use modern imaging techniques, and/or used non-standard locoregional management. Care should be taken to follow the procedures outlined in BINV-12 and BINV-14 to assure appropriate locoregional management. Not all patients are appropriate candidates for preoperative systemic therapy. Accurate clinical staging at baseline prior to initiation of preoperative systemic therapy is critical. See Potentially Operable Disease: Breast and Axillary Evaluation Prior to Preoperative Systemic Therapy (BINV-12). • Tumor response should be routinely assessed by clinical exam and imaging studies (see footnote uu on BINV-13) during delivery of preoperative therapy. It is preferred that the standard regimen is completed prior to surgery. If all intended treatment is not completed prior to surgery, the remainder may be given in the adjuvant setting. Patients with operable breast cancer experiencing progression of disease during preoperative systemic therapy may be given an alternate systemic regimen or proceed to surgery if deemed resectable. Locoregional therapy principles should be applied in the same manner as in patients treated with adjuvant systemic therapy. c Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long- term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet a Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: Updates of 2014;384:164-172. National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J d An FDA-approved biosimilar is an appropriate substitute for trastuzumab. Clin Oncol 2008;26:778-785. e Early Breast Cancer Trialists' Collaborative Group (EBTCG). Long-term b von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: complete response on prognosis after neoadjuvant chemotherapy in various metaanalysis of individual patient data from ten randomised trials. Lancet Oncol intrinsic breast cancer subtypes. J Clin Oncol 2012;30:1796-1804. 2018;19:27-39. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-M Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 2 OF 2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPYa,b NCCN Category Recurrence Risk NCCN Category Assay Predictive Prognostic of Evidence and and of Preference Consensus Treatment Implications 21-gene (Oncotype Dx) Yes Yes Preferred 1 BINV-N (2) (for pN0) Postmenopausal: 1 Preferred 21-gene (Oncotype Dx) Yes BINV-N (2) for pN1 (1–3 positive nodes)c Yes Premenopausal: 2A Other 70-gene (MammaPrint) Not determined Yes Other 1 BINV-N (3) for pN0 and pN1 (1–3 positive nodes) 50-gene (Prosigna) Not determined Yes Other 2A BINV-N (3) for pN0 and pN1 (1–3 positive nodes) 12-gene (EndoPredict) Not determined Yes Other 2A BINV-N (3) for pN0 and pN1 (1–3 positive nodes) Predictive of benefit of Breast Cancer Index (BCI) Yes Other 2A BINV-N (4) extended adjuvant endocrine therapy a Gene expression assays provide prognostic and therapy-predictive information that complements T,N,M and biomarker information. Use of these assays is not required for staging. The 21-gene assay (Oncotype Dx) is preferred by the NCCN Breast Cancer Panel for prognosis and prediction of chemotherapy benefit. Other prognostic gene expression assays can provide prognostic information but the ability to predict chemotherapy benefit is unknown. b See Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). c In the overall study population of the RxPONDER trial, 10.3% had high-grade disease and 9.2% had 3 involved nodes. References Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-N Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 1 OF 5 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPYa,b Assay Recurrence Risk Treatment Implications 21-gene Patients with T1b/c–2, pN0, HR-positive, HER2-negative tumors, with risk scores (RS) between 0–10 (Oncotype Dx) have a risk of distant recurrence of <4% and those with RS 11–25 derived no benefit from the addition of (for <26 chemotherapy to endocrine therapy in the prospective TAILORx study.1 postmenopausal Postmenopausal patients with pT1–3, pN1, HR-positive, HER2-negative, with RS <26 derived no benefit patients with pN0 from the addition of chemotherapy to endocrine therapy in the prospective RxPONDER study.2 and pN1 [1–3 In postmenopausal patients with pT1–3, HR-positive, HER2-negative, and pN0 and pN1 (1–3 positive positive nodes])c ≥26 nodes) tumors and an RS ≥26, the addition of chemotherapy to endocrine therapy is recommended.1,2 Premenopausal patients with T1b/c –2, pN0, HR-positive, HER2-negative tumors with RS <16 derived no ≤15 benefit from the addition of chemotherapy to endocrine therapy in the prospective TAILORx study.1 21-gene In premenopausal patients with RS between 16–25, a small benefit from the addition of chemotherapy (Oncotype Dx) 16–25 could not be ruled out, but it is unclear if the benefit was due to the ovarian suppression effect promoted by (for premenopausal chemotherapy in premenopausal patients.1,2 For this group, consider chemotherapy followed by endocrine patients: pN0) therapy or alternatively, ovarian function suppression combined with either tamoxifen or an AI. In premenopausal patients with HR-positive, HER2-negative, and pN0 tumors and an RS ≥26, the addition ≥26 of chemotherapy to endocrine therapy is recommended.1 In premenopausal patients with pT1–3 and pN1 (1–3 positive nodes) tumors and an RS <26, the addition 21-gene (Oncotype of chemotherapy to endocrine therapy was associated with a lower rate of distant recurrence compared Dx) <26 with endocrine monotherapy2 but it is unclear if the benefit was due to the ovarian suppression effects (for premenopausal promoted by chemotherapy. For this group of patients, consider chemotherapy followed by endocrine patients with 1–3 therapy or alternatively, ovarian function suppression combined with either tamoxifen or an AI.2 positive nodes)c In premenopausal patients with HR-positive, HER2-negative, pT1–3 and pN1 (1–3 positive nodes) tumors ≥26 and an RS ≥26, the addition of chemotherapy to endocrine therapy is recommended.2 a Gene expression assays provide prognostic and therapy-predictive information that complements T,N,M and biomarker information. Use of these assays is not required for staging. The 21-gene assay (Oncotype Dx) is preferred by the NCCN Breast Cancer Panel for prognosis and prediction of chemotherapy benefit. Other prognostic gene expression assays can provide prognostic information but the ability to predict chemotherapy benefit is unknown. b See Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). c In the overall study population of the RxPONDER trial, 10.3% had high-grade disease and 9.2% had 3 involved nodes. References Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-N Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 2 OF 5 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPYa,b Assay Recurrence Risk Treatment Implications Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n = 749) or not (n = 748); this was the intention-to-treat population. The 8-year estimates for distant High metastasis-free survival in the intention-to-treat population were 92.0% (95% CI, 89.6–93.8) for chemotherapy versus 89.4% (86.8–91.5) for no chemotherapy (HR, 0.66; 95% CI, 0.48–0.92). An exploratory analysis confined to the subset of patients with HR-positive, HER2-negative disease (1358 70-gene [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows (MammaPrint) different effects of chemotherapy administration on 8-year distant metastasis-free survival according to (for pN0 and age: 93.6% (95% CI, 89.3–96.3) with chemotherapy versus 88.6% (83.5–92.3) without chemotherapy 1–3 positive in 464 patients aged ≤50 years (absolute difference 5.0 percentage points [SE, 2.8; 95% CI, −0.5–10.4]) nodes) Lowc and 90.2% (86.8–92.7) versus 90.0% (86.6–92.6) in 894 females >50 years (absolute difference 0.2 percentage points [2.1, −4.0–4.4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91.7% (95% CI, 88.1–94.3) with chemotherapy and 89.2% (85.2– 92.2) without chemotherapy in 699 node-negative patients (absolute difference 2.5 percentage points [SE, 2.3; 95% CI, −2.1 –7.2]) and 91.2% (87.2–94.0) versus 89.9% (85.8–92.8) for 658 patients with one to three positive nodes (absolute difference 1.3 percentage points [2.4, −3.5–6.1]).3 Node negative: Low (0–40), For patients with T1 and T2 HR-positive, HER2-negative, pN0 tumors, a risk of recurrence score in the low 50-gene Intermediate (41–60), High range, regardless of T size, places the tumor into the same prognostic category as T1a–T1b,N0,M0.4 (Prosigna) (for pN0 and (61–100) 1–3 positive Node positive: nodes) Low (0–40) In patients with HR-positive, HER2-negative, pN+ tumors (1–3 positive lymph nodes) with low risk of recurrence score, treated with endocrine therapy alone, the distant recurrence risk was less than 3.5% at Node positive: 10 years and no distant recurrence was seen at 10 years in the TransATAC study in a similar group.5 High (41–100) 12-gene For patients with T1 and T2 HR-positive, HER2-negative, and pN0 tumors, a 12-gene low-risk score, (EndoPredict) Low (≤3.3) regardless of T size, places the tumor into the same prognostic category as T1a–T1b,N0,M0.6 (pN0 and In ABCSG 6/8, patients in the low-risk group had risk of distant recurrence of 4% at 10 years and in 1–3 positive High (>3.3) the TransATAC study, patients with 1–3 positive nodes in the low-risk group had a 5.6% risk of distant nodes) recurrence at 10 years.6,7 The assay is prognostic in endocrine and chemo-endocrine treated patients.7 a Gene expression assays provide prognostic and therapy-predictive information that complements T,N,M and biomarker information. Use of these assays is not required for staging. The 21-gene assay (Oncotype Dx) is preferred by the NCCN Breast Cancer Panel for prognosis and prediction of chemotherapy benefit. Other prognostic gene expression assays can provide prognostic information but the ability to predict chemotherapy benefit is unknown. b See Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). c Postmenopausal patients with UltraLow risk in the Stockholm Tamoxifen trial had a 20-year breast cancer specific survival of 97% with 2-5 years of Tamoxifen (Esserman LJ, et al. JAMA Oncology 2017;3:1503-1510). Patients with an ultralow-risk in the MINDACT trial have shown 8-year breast cancer specific survival above 99%. (Lopes Cardozo JMN, et al. J Clin Oncol 2022;40:1335-1345). References Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-N Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 3 OF 5 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion GENE EXPRESSION ASSAYS FOR CONSIDERATION OF EXTENDED ADJUVANT SYSTEMIC THERAPYa,b Assay Recurrence Risk/ Treatment Implications Predictive Result • For patients with T1 and T2 HR-positive, HER2-negative, and pN0 tumors, a BCI (H/I) in the low-risk range (0–5), regardless of T size, places the tumor into the same prognostic category as T1a–T1b, N0, M0. BCI (H/I) Low • Patients with BCI (H/I) low demonstrated a lower risk of distant recurrence (compared to BCI [H/I] high) and no significant improvement in disease-free survival (DFS) or OS compared to the control arm in terms of extending endocrine therapy duration.8 Breast Cancer Index (BCI) • For patients with T1 HR-positive, HER2-negative, and pN0 tumors, a BCI (H/I) high (5.1–10) demonstrated significant rates of late distant recurrence. • In secondary analyses of the MA.17, Trans-aTTom, and IDEAL trials, patients with HR-positive, T1–T3, pN0 BCI (H/I) High or pN+ who had a BCI (H/I) high demonstrated significant improvements in DFS when adjuvant endocrine therapy was extended, compared to the control arm.8-11 • In contrast, BCI (H/I) low patients derived no benefit from extended adjuvant therapy.8 a Gene expression assays provide prognostic and therapy-predictive information that complements T,N,M and biomarker information. Use of these assays is not required for staging. The 21-gene assay (Oncotype Dx) is preferred by the NCCN Breast Cancer Panel for prognosis and prediction of chemotherapy benefit. Other prognostic gene expression assays can provide prognostic information but the ability to predict chemotherapy benefit is unknown. b See Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). References Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-N Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 4 OF 5 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPY REFERENCES 1 Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 2018;379:111-121. 2 Kalinsky K, Barlow WE, Meric-Bernstam F, et al. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder). SABCS 2021;81(4): Abstract GS3-00. 3 Piccart M, van 't Veer LJ, Poncet C, et al. 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol. 2021;22:476-488. 4 Laenkholm AV, Jensen MB, Eriksen JO, et al. PAM50 risk of recurrence score predicts 10-year distant recurrence in a comprehensive Danish cohort of postmenopausal women allocated to 5 years of endocrine therapy for hormone receptor-positive early breast cancer. J Clin Oncol 2018;36:735-740. 5 Sestak I, Buus R, Cuzick J, et al. Comparison of the performance of 6 prognostic signatures for estrogen receptor–positive breast cancer: A secondary analysis of a randomized clinical trial. JAMA Oncol 2018;4:545-553. 6 Filipits M, Rudas M, Jakesz R, et al. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res 2011;17:6012-6020. 7 Sestak I, Martín M, Dubsky P, et al. Prediction of chemotherapy benefit by EndoPredict in patients with breast cancer who received adjuvant endocrine therapy plus chemotherapy or endocrine therapy alone. Breast Cancer Res Treat 2019;176:377-386. 8 Noordhoek I, Treuner K, Putter H, et al. Breast cancer index predicts extended endocrine benefit to individualize selection of patients with HR(+) early-stage breast cancer for 10 years of endocrine Therapy. Clin Cancer Res 2021;27:311-319. 9 Sgroi DC, Carney E, Zarrella E, et al. Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker. J Natl Cancer Inst 2013;105:1036-1042. 10 Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg E, et al. Optimal duration of extended adjuvant endocrine therapy for early breast cancer; Results of the IDEAL Trial (BOOG 2006-05). J Natl Cancer Inst 2017;110:40-48. 11 Bartlett JMS, Sgroi DC, Treuner K, et al. Breast cancer index and prediction of benefit from extended endocrine therapy in breast cancer patients treated in the Adjuvant Tamoxifen-To Offer More? (aTTom) trial. Ann Oncol 2019;30:1776-1783. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-N Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 5 OF 5 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion DEFINITION OF MENOPAUSE • Menopause is the permanent cessation of menses and includes a profound and permanent decrease in ovarian estrogen synthesis. • Determination of menopausal status may be required to guide selection of endocrine therapy for breast cancer. • Menopause is usually a clinical diagnosis made after ≥12 months of amenorrhea. Natural menopause is experienced between ages 42–58 years. • Breast cancer treatments may affect ovarian function and menses. In those who are premenopausal at the beginning of chemotherapy and who develop chemotherapy-induced amenorrhea, ovarian function may still be intact despite amenorrhea or may resume over time. The likelihood of ovarian function resuming after chemotherapy is higher among those aged <40 years. Tamoxifen may cause amenorrhea without inducing menopause in premenopausal individuals. Ovarian function suppression induces amenorrhea and reduces ovarian estrogen synthesis without causing permanent menopause. • Twelve months of amenorrhea alone is insufficient to diagnose menopause with chemotherapy-induced amenorrhea or with tamoxifen ± ovarian suppression. Follicle-stimulating hormone (FSH) and estradiol levels are used to support the diagnosis of menopause; however, clear criteria to guide interpretation of FSH and estradiol in this population is lacking. Tamoxifen may alter FSH levels, limiting its utility in determination of menopausal status. FSH and estradiol should be repeated serially to ensure menopausal status in patients with breast cancer with chemotherapy-induced amenorrhea. • Evidence-based criteria for the diagnosis of menopause in patients with breast cancer are lacking. Clinical trials in breast cancer have utilized a variety of definitions of menopause. Reasonable criteria for determining menopause in patients with breast cancer include any of the following: Prior bilateral oophorectomy Age ≥60 years Age <60 with amenorrhea for ≥12 months in the absence of prior chemotherapy, receipt of tamoxifen, toremifene, or ovarian suppression and estradiol and FSH in the post-menopausal range Age <60 years: chemotherapy-induced amenorrhea for ≥12 months with FSH and estradiol in post-menopausal range on serial assessments Age <60 years: on tamoxifen with FSH and estradiol level in post-menopausal range • Menopausal status cannot be determined in those receiving ovarian function suppression Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-O Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC THERAPY FOR ER- AND/OR PR-POSITIVE RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASEa HER2-Negative and Postmenopausal or HER2-Positive and Postmenopausalm,n Premenopausal Receiving Ovarian Ablation or Suppression or Premenopausal Receiving Ovarian Preferred Regimens Other Recommended Regimens Ablation or Suppression First-Line Therapy First- and/or Subsequent-Line Therapy • Aromatase inhibitor + CDK4/6 inhibitorb • Selective ER down-regulator • Aromatase inhibitor ± trastuzumab Aromatase inhibitor + ribociclib (category 1)c Fulvestrantk • Aromatase inhibitor ± lapatinib Aromatase inhibitor + abemaciclib For ESR1 mutated tumors, see BINV-Q (6) • Aromatase inhibitor ± lapatinib + trastuzumab Aromatase inhibitor + palbociclib • Selective ER down-regulator (fulvestrant, • Fulvestrant ± trastuzumab • Fulvestrantd + CDK4/6 inhibitorb category 1) + non-steroidal aromatase inhibitor • Tamoxifen ± trastuzumab Fulvestrant + ribociclib (category 1)e (anastrozole, letrozole) (category 1)k Fulvestrant + abemaciclib (category 1) e • Non-steroidal aromatase inhibitor Fulvestrant + palbociclib Anastrozole Letrozole Second- and Subsequent-Line Therapy • Selective ER modulator • Fulvestrant + CDK4/6 inhibitor (abemaciclib, Tamoxifen • Steroidal aromatase inactivator palbociclib, or ribociclib) if CKD4/6 inhibitor not Exemestane previously used (category 1)f,g • For PIK3CA or AKT1/PTEN-activating mutations, Useful in Certain Circumstances see additional targeted therapy options, see Subsequent-Line Therapy BINV-Q (6)h • Megestrol acetate • Everolimus + endocrine therapy (exemestane, • Estradiol fulvestrant, tamoxifen)i,j • Abemaciclibl • Addtional targeted therapy options, see BINV-Q (6) a Baseline assessment of bone density recommended for patients receiving an aromatase inhibitor who are at risk of osteoporosis (eg, age >65, family history, chronic steroids). b There is controversy on the choice of CDK4/6 inhibitor as there are no head to i If there is disease progression while on an everolimus-containing regimen, there are no data to support an additional head comparisons between the agents and there are some differences in the study line of therapy with another everolimus regimen. j A combination of exemestane with everolimus can be considered for patients who meet the eligibility criteria for populations in the phase 3 randomized studies. c In phase 3 randomized controlled trials, ribociclib + endocrine therapy has shown OS BOLERO-2 (progressed within 12 mo or on non-steroidal aromatase inhibitor). k A single study (S0226) in patients with HR-positive breast cancer and no prior chemotherapy, biological therapy, benefit in the first-line setting. d Consider for disease progression on adjuvant endocrine therapy or with early disease or endocrine therapy for metastatic disease demonstrated that the addition of fulvestrant to anastrozole resulted in relapse within 12 months of adjuvant endocrine therapy completion prolongation of time to progression and OS. Subset analysis suggested that patients without prior adjuvant tamoxifen e In phase 3 randomized controlled trials, fulvestrant + ribociclib or abemaciclib has shown and more than 10 years since diagnosis experienced the greatest benefit. Two studies with similar design (FACT and OS benefit in the first-line setting SOFEA) demonstrated no advantage in time to progression with the addition of fulvestrant to anastrozole. f In phase 3 randomized controlled trials, fulvestrant in combination with a CDK4/6 l Indicated after progression on prior endocrine therapy and prior chemotherapy in the metastatic setting. inhibitor (abemaciclib, palbociclib, and ribociclib) has shown OS benefit in the second- m An FDA-approved biosimilar is an appropriate substitute for trastuzumab. Trastuzumab and hyaluronidase-oysk line setting. injection for subcutaneous use may be substituted for trastuzumab. It has different dosage and administration g If there is disease progression while on palbociclib, there are limited phase II data to instructions compared to intravenous trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or with support the use of ribociclib in the second line setting ado-trastuzumab emtansine or fam-trastuzumab deruxtecan-nxki. h If there is progression while on a PI3K inhibitor, there are limited data to support another n If treatment was initiated with chemotherapy and trastuzumab + pertuzumab, and the chemotherapy was stopped, line of therapy with a PI3K-pathway inhibitor-containing regimen. endocrine therapy may be added to trastuzumab + pertuzumab. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. BINV-P Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASEa HR-Positive and HER2-Negative with Visceral Crisis† or Endocrine Refractory Setting Subtype/Biomarker Regimen First Line No germline BRCA1/2 mutationb Systemic chemotherapy see BINV-Q (5) Germline BRCA1/2 mutationb PARPi (olaparib, talazoparib)c (Category 1, preferred) Second Line HER2 IHC 1+ or 2+/ISH negatived Fam-trastuzumab deruxtecan-nxkie (Category 1, preferred) Not a candidate for fam-trastuzumab Sacituzumab govitecanf (Category 1, preferred) deruxtecan- nxki Systemic chemotherapy see BINV-Q (5) Third Line and Any Systemic chemotherapy see BINV-Q (5) beyond Biomarker positive (ie, MSI-H, NTRK, Targeted agents see BINV-Q (6) RET, TMB-H) † According to the 5th ESO-ESMO international consensus guidelines (Cardoso F, et al. Ann Oncol 2020;31:1625) for advanced breast cancer visceral crisis is defined as: “severe organ dysfunction, as assessed by signs and symptoms, laboratory studies and rapid progression of disease. Visceral crisis is not the mere presence of visceral metastases but implies important organ compromise leading to a clinical indication for the most rapidly efficacious therapy.” a For treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers. b Assess for germline BRCA1/2 mutations in all patients with recurrent or metastatic breast cancer to identify candidates for PARP inhibitor therapy. c PARPi can be considered for a later line for those with BRCA1/2 mutation, however available evidence suggests it is more effective if used earlier. d See Principles of HER2 Testing (BINV-A). e Fam-trastuzumab deruxtecan maybe considered in a later line for HER2 IHC 1+ or 2+/ISH negative, if not used in second–line. Fam-trastuzumab deruxtecan-nxki is associated with interstitial lung disease (ILD)/pneumonitis. Regular monitoring for this serious side effect is recommended. For patients with a history of ILD/ pneumonitis, there are no data on managing safety or toxicity of this drug in a trial. f Sacituzumab govitecan-hziy may be used for adult patients with HR-positive, HER2-negative metastatic/locally advanced unresectable breast cancer after prior treatment including endocrine therapy, a CDK4/6 inhibitor, and at least two lines of chemotherapy, one of which was a taxane, and at least one of which was in the metastatic setting. It may be considered for later line if not used as second line therapy. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 1 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASEa HR-Negative and HER2-Negative (Triple-Negative Breast Cancer; TNBC) Setting Subtype/Biomarker Regimen First Line PD-L1 CPS ≥10g regardless of germline BRCA Pembrolizumab + chemotherapy (albumin-bound paclitaxel, mutation statusb paclitaxel, or gemcitabine and carboplatin)h (Category 1, preferred) PD-L1 CPS <10g and no germline BRCA1/2 Systemic chemotherapy see BINV-Q (5) mutationb • PARPi (olaparib, talazoparib) (Category 1, preferred) PD-L1 CPS <10g and germline BRCA1/2 mutationb • Platinum (cisplatin or carboplatin) (Category 1, preferred) Second Germline BRCA1/2 mutationb PARPi (olaparib, talazoparib) (Category 1, preferred) Line Sacituzumab govitecani (Category 1, preferred) Any Systemic chemotherapy see BINV-Q (5) No germline BRCA1/2 mutationb Fam-trastuzumab deruxtecan-nxkie (Category 1, preferred) and HER2 IHC 1+ or 2+/ISH negatived Third Line Biomarker positive (ie, MSI-H, NTRK, RET, TMB-H) Targeted agents see BINV-Q (6) and beyond Any Systemic chemotherapy see BINV-Q (5) a For treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers. b Assess for germline BRCA1/2 mutations in all patients with recurrent or metastatic breast cancer to identify candidates for PARP inhibitor therapy d See Principles of HER2 Testing (BINV-A). e Fam-trastuzumab deruxtecan maybe considered in a later line for HER2 IHC 1+ or 2+/ISH negative, if not used in second–line. Fam-trastuzumab deruxtecan-nxki is associated with interstitial lung disease (ILD)/pneumonitis. Regular monitoring for this serious side effect is recommended. For patients with a history of ILD/ pneumonitis, there are no data on managing safety or toxicity of this drug in a trial. g PD-L1 expression is assessed using 22C3 antibody. Threshold for positivity combined positive score ≥10. h While available data are in the first-line setting, this regimen can be used for second and subsequent lines of therapy if PD-1/PD-L1 inhibitor therapy has not been previously used. If there is disease progression while on a PD-1/PD-L1 inhibitor, there are no data to support an additional line of therapy with another PD-1/PD-L1 inhibitor. i Sacituzumab govitecan-hziy may be used for adult patients with metastatic TNBC who have received at least 2 prior therapies, at least one of which was for metastatic disease. It may be considered for later line if not used as second line therapy. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 2 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASEk HR-Positive or -Negative and HER2-Positivej,k Setting Regimen Pertuzumab + trastuzumab + docetaxel (Category 1, preferred) First Linel Pertuzumab + trastuzumab + paclitaxel (preferred) Second Linen Fam-trastuzumab deruxtecan-nxkim (Category 1, preferred) Tucatinib + trastuzumab + capecitabinen (Category 1, preferred) Third Line Ado-trastuzumab emtansine (T-DM1)o Trastuzumab + docetaxel or vinorelbine Trastuzumab + paclitaxel ± carboplatin Fourth Line Capecitabine + trastuzumab or lapatinib and Beyond Trastuzumab + lapatinib (without cytotoxic therapy) (optimal sequence is Trastuzumab + other chemotherapy agentsq,r not known)p Neratinib + capecitabine Margetuximab-cmkb + chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine) Additional Targeted Therapy Options see BINV-Q (6) j See additional considerations for those receiving systemic HER2-targeted therapy (BINV-Q 4). k Assess for germline BRCA1/2 mutations in all patients with recurrent or metastatic breast cancer to identify candidates for PARP inhibitor therapy. While olaparib and talazoparib are FDA- indicated in HER2-negative disease, the panel supports use in any breast cancer subtype associated with a germline mutation. There is lower-level evidence for HER2-positive tumors, therefore category 2A for this setting. l Maintenance trastuzumab/pertuzumab after response (with concurrent endocrine therapy if ER+ and HER2+ metastatic breast cancer). m Fam-trastuzumab deruxtecan-nxki may be considered in the first-line setting as an option for select patients (ie, those with rapid progression within 6 months of neoadjuvant or adjuvant therapy [12 months for pertuzumab-containing regimens]). Fam-trastuzumab deruxtecan-nxki is associated with interstitial lung disease (ILD)/pneumonitis. Regular monitoring for this serious side effect is recommended. For patients with a history of ILD/pneumonitis, there are no data on managing safety or toxicity of this drug in a trial. n Tucatinib + trastuzumab + capecitabine is preferred in patients with both systemic and CNS progression in the third-line setting and beyond; and it may be given in the second-line setting. o May be used as an option for third-line and beyond; the optimal sequence for third-line therapy and beyond is not known. If not a candidate fam-trastuzumab T-DM1 could be considered in the second-line. p Multiple lines of concurrent chemotherapy with anti-HER2 therapy (trastuzumab or a TKI) offer clinical benefit for recurrent unresectable HER2+ metastatic breast cancer and have been studied in phase 2 or 3 trials. Clinical experience suggests frequent clinical benefit for such treatment. However, there are no meaningful data for use of any of these regimens among patients previously treated with pertuzumab-based chemotherapy, ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, or trastuzumab/capecitabine/tucatinib regimens. Thus, the optimal sequence or true benefit of therapy is not known. q Trastuzumab given in combination with an anthracycline is associated with significant cardiac toxicity. Concurrent use of trastuzumab and pertuzumab with an anthracycline should be avoided. r Trastuzumab may be safely combined with all non-anthracycline–containing preferred and other single agents listed on (BINV-Q 5) for recurrent or metastatic breast cancer. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 3 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion Additional Considerations for Those Receiving Systemic Therapy for HER2-Positive Disease • When receiving taxane-containing regimen: Alternative taxanes (ie, docetaxel, paclitaxel, albumin-bound paclitaxel) may be substituted for select patients due to medical necessity (ie, hypersensitivity reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly dose of albumin-bound paclitaxel should not exceed 125 mg/m2. Consider cryotherapy of hands and feet to decrease the risk of peripheral neuropathy. • An FDA-approved biosimilar is an appropriate substitute for trastuzumab. • Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for trastuzumab. It has different dosage and administration instructions compared to intravenous trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan-nxki. • Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use may be substituted anywhere that the combination of intravenous pertuzumab and intravenous trastuzumab are given as part of systemic therapy. Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different dosing and administration instructions compared to the intravenous products. • Patients previously treated with chemotherapy plus trastuzumab in the absence of pertuzumab in the metastatic setting may be considered for one line of therapy including both trastuzumab plus pertuzumab in combination with or without cytotoxic therapy (such as vinorelbine or taxane). Further research is needed to determine the ideal sequencing strategy for anti-HER2 therapy. • For treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 4 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion Systemic Chemotherapy for HR-Positive or -Negative and HER2-Negativea,s,t,u Preferred Regimens Other Recommended Regimens Useful in Certain Circumstances • Anthracyclines • Cyclophosphamide • AC (doxorubicin/cyclophosphamide) Doxorubicin • Docetaxel • EC (epirubicin/cyclophosphamide) Liposomal doxorubicin • Albumin-bound paclitaxel • CMF (cyclophosphamide/ • Taxanes • Epirubicin methotrexate/fluorouracil) Paclitaxel • Ixabepilone • Docetaxel/capecitabine • GT (gemcitabine/paclitaxel) • Anti-metabolites • Gemcitabine/carboplatin Capecitabine • Carboplatin + paclitaxel or albumin-bound paclitaxel Gemcitabine • Microtubule inhibitors Vinorelbine Eribulin • For specific lines of systemic therapy options for HR-positive and HER2-negative with visceral crisis or endocrine refractory, see BINV-Q (1). • For specific lines of systemic therapy options for HR-negative and HER2-negative (TNBC), see BINV-Q (2). • For specific lines of systemic therapy options for HR-negative or -positive and HER2-positive, see BINV-Q (3). a For treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers. t Sequential single agents are preferred, but chemotherapy combinations may be used in select patients with high tumor burden, rapidly progressing disease, and visceral crisis. s Alternative taxanes (ie, docetaxel, paclitaxel, albumin-bound paclitaxel) may be ubstituted for select patients due to medical necessity (ie, hypersensitivity reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly dose of albumin-bound paclitaxel should not exceed 125 mg/m2. t Consider scalp cooling to reduce incidence of chemotherapy-induced alopecia for patients receiving chemotherapy. Results may be less effective with anthracycline containing regimens. u Consider cryotherapy of hands and feet to decrease the risk of peripheral neuropathy when receiving taxane therapies. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 5 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion ADDITIONAL TARGETED THERAPIES AND ASSOCIATED BIOMARKER TESTING FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE Biomarkers Associated with FDA-Approved Therapies Breast Cancer Biomarker Detection FDA-Approved Agents NCCN Category NCCN Category Subtype of Evidence of Preference HR-positive/ Preferred second- PCR (blood or tissue HER2-negativev PIK3CA activating mutation Alpelisib + fulvestrantw Category 1 or subsequent-line block if blood negative) therapy Preferred second- HR-positive/ PIK3CA/AKT1/PTEN or subsequent-line HER2-negativex NGS Capivasertib + fulvestrant Category 1 activating mutations therapy in select patientsx Other HR-positive/ ESR1 mutation NGS, PCR (blood) Elacestrant Category 2A recommended HER2-negativey regimen FISH, NGS, PCR (tissue Larotrectinibz Any NTRK fusion Category 2A block) Entrectinibz IHC, NGS, PCR (tissue Pembrolizumabaa,bb Useful in certain Any MSI-H/dMMR Category 2A block) Dostarlimab-gxlycc circumstances Any TMB-H (≥10 mut/mb) NGS Pembrolizumabaa,bb Category 2A Any RET-fusion NGS Selpercatinibdd Category 2A z Larotrectinib and entrectinib are indicated for the treatment of solid tumors that have v For HR-positive/HER2-negative breast cancer, assess for PIK3CA mutations an NTRK gene fusion without a known acquired resistance mutation and have no with tumor or liquid biopsy to identify candidates for alpelisib plus fulvestrant. satisfactory alternative treatments or that have progressed following treatment. PIK3CA mutation testing can be done on tumor tissue or ctDNA in peripheral aa See NCCN Guidelines for Management of Immunotherapy-Related Toxicities. blood (liquid biopsy). If liquid biopsy is negative, tumor tissue testing is bb Pembrolizumab is indicated for the treatment of patients with unresectable or recommended. metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient w The safety of alpelisib in patients with Type 1 or uncontrolled Type 2 diabetes (dMMR) solid tumors, or TMB-H tumors that have progressed following prior has not been established. treatment and who have no satisfactory alternative treatment options. x In adult patients with PIK3CA/AKT1/PTEN activating mutations after disease cc Dostarlimab-gxly is indicated for adult patients with MSI-H/dMMR unresectable progression or recurrence after one or more prior lines of endocrine therapy, or metastatic tumors that have progressed on or following prior treatment and who including one line containing a CDK4/6 inhibitor. have no satisfactory alternative treatment options. y For postmenopausal females or adult males with ER-positive, HER2-negative, dd Selpercatinib is indicated for adult patients with locally advanced or metastatic ESR1-mutated disease after progression on one or two prior lines of endocrine solid tumors with a RET gene fusion that have progressed on or following prior therapy, including one line containing a CDK4/6 inhibitor. systemic treatment or who have no satisfactory alternative treatment options. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 6 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion EMERGING BIOMARKERS TO IDENTIFY NOVEL THERAPIES FOR PATIENTS WITH STAGE IV (M1) DISEASE Breast Cancer Emerging Detection Potential targeted NCCN Category NCCN Category of Subtype Biomarkers therapyff of Evidence Preference ER+/HER2- HER2 activating NGSee Neratinib ± fulvestrantgg Category 2B Useful in certain ER-/HER2- mutations Neratinib ± trastuzumab/ circumstances fulvestranthh • If ER+/HER2-, in patients who have already received CDK4/6 inhibitor therapy. Any Somatic BRCA1/2 NGSee Olaparibii Category 2B Useful in certain mutations circumstances Any Germline PALB2 Germline Olaparibii Category 2B Useful in certain sequencing circumstances ee Tumor tissue or ctDNA. ff At the present time, the data for the emerging biomarkers for the potential targeted agents noted in the table are promising but limited. gg Ma CX, Luo J, Freedman RA, et al. The phase II MutHER study of neratinib alone and in combination with fulvestrant in HER2-mutated, non-amplified metastatic breast cancer. Clin Cancer Res 2022; 28:1258-1267. hh Jhaveri KL, Goldman JW, Hurvitz SA, et al. Neratinib plus fulvestrant plus trastzuzumab (N+F+T) for hormone receptor-positive (HR+), HER2-negative, HER2-mutant metastatic breast cancer (MBC): Outcomes and biomarker analysis from the SUMMIT trial. Journal of Clinical Oncology 2022;40:1028-1028. ii Tung NM, Robson ME, Ventz S, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol 2020;38:4274-4282. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 7 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion DOSING: SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE HER2-Negative Regimens: • Anthracyclines: • Docetaxel14,15 • AC24 • Carboplatin/albumin-bound paclitaxel30 Doxorubicin 60–75 mg/m2 IV day 1; cycled 60–100 mg/m2 IV day 1 Doxorubicin 60 mg/m IV day 1 2 Carboplatin AUC 2 IV on days 1 and 8 every 21 days1 Cycled every 21 days Cyclophosphamide 600 mg/m2 IV day Albumin-bound paclitaxel 125 mg/m2 IV on Doxorubicin 20 mg/m2 IV day 1 weekly2 1 days 1 and 8 Liposomal doxorubicin3 50 mg/m2 IV day 1; • Docetaxel16 ◊ Cycled every 21 days Cycled every 21 days cycled every 28 days 35 mg/m2 IV weekly for 6 weeks • EC25 • Carboplatin/paclitaxel31,32 followed by a 2-week rest, then repeat • Taxanes: Epirubicin 75 mg/m IV day 1 2 Paclitaxel 175–200 mg/m2 IV day 1 Paclitaxel 175 mg/m2 IV day 1; cycled every 21 • Albumin-bound paclitaxel17,18 Cyclophosphamide 600 mg/m IV day Carboplatin AUC 6 IV day 1 2 days4 100 mg/m2 1 Cycled every 21 days Paclitaxel 80 mg/m2 IV day 1 weekly5 or 125 mg/m2 IV days 1, 8, and 15 ◊ Cycled every 21 days or Cycled every 28 days 26 Paclitaxel 100 mg/m2 IV days 1, 8, and 15 • Antimetabolites: • CMF Capecitabine6 1000–1250 mg/m2 PO twice Cyclophosphamide 100 mg/m2 PO Carboplatin AUC 2 IV days 1, 8, and 15 • Albumin-bound paclitaxel17 Cycled every 28 days daily days 1–14; cycled every 21 days days 1–14 260 mg/m2 IV Gemcitabine7 800–1200 mg/m2 IV days 1, 8, Methotrexate 40 mg/m2 IV days 1 Cycled every 21 days and 15; cycled every 28 days and 8 • Microtubule inhibitors: • Epirubicin19 5-fluorouracil 600 mg/m2 IV days 1 See dosing for additional targeted Vinorelbine8,9 60–90 mg/m2 IV day 1 and 8 therapies on BINV-Q (13) Cycled every 21 days ◊ Cycled every 28 days ◊ 25 mg/m2 IV day 1 weekly; or ◊ 20–35 mg/m2 IV days 1 and 8; cycled every • Ixabepilone20 • Docetaxel/capecitabine27 21 days; or Docetaxel 75 mg/m2 IV day 1 40 mg/m2 IV day 1 ◊ 25–30 mg/m2 IV days 1, 8, and 15; cycled Capecitabine 950 mg/m2 PO twice Cycled every 21 days every 28 days daily days 1–14 Eribulin10 1.4 mg/m2 IV days 1 and 8; cycled • Sacituzumab govitecan-hziy ◊ Cycled every 21 days every 21 days (for TNBC or HR+/HER2-)21,22 • GT28 • Platinum (for TNBC and germline BRCA1/2 10 mg/kg IV on days 1 and 8 Paclitaxel 175 mg/m2 IV day 1 mutation) Cycled every 21 days Gemcitabine 1250 mg/m2 IV days 1 Carboplatin11 AUC 6 IV on day 1 and 8 (following paclitaxel on day 1) ◊ Cycled every 21–28 days • Fam-trastuzumab deruxtecan-nxki ◊ Cycled every 21 days Cisplatin12 75 mg/m2 IV on day 1 (for HER2 IHC 1+ or 2+/ISH negative)23 • Gemcitabine/carboplatin29 ◊ Cycled every 21 days 5.4 mg/kg IV day 1 Gemcitabine 1000 mg/m2 on days 1 • Cyclophosphamide13 Cycled every 21 days and 8 50 mg PO daily on days 1–21 Carboplatin AUC 2 IV on days 1 and 8 Cycled every 28 days ◊ Cycled every 21 days The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti- cancer agents and the management of associated toxicities in patients with cancer. Continued Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 8 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion DOSING: SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE HER2-Positive Regimens:jj,kk,ll • Pertuzumab + trastuzumab + docetaxel33 • Tucatinib + trastuzumab + capecitabine36 • Weekly paclitaxel/carboplatin + trastuzumab40 Pertuzumab 840 mg IV day 1 followed by 420 Tucatinib 300 mg orally twice daily on Paclitaxel 80 mg/m2 IV days 1, 8, and 15 mg IV days 1–21 Carboplatin AUC 2 IV days 1, 8, and 15 Trastuzumab 8 mg/kg IV day 1 followed by 6 Trastuzumab 8 mg/kg IV day 1 followed ◊ Cycled every 28 days mg/kg IV day 1 every 21 days by 6 mg/kg IV day 1 every 21 days Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV Docetaxel 75–100 mg/m2 IV day 1 Capecitabine 1000 mg/m2 orally twice weekly ◊ Cycled every 21 days daily on days 1–14 or Cycled every 21 days Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV • Pertuzumab + trastuzumab + paclitaxel34,35 day 1 every 21 days35 • Ado-trastuzumab emtansine (T-DM1)37 Pertuzumab 840 mg IV day 1 followed by 420 • Trastuzumab + paclitaxel41,42 3.6 mg/kg IV day 1 mg IV Paclitaxel 175 mg/m2 IV day 1 cycled every 21 days41 ◊ Cycled every 21 days ◊ Cycled every 21 days or Trastuzumab 4 mg/kg IV day 1 followed by 2 • Fam-trastuzumab deruxtecan-nxki38 Paclitaxel 80–90 mg/m2 IV day 1 weekly43 mg/kg IV weekly 5.4 mg/kg IV day 1 Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV or ◊ Cycled every 21 days weekly Trastuzumab 8 mg/kg IV day 1 followed by 6 • Paclitaxel/carboplatin + trastuzumab39 or mg/kg IV day 1 every 21 days35 Carboplatin AUC 6 IV day 1 Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV Paclitaxel 80 mg/m2 IV day 1 weekly34 or Paclitaxel 175 mg/m2 IV day 1 day 1 every 21 days35 Paclitaxel 175 mg/m2 day 1 ◊ Cycled every 21 days ◊ Cycled every 21 days • Trastuzumab + docetaxel43,44 Trastuzumab 4 mg/kg IV day 1 followed Docetaxel 80–100 mg/m2 IV day 1 cycled every 21 days43 by 2 mg/kg IV weekly or or Docetaxel 35 mg/m2 IV days 1, 8, and 15 weekly cycled Trastuzumab 8 mg/kg IV day 1 followed every 28 days44 by 6 mg/kg IV day 1 every 21 days35 Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV jj An FDA-approved biosimilar is an appropriate substitute for trastuzumab. weekly kk Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for or trastuzumab. It has different dosage and administration instructions compared to intravenous Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab day 1 every 21 days35 emtansine or fam-trastuzumab deruxtecan-nxki. ll Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use may be substituted See dosing for additional targeted anywhere that the combination of intravenous pertuzumab and intravenous trastuzumab are given as therapies on BINV-Q (13) part of systemic therapy. Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different dosing and administration instructions compared to the intravenous products. The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer. Continued Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 9 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion DOSING: SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE HER2-Positive Regimens (continued):jj,kk • Trastuzumab + vinorelbine9,45,46 • Trastuzumab + lapatinib51 • Margetuximab-cmkb + capecitabine53 Vinorelbine Lapatinib 1000 mg PO daily for 21 days Margetuximab 15 mg/kg IV day 1 ◊ 25 mg/m2 IV day 1 weekly; or Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV Capecitabine 1000 mg/m2 po twice daily ◊ 20–35 mg/m2 IV days 1 and 8; cycled every 21 weekly days 1–14 days; or or ◊ Cycled every 21 days ◊ 25–30 mg/m2 IV days 1, 8, and 15; cycled every 28 days Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV • Margetuximab-cmkb + eribulin53 day 1 every 21 days35 Margetuximab 15 mg/kg IV day 1 Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly • Neratinib + capecitabine52 Eribulin 1.4 mg/m2 IV days 1 and 8 or Neratinib 240 mg PO daily on days 1–21 ◊ Cycled every 21 days Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg Capecitabine 750 mg/m2 PO twice daily on days 1–14 • Margetuximab-cmkb + gemcitabine53 IV day 1 every 21 days35 ◊ Cycled every 21 days Margetuximab 15 mg/kg IV day 1 or Gemcitabine 1000 mg/m2 IV days 1 and 8 • Trastuzumab + capecitabine47,48,49 Capecitabine 1000–1250 mg/m2 PO twice daily Neratinib ◊ Cycled every 21 days ◊ 120 mg PO daily on days 1–7; followed by days 1–14 cycled every 21 days • Margetuximab-cmkb + vinorelbine53 Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg ◊ 160 mg PO daily on days 8–14; followed by Margetuximab 15 mg/kg IV day 1 IV weekly41,48 ◊ 240 mg PO daily on days 15–21 Vinorelbine 25–30 mg/m2 IV days 1 and 8 or Capecitabine 750 mg/m² PO twice daily on days 1–14 ◊ Cycled every 21 days Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg ◊ Cycled every 21 days x 1 cycle IV day 1 every 21 days33,35 Followed by Neratinib 240 mg PO daily on days 1 – 21 See dosing for additional targeted • Lapatinib + capecitabine50 Capecitabine 750 mg/m² PO twice daily on days 1–14 therapies on BINV-Q (13) Lapatinib 1250 mg PO daily days 1–21 ◊ Cycled every 21 days beginning with cycle 2 Capecitabine 1000 mg/m2 PO twice daily days 1–14 ◊ Cycled every 21 days jj An FDA-approved biosimilar is an appropriate substitute for trastuzumab. kk Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for trastuzumab. It has different dosage and administration instructions compared to intravenous trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan- nxki. The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 10 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE REFERENCES 1 Chan S, Friedrichs K, Noel D, et al. Prospective randomized trial of docetaxel versus 17 Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin- doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1999;17:2341-2354. bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with 2 Gasparini G, Dal Fior S, Panizzoni GA, et al. Weekly epirubicin versus doxorubicin as breast cancer. J Clin Oncol 2005;23:7794-7803. second line therapy in advanced breast cancer. A randomized clinical trial. Am J Clin Oncol 18 Gradishar W, Dimitry K, Sergey C, et al: Significantly longer progression-free survival 1991;14:38-44. with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast 3 O'Brien ME, Wigler N, Inbar M, et al. Reduced cardiotoxicity and comparable efficacy in a cancer. J Clin Oncol 2009;27:3611-3619. phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional 19 Bastholt L, Dalmark M, Gjedde SB, et al. Dose-response relationship of epirubicin in doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004;15:440-449. the treatment of postmenopausal patients with metastatic breast cancer: a randomized 4 Seidman AD, Tiersten A, Hudis C, et al. Phase II trial of paclitaxel by 3-hour infusion as study of epirubicin at four different dose levels performed by the Danish Breast Cancer initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol 1995;13:2575- Cooperative Group. J Clin Oncol 1996;14:1146-1155. 2581. 20 Perez E, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a 5 Perez EA, Vogel CL, Irwin DH, et al. Multicenter phase II trial of weekly paclitaxel in phase II study of patients with advanced breast cancer resistant to an anthracycline, a women with metastatic breast cancer. J Clin Oncol 2001;19:4216-4223. taxane, and capecitabine. J Clin Oncol 2007;25:3407-3414. 6 Bajetta E, Procopio G, Celio L, et al. Safety and efficacy of two different doses of 21 Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol metastatic triple negative breast cancer. N Engl J Med 2019;380:741-751. 2005;23:2155-2161. 22 Rugo HS, et al. Primary Results from TROPiCS-02: A randomized phase 3 study of 7 Seidman AD. Gemcitabine as single-agent therapy in the management of advanced breast sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients cancer. Oncology (Williston Park) 2001;15:11-14. with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer 8 Zelek L, Barthier S, Riofrio M, et al. Weekly vinorelbine is an effective palliative regimen [abstract]. 2022: Abstract LB1001. after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer 23 Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated 2001;92:2267-2272. HER2-lowadvanced breast cancer. N Engl J Med 2022;7;387:9-20. 9Esfahani K, Ferrario C, Le P, Panasci L. The trastuzumab and vinorelbine combination: 24 Nabholtz JM, Falkson C, Campos D, et al. Docetaxel and doxorubicin compared with an alternative to taxane-based chemotherapy for early-stage and locally advanced her2- doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast positive breast cancer. Curr Oncol 2014;21:e723-e727. cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol 2003;21:968- 10 Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of 975. physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open- 25 Langley RE, Carmichel J, Jones AL, et al. Phase III trial of epirubicin plus paclitaxel label randomised study. Lancet 2011;377:914-923. compared with epirubicin plus cyclophosphamide as first-line chemotherapy for 11 Isakoff SJ, Mayer EL, He L, et al. TBCRC009: A multicenter phase II clinical trial of metastatic breast cancer: United Kingdom Cancer Research Institute. J Clin Oncol platinum monotherapy with biomarker assessment in metastatic triple-negative breast 2005;23:8322-8330. cancer. J Clin Oncol 2015;33:1902-1909. 26Bonadonna G, Brusamolino E, Valagussa P, et al. Combination chemotherapy as an 12 Silver DP, Richardson AL, Eklund AC, et al. Efficacy of neoadjuvant cisplatin in triple- adjuvant treatment in operable breast cancer. N Engl J Med 1976;294:405-410. negative breast cancer. J Clin Oncol 2010;28:1145-1153. 27Mavroudis D, Papakotoulas P, Ardavanis A, et al. Randomized phase III trial comparing 13 Licchetta A, Correale P, Migali C, et al. Oral metronomic chemo-hormonal-therapy of docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in metastatic breast cancer with cyclophosphamide and megestrol acetate. J Chemother women with advanced breast cancer. Ann Oncol 2010;21:48-54. 2010;22:201-204. 28Albain KS, Nag S, Calderillo-Ruiz G, et al. Gemcitabine plus paclitaxel versus 14 Burris HA, 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline Oncol 1999;26:1-6. treatment. J Clin Oncol 2008;26:3950-3957. 15 Harvey V, Mouridsen H, Semiglazov V, et al: Phase III trial comparing three doses of 29O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol 2006;24:4963- study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in 4970. metastatic triple-negative breast cancer (TNBC). [abstract]. J Clin Oncol 2011;29 16 Rivera E, Mejia JA, Arun BJ, et al. Phase 3 study comparing the use of docetaxel on an (Suppl_15):Abstract 1007. every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer 2008;112:1455-1461. Continued Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 11 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE REFERENCES 30 Yardley DA, Coleman R, Conte P, et al. nab-Paclitaxel plus carboplatin or 43 Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients of trastuzumab combined with docetaxel in patients with human epidermal growth factor with triple-negative metastatic breast cancer: results from the tnAcity trial. Ann Oncol receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 2018;29:1763-1770. study group. J Clin Oncol 2005;23:4265-4274. 31 Perez EA, Hillman DW, Stella PJ, et al. A phase II study of paclitaxel plus 44 Esteva FJ, Valero V, Booser D, et al. Phase II study of weekly docetaxel and trastuzumab for carboplatin as first-line chemotherapy for women with metastatic breast carcinoma. patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:1800-1808. Cancer 2000;88:124-131. 45 Burstein HJ, Keshaviah A, Baron AD, et al. Trastuzumab plus vinorelbine or taxane 32 Loesch D, Robert N, Asmar L, et al. Phase II multicenter trial of a weekly paclitaxel chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and and carboplatin regimen in patients with advanced breast cancer. J Clin Oncol vinorelbine or taxane study. Cancer 2007;110:965-972. 2002;20:3857-3864. 46Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel 33 Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally for metastatic breast cancer. N Engl J Med 2012;366:109-119. advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA 34 Datko F, D'Andrea G, Dickler M, et al. Phase II study of pertuzumab, trastuzumab, study. J Clin Oncol 2011;29:264-271. and weekly paclitaxel in patients with metastatic HER2-overexpressing metastatic 47 von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human breast cancer [abstract]. Cancer Research 2012;72:Abstract P5-18-20. epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/ 35 Leyland-Jones B, Gelmon K, Ayoub JP, et al. Pharmacokinetics, safety, and breast international group 03-05 study. J Clin Oncol 2009;27:1999-2006. efficacy of trastuzumab administered every three weeks in combination with 48Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of paclitaxel. J Clin Oncol 2003;21:3965-3971. humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing 36 Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J HER2-positive metastatic breast cancer. N Engl J Med 2020;382(7):597-609. Clin Oncol 1999;17:2639-2648. 37 Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive 49 Bartsch  R, Wenzel C, Altorjai G, et al. Capecitabine and trastuzumab in heavily pretreated advanced breast cancer [supplementary appendix available online]. N Engl J Med metastatic breast cancer. J Clin Oncol 2007;25:3853-3858. 2012;367:1783-1791. 50 Geyer  C, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced 38 Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated breast cancer. N Engl J Med 2006;355:2733-2743. HER2-positive breast cancer. N Engl J Med 2020;382:610-621. 51 Blackwell KL, Burstein H, Storniolo A, et al. Randomized study of lapatinib alone or in 39 Robert N, Leyland-Jones B, Asmar L, et al. Randomized phase III study of combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel breast cancer. J Clin Oncol 2010;28:1124-1130. in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 52 Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine versus lapatinib plus 2006;24:2786-2792. capecitabine in patients with HER2-positive metastatic breast cancer previously treated with 40 Perez EA, Suman VJ, Rowland KM, et al. Two concurrent phase II trials of ≥2 HER2-directed regimens: Findings from the multinational, randomized, phase 3 NALA trial. paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting. May 31-June therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG 4, 2019; Chicago, IL. J Clin Oncol 2019;37:(suppl; abstr 1002). study 983252. Clin Breast Cancer 2005;6:425-432. 53 Rugo HS, Im S, Cardoso F, et al. Efficacy of margetuximab vs trastuzumab in patients with 41 Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a pretreated ERBB2-positive advanced breast cancer. JAMA Oncol 2021;573-584. monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783-792. 42 Seidman A, Berry DA, Cirrincione C, et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 2008;26:1642-1649. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 12 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion DOSING: ADDITIONAL TARGETED THERAPIES AND ASSOCIATED BIOMARKER TESTING FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE • Alpelisib + fulvestrant1 • Olaparib7 tablet Alpelisib 300 mg PO daily on days 1–28; fulvestrant 500 mg IM on 300 mg PO twice daily days 1 and 15 Cycled every 28 days ◊ 28-day cycle for 1 cycle Followed by alpelisib 300 mg PO daily on days 1–28; fulvestrant 500 mg IM on day 1 • Pembrolizumab8-11 ◊ Cycled every 28 days until disease progression or unacceptable toxicity 200 mg IV on day 1, every 21 days until disease progression or unacceptable toxicity, or up to 24 months • Capivasertib + fulvestrant2 or Capivasertib 400 mg PO twice daily on days 1-4, 8-11, 15-18, 22-25 400 mg IV on day 1, every 6 weeks until disease progression or Fulvestrant 500 mg IM day 1 and day 15 unacceptable toxicity, or up to 24 months ◊ Cycled every 28 days for 1 cycle Followed by • Pembrolizumab + chemotherapy (albumin-bound paclitaxel, paclitaxel, Capivasertib 400 mg PO twice daily on days 1-4, 8-11, 15-18, 22-25 or gemcitabine and carboplatin)12 Fulvestrant 500 mg IM day 1 starting with cycle 2 Pembrolizumab 200 mg IV day 1 (given every 21 days) ◊ Cycled every 28 days until disease progression or unacceptable toxicity Albumin-bound paclitaxel 100 mg/m2 days 1, 8, 15 (given every 28 days) OR • Dostarlimab-gxly3 Paclitaxel 90 mg/m2 IV days 1, 8, 15 (given every 28 days) 500 mg IV on day 1 OR ◊ Cycled every 21 days for cycles 1–4 Pembrolizumab 200 mg IV day 1 Followed by 1000 mg IV on day 1 of cycle 5 Gemcitabine 1000 mg/m2 IV days 1 and 8 ◊ Cycled every 42 days starting with cycle 5 Carboplatin AUC 2 IV days 1 and 8 ◊ Given every 21 days • Elacestrant4 345 mg PO daily on days 1-28 • Selpercatinib13 Cycled every 28 days until disease progression or unacceptable toxicity Patients < 50kg: 120 mg PO twice daily until disease progression or unacceptable toxicity • Entrectinib5 Patients ≥ 50kg: 160 mg PO twice daily until disease progression or 600 mg PO daily on days 1–28 unacceptable toxicity Cycled every 28 days until disease progression or unacceptable toxicity • Talazoparib14 tablet • Larotrectinib6 1 mg PO daily 100 mg PO twice daily on days 1–28 Cycled every 28 days Cycled every 28 days until disease progression or unacceptable toxicity The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 13 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion ADDITIONAL TARGETED THERAPIES AND ASSOCIATED BIOMARKER TESTING FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE REFERENCES 1 Andre F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 2019;380:1929-1940. 2 Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med 2023; 388:2058-2070. 3 Berton D, Banerjee S, Curigliano G, et al. Antitumor activity of dostarlimab in patients with mismatch repair–deficient (dMMR) tumors: a combined analysis of 2 cohorts in the GARNET study. Poster presented at American Society for Clinical Oncology (ASCO), Virtual Meeting, June 4–8, 2021. [Abstract ID: 2564]. 4 Bidard FC, Kaklamani V, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Results from the randomized phase III EMERALD trial. J Clin Oncol 2022;40(28):3246- 3256. 5 Drilon A, Siena S, Ou SI, et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: Combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov 2017;7:400-409. 6 Drilon A, Laetsch TW, Kummar W, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018;378:731-739. 7 Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 2017;377:523-533. 8 Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-413. 9 Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-2520. 10 Lala M, Li TR, De Alwis DP, et al. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer 2020;131:68-75. 11 Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 2020;21:1353-1365. 12 Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020;396:1817-1828. 13 Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol. 2022 Oct;23:1261-1273. 14 Litton J, Rugo H, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018;379:753-763. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-Q Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 14 OF 14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF MONITORING METASTATIC DISEASE Monitoring of patient symptoms and cancer burden during treatment of metastatic breast cancer is important to determine whether the treatment is providing benefit and that the patient does not have toxicity from an ineffective therapy. Components of Monitoring Monitoring includes periodic assessment of varied combinations of symptoms, physical examination, routine laboratory tests, imaging studies, and blood biomarkers where appropriate. Results of monitoring are classified as response/continued response to treatment, stable disease, uncertainty regarding disease status, or progression of disease. The clinician typically must assess and balance multiple different forms of information to make a determination regarding whether disease is being controlled and the toxicity of treatment is acceptable. Sometimes, this information may be contradictory. Clinicians should take into account patient preferences through a shared decision-making process. Definition of Disease Progression Unequivocal evidence of progression of disease by one or more of these factors is required to establish progression of disease, either because of ineffective therapy or acquired resistance of disease to an applied therapy. Progression of disease may be identified through evidence of growth or worsening of disease at previously known sites of disease and/or of the occurrence of new sites of metastatic disease. • Findings concerning for progression of disease include: Worsening symptoms such as pain or dyspnea Evidence of worsening or new disease on physical examination Declining performance status Unexplained weight loss Increasing alkaline phosphatase, alanine aminotransferase (ALT), aspartate transaminase (AST), or bilirubin Hypercalcemia New radiographic abnormality or increase in the size of pre-existing radiographic abnormality New areas of abnormality on functional imaging (eg, bone scan, PET/CT) Increasing tumor markers (eg, carcinoembryonic antigen [CEA], CA 15-3, CA 27.29)a a Rising tumor markers (eg, CEA, CA 15-3, CA 27.29) are concerning for tumor progression, but may also be seen in the setting of responding disease. An isolated increase in tumor markers should rarely be used to declare progression of disease. Changes in bone lesions are often difficult to assess on plain or cross-sectional radiology or on bone scan. For these reasons, patient symptoms and serum tumor markers may be more helpful in patients with bone-dominant metastatic disease. Continued Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-R Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 1 OF 3 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF MONITORING METASTATIC DISEASE Use of Objective Criteria for Response/Stability/Progression • The most accurate assessments of disease activity typically occur when previously abnormal studies are repeated on a serial and regular basis. Generally, the same method of assessment should be used over time (eg, an abnormality found on chest CT should generally be monitored with repeat chest CT). • Some non-clinically important variation in measurement of abnormalities by all serial studies is common and expected. Therefore, the use of objective and widely accepted criteria for response, stability, and progression of disease are encouraged. Such systems include the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines [Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247] and the WHO criteria (Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207-214). • Studies of functional imaging, such as radionuclide bone scans and PET imaging, are particularly challenging when used to assess response. In the case of bone scans, responding disease may result in a flare or increased activity on the scan that may be misinterpreted as disease progression, especially on the first follow-up bone scan after initiating a new therapy. PET imaging is challenging because of the absence of a reproducible, validated, and widely accepted set of standards for disease activity assessment. Continued Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-R Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 2 OF 3 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Invasive Breast Cancer Discussion PRINCIPLES OF MONITORING METASTATIC DISEASE Frequency of Monitoring The optimal frequency of repeat testing is uncertain, and is primarily based on the monitoring strategies utilized in breast cancer clinical trials. The frequency of monitoring must balance the need to detect progressive disease, avoid unnecessary toxicity of any ineffective therapy, resource utilization, and determine cost. The following table is to provide guidance, and should be modified for the individual patient based on sites of disease, biology of disease, and treatment regimen. Reassessment of disease activity should be performed in patients with new or worsening signs or symptoms of disease, regardless of the time interval from previous studies. Suggested Intervals of Follow-up for Patients with Metastatic Diseaseb Baseline Prior to New Chemotherapy Endocrine Therapy Restaging if Concern for Therapy Progression of Disease Symptom Assessment Yes Prior to each cycle Every 1–3 months Yes Physical Examination Yes Prior to each cycle Every 1–3 months Yes Performance Status Yes Prior to each cycle Every 1–3 months Yes Weight Yes Prior to each cycle Every 1–3 months Yes LFTs, CBC Yes Prior to each cycle, as Every 1–3 months Yes indicated CT Chest/Abdomen/ Yes Every 2–4 cycles Every 2–6 months Yes Pelvis with Contrast Bone Scan Yes Every 4–6 cycles Every 2–6 months Yes PET/CT As clinically indicated As clinically indicated As clinically indicated As clinically indicated Tumor Markers As clinically indicated As clinically indicated As clinically indicated As clinically indicated b In patients who have long-term stable disease, the frequency of monitoring can be reduced. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. BINV-R Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. ® ® ® 3 OF 3 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Phyllodes Tumor Discussion CLINICAL WORKUP FINDINGS TREATMENT SURVEILLANCE PRESENTATION Fibroadenoma Observe Excisional Benign phyllodes tumor Clinical biopsya follow-up for Phyllodes tumor, Wide excisionc 3y borderline or without axillary Clinical suspicion of malignant stagingd phyllodes tumor: • Palpable mass • History and Invasive or • Rapid growth See appropriate guidelines physical exam in situ cancer • Large size (>3 cm) • Ultrasound • Imaging with • Mammogram for ultrasound suggestive patients ≥30 y Indeterminate of fibroadenoma Excisional See findings except for size and/or or benign biopsya above history of growth phyllodes tumor Borderline Wide excisionc Clinical Core needle or malignant without axillary follow-up for biopsyb phyllodes tumor stagingd 3y Invasive or See appropriate guidelines in situ cancer c For malignant or borderline disease, wide excision means excision with the a Excisional biopsy includes complete mass removal, but without the intent intention of obtaining surgical margins ≥1 cm. Narrow surgical margins are of obtaining surgical margins. associated with heightened local recurrence risk, but are not an absolute indication b FNA or core biopsy may not distinguish a fibroadenoma from a phyllodes for mastectomy when partial mastectomy fails to achieve a margin width ≥1 cm. tumor in some cases. The sensitivity of core biopsy for the diagnosis d There are no prospective randomized data supporting the use of RT for phyllodes of phyllodes tumor is greater than that of FNA biopsy, but neither core tumors. However, in the setting where additional recurrence would create biopsy nor FNA biopsy can always differentiate phyllodes tumors from significant morbidity (eg, chest wall recurrence following mastectomy), RT may be fibroadenomas. In cases with clinical suspicion for phyllodes tumor, considered following the same principles that are applied to the treatment of soft excision of the lesion may be needed for definitive pathologic classification. tissue sarcoma. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. PHYLL-1 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Phyllodes Tumor Discussion PHYLLODES TUMOR RECURRENCE CLINICAL PRESENTATION WORKUP FINDINGS TREATMENT Re-excision with wide Consider post- No metastatic margins without axillary operative radiation • History and physical disease exam staging (category 2B)d • Ultrasound Locally recurrent breast • Mammogram mass following excision • Tissue samplingb of phyllodes tumor (histology preferred) • Consider chest imaging (x-ray or CT, CT contrast optional) Metastatic disease management following Metastatic principles of soft tissue sarcoma disease (See NCCN Guidelines for Soft Tissue Sarcoma) b FNA or core biopsy may not distinguish a fibroadenoma from a phyllodes tumor in some cases. The sensitivity of core biopsy for the diagnosis of phyllodes tumor is greater than that of FNA biopsy, but neither core biopsy nor FNA biopsy can always differentiate phyllodes tumors from fibroadenomas. In cases with clinical suspicion for phyllodes tumor, excision of the lesion may be needed for definitive pathologic classification. d There are no prospective randomized data supporting the use of RT for phyllodes tumors. However, in the setting where additional recurrence would create significant morbidity (eg, chest wall recurrence following mastectomy), RT may be considered following the same principles that are applied to the treatment of soft tissue sarcoma. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. PHYLL-2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Paget Disease Discussion CLINICAL WORKUP PRESENTATION Examination or imaging positive for breast lesion • Clinical breast exam Clinical suspicion • Diagnostic bilateral mammogram, of Paget diseasea See PAGET-2 ultrasound as necessary Examination and imaging negative for breast lesion a Nipple or areolar eczema, ulceration, bleeding, or itching. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. PAGET-1 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Paget Disease Discussion WORKUP TREATMENT Breast and NAC Clinical follow-up biopsy negative Re-biopsy if not healing Breast DCIS See NCCN Guidelines for Noninvasive Breast and NAC Paget Cancer for DCIS (DCIS-1) Core biopsy of Examination breast lesion and or imaging full-thickness skin positive for biopsy of involved breast lesion Appropriate NAC systemic adjuvant therapy Breast invasive cancer See NCCN Guidelines for Invasive Breast as clinically and NAC Paget Cancer (BINV-1) indicated See NCCN Central lumpectomy including NAC Guidelines for Breast negative for with WBRT cancer and positive DCIS or Invasive Consider or Breast Cancer NAC Paget breast MRIb Total mastectomyc ± SLNB with or and tissue without breast reconstruction sampling or NAC biopsy positive Central lumpectomy including NAC for Paget ± SLNB without RT (category 2B) Examination Full-thickness and imaging skin biopsy of negative for involved NAC breast lesion NAC biopsy Clinical follow-up negative for Paget Re-biopsy if not healing b See Principles of Dedicated Breast MRI Testing (BINV-B). c Mastectomy is always an option with any manifestation of Paget disease (See Discussion). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. PAGET-2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer During Pregnancy Discussion WORKUPa CLINICAL PRESENTATION PRIMARY TREATMENTb,c ADJUVANT TREATMENTb,d Begin adjuvant chemotherapy in second Discuss trimesterb,d First Continuing Mastectomy + termination: ± Adjuvant RT trimester pregnancy axillary stagingb,c,e Non-therapeutic postpartumb ± Adjuvant endocrine • Chest x-ray therapy postpartumb (with abdominal shielding) Adjuvant chemotherapyb,d • Abdominal ± Adjuvant RT Pregnant Mastectomyb or BCS + axillary postpartumb ultrasound if stagingb,c,d patient with ± Adjuvant endocrine indicated to assess liver confirmed Second trimester/ therapy postpartumb breast cancer; Early third trimester or metastases No distant Preoperative chemotherapy,b,d ± Adjuvant RT • Consider metastases mastectomy, or BCS + axillary postpartumb non-contrast on staging stagingb,c,d ± Adjuvant endocrine MRI of spine if indicated to therapy postpartumb assess for bone metastases Adjuvant chemotherapyb,d ± Adjuvant RT Late third Mastectomya or BCS + axillary postpartumb trimester stagingb,c ± Adjuvant endocrine therapy postpartumb a CT scans and nuclear imaging are contraindicated during pregnancy. b Considerations and selection of optimal local therapy and systemic therapy are similar to that recommended in non–pregnancy-associated breast cancer; see other sections of this c Use of blue dye is contraindicated in pregnancy; radiolabeled sulfur guideline. However, the selection and timing of chemotherapy, endocrine therapy, and RT colloid appears to be safe for SLNB in pregnancy. See Considerations is different in the pregnant versus non-pregnant patient (See Discussion). Chemotherapy for Surgical Axillary Staging (BINV-D). should not be administered during the first trimester of pregnancy, and RT should not d There are limited data on the use of taxanes during pregnancy. The be administered during any trimester of pregnancy. Coordination is recommended optimal schedule is unclear. If used, the NCCN Panel recommends between the oncology and obstetrics teams to plan the optimal timing of systemic therapy weekly administration of paclitaxel after the first trimester if clinically administration during pregnancy. Most experience with chemotherapy during pregnancy indicated by disease status. The use of anti-HER2 therapy is for breast cancer is from regimens that utilize various combinations of doxorubicin, contraindicated during pregnancy. cyclophosphamide, and fluorouracil. Considerations for postpartum chemotherapy are the e If late first trimester, may consider preoperative chemotherapy in the same as for non–pregnancy-associated breast cancer. second trimester. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. PREG-1 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Inflammatory Breast Cancer Discussion CLINICAL WORKUP PRESENTATIONa • History and physical exam by multidisciplinary team and obtain medical photography • CBC • Comprehensive metabolic panel, including LFTs and alkaline phosphatase • Pathology reviewb • Determination of tumor ER/PR status and HER2 statusc See Preoperative/ Clinical • Fertility counseling if premenopausald Adjuvant Therapy pathologic See IBC-2 • Genetic counseling if patient is at riske for hereditary breast Regimens (BINV-L) diagnosis of IBC cancer • Imaging: Bilateral diagnostic mammogram, ultrasound as necessary Chest diagnostic CT ± contrast Abdominal ± pelvic diagnostic CT with contrast or MRI with contrast Bone scan or FDG PET/CTf,g Breast MRI (optional) a IBC is a clinical syndrome in patients with invasive breast cancer that is characterized by erythema and edema (peau d'orange) of a third or more of the skin of the breast. The differential diagnosis includes cellulitis of the breast or mastitis. Pathologically, a tumor is typically present in the dermal lymphatics f If FDG PET/CT is performed and clearly indicates bone metastasis on both the of the involved skin, but dermal lymphatic involvement is neither required, nor PET and CT component, bone scan or sodium fluoride PET/CT may not be sufficient by itself for a diagnosis of IBC. needed. b The panel endorses the College of American Pathologists Protocol for pathology g FDG PET/CT can be performed at the same time as diagnostic CT. FDG PET/ reporting for all invasive and noninvasive carcinomas of the breast. CT is most helpful in situations where standard staging studies are equivocal or http://www.cap.org. suspicious. FDG PET/CT may also be helpful in identifying unsuspected regional c See Principles of Biomarker Testing (BINV-A). nodal disease and/or distant metastases when used in addition to standard d See Fertility and Birth Control (BINV-C). staging studies. e For risk criteria, see NCCN Guidelines for Genetic/Familial High-Risk h A pertuzumab-containing regimen may be administered preoperatively to patients Assessment: Breast, Ovarian, and Pancreatic. with HER2-positive IBC. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. IBC-1 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Inflammatory Breast Cancer Discussion RESPONSE TO TREATMENTj PREOPERATIVE THERAPY • Complete planned chemotherapy regimen course if not completed preoperatively plus endocrine Total mastectomy + level l/ll axillary treatment if ER-positive and/or PR-positive (sequential dissection + RT to chest wall and chemotherapy followed by endocrine therapy).m Responsei comprehensive RNI with inclusion of • Complete up to one year of HER2-targeted therapy any portion of the undissected axilla at if HER2-positive (category 1). May be administered risk ± delayed breast reconstructionl concurrently with RTn and with endocrine therapy if indicated. Patients may be candidates for multiple lines of systemic therapy to palliate advanced breast cancer. At each reassessment Responsei See above pathway Consider clinicians should assess No additional systemic value of ongoing treatment, responsei chemotherapym and/or the risks and benefits preoperative radiation. of an additional line of systemic therapy, patient No responsei Individualized treatment performance status, and patient preferences through a shared decision- making process. i The accurate assessment of in-breast tumor or regional lymph node response to preoperative systemic therapy is difficult, and should include physical examination and performance of imaging studies (mammogram and/or breast MRI) that were abnormal at the time of initial tumor staging. Selection of imaging methods prior to surgery should be determined by the multidisciplinary team. j Patients with recurrent IBC should be treated according to the guideline for recurrence/stage IV (M1) disease (BINV-19). k See Principles of Breast Reconstruction Following Surgery (BINV-H). l See Systemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q). m See Adjuvant Endocrine Therapy (BINV-K). n See Principles of Radiation Therapy (BINV-I). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. IBC-2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion American Joint Committee on Cancer (AJCC) TNM Staging System For Breast Cancer Primary Tumor (T) The T category of the primary tumor is defined by the same criteria regardless of whether it is based on clinical or pathological criteria, or both. The T category is based primarily on the size of the invasive component of the cancer. The maximum size of a tumor focus is used as an estimate of disease volume. The largest contiguous dimension of a tumor focus is used, and small satellite foci of noncontiguous tumor are not added to the size. The cellular fibrous reaction to invasive tumor cells is generally included in the measurement of a tumor prior to treatment; however, the dense fibrosis observed following neoadjuvant treatment is generally not included in the pathological measurement because its extent may overestimate the residual tumor volume. The clinical size of a primary tumor (T) can be measured based on clinical findings (physical examination and imaging modalities, such as mammography, ultrasound, and MR imaging) and pathological findings (gross and microscopic measurements). Clinical tumor size (cT) should be based on the clinical findings that are judged to be most accurate for a particular case, although it may still be somewhat inaccurate because the intent of some breast cancers is not always apparent with current imaging techniques and because tumors are composed of varying proportions of noninvasive and invasive disease, which these techniques are currently unable to distinguish. Size should be measured to the nearest millimeter. If the tumor size is slightly less than or greater than a cutoff for a given T classification the size should be rounded to the millimeter reading that is closest to the cutoff. For example, a reported size of 4.9 mm is reported as 5 mm, or a size of 2.04 cm is reported as 2.0 cm (20 mm). The exception to this rounding rule is for a breast tumor sized between 1.0 and1.4 mm. These sizes are rounded up to 2 mm, because rounding down would result in the cancer’s being categorized as microinvasive carcinoma (T1mi) defined as a size of 1.0 mm or less. Table 1. Definitions for T, N, M T2 Tumor >20 mm but ≤50 mm in greatest dimension TX Primary tumor cannot be assessed T3 Tumor >50 mm in greatest dimension T0 No evidence of primary tumor T4 Tumor of any size with direct extension to the chest wall and/ Tis Ductal carcinoma in situ or to the skin (ulceration or macroscopic nodules); invasion (DCIS)* of the dermis alone does not qualify as T4 Tis  aget disease of the nipple NOT associated with invasive P T4a Extension to the chest wall; invasion or adherence to (Paget) carcinoma and/or carcinoma in situ (DCIS) in the underlying pectoralis muscle in the absence of invasion of chest wall breast parenchyma. Carcinomas in the breast parenchyma structures does not qualify as T4 associated with Paget disease are categorized based on T4b Ulceration and/or ipsilateral macroscopic satellite nodules the size and characteristics of the parenchymal disease, and/or edema (including peau d’orange) of the skin that does although the presence of Paget disease should still be noted not meet the criteria for inflammatory carcinoma T1 Tumor ≤20 mm in greatest dimension T4c Both T4a and T4b are present T1mi Tumor ≤1 mm in greatest dimension T4d Inflammatory carcinoma T1a Tumor >1 mm but ≤5 mm in greatest dimension (round any measurement >1.0–1.9 mm to 2 mm) *Note: Lobular carcinoma in situ (LCIS) is a benign entity and is T1b Tumor >5 mm but ≤10 mm in greatest dimension removed from TNM staging in the AJCC Cancer Staging Manual, 8th Edition. T1c Tumor >10 mm but ≤20 mm in greatest dimension Continued Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. ST-1 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Table 1. Definitions for T, N, M (continued) Pathologic (pN) Regional Lymph Nodes (N) pNX Regional lymph nodes cannot be assessed (e.g., not Clinical (cN) removed for pathological study or previously removed) cNX* Regional lymph nodes cannot be assessed (e.g., previously pN0 No regional lymph node metastasis identified or ITCs only removed) cN0 No regional lymph node metastases (by imaging or clinical pN0(i+) ITCs only (malignant cells clusters no larger than 0.2 mm) examination) in regional lymph node(s) cN1 Metastases to movable ipsilateral level I, II axillary lymph node(s) pN0(mol+) Positive molecular findings by reverse transcriptase polymerase chain reaction (RT-PCR); no ITCs detected cN1mi** Micrometastases (approximately 200 cells, larger than 0.2 mm, but pN1 Micrometastases; or metastases in 1–3 axillary lymph none larger than 2.0 mm) nodes; and/or in clinically negative internal mammary nodes with micrometastases or macrometastases by cN2 Metastases in ipsilateral level I, II axillary lymph nodes that are sentinel lymph node biopsy clinically fixed or matted; or in ipsilateral internal mammary nodes in the absence of axillary pN1mi Micrometastases (approximately 200 cells, larger than lymph node metastases 0.2 mm, but none larger than 2.0 mm) cN2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one pN1a Metastases in 1–3 axillary lymph nodes, at least one another (matted) or to other structures metastasis larger than 2.0 mm cN2b Metastases only in ipsilateral internal mammary nodes in the pN1b Metastases in ipsilateral internal mammary sentinel absence of axillary lymph node metastases nodes, excluding ITCs cN3 Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement; pN1c pN1a and pN1b combined. or in ipsilateral internal mammary lymph node(s) with level I, II pN2 Metastases in 4–9 axillary lymph nodes; or positive axillary lymph node metastases; ipsilateral internal mammary lymph nodes by imaging in or metastases in ipsilateral supraclavicular lymph node(s) with or the absence of axillary lymph node metastases without axillary or internal mammary lymph node involvement pN2a Metastases in 4–9 axillary lymph nodes (at least one cN3a Metastases in ipsilateral infraclavicular lymph node(s) tumor deposit larger than 2.0 mm) cN3b Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) pN2b Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with cN3c Metastases in ipsilateral supraclavicular lymph node(s) pathologically negative axillary nodes Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine needle aspiration/core needle biopsy respectively. *The cNX category is used sparingly in cases where regional lymph nodes have previously been surgically removed or where there is no documentation of physical examination of the axilla. **cN1mi is rarely used but may be appropriate in cases where sentinel node biopsy is performed before tumor resection, most likely to occur in cases treated Continued with neoadjuvant therapy. Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. ST-2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Table 1. Definitions for T, N, M (continued) Table 2. AJCC Anatomic Stage Groups Pathologic (pN) pN3  etastases in 10 or more axillary lymph nodes; M The Anatomic Stage Group table should only be used in global regions where or in infraclavicular (level III axillary) lymph nodes; biomarker tests are not routinely available. or positive ipsilateral internal mammary lymph nodes by Cancer registries in the U.S. must use the Clinical and Pathological Prognostic imaging in the presence of one or more positive level I, II Stage Group tables for case reporting. axillary lymph nodes; or in more than three axillary lymph nodes and Stage 0 Tis N0 M0 Stage IIIA T0 N2 M0 micrometastases or macrometastases by sentinel lymph Stage IA T1 N0 M0 T1 N2 M0 node biopsy in clinically negative ipsilateral internal mammary lymph nodes; Stage IB T0 N1mi M0 T2 N2 M0 or in ipsilateral supraclavicular lymph nodes T1 N1mi M0 T3 N1 M0 pN3a Metastases in 10 or more axillary lymph nodes (at least Stage IIA T0 N1 M0 T3 N2 M0 one tumor deposit larger than 2.0 mm); or metastases to the infraclavicular (level III axillary T1 N1 M0 Stage IIIB T4 N0 M0 lymph) nodes T2 N0 M0 T4 N1 M0 pN3b pN1a or pN2a in the presence of cN2b (positive internal Stage IIB T2 N1 M0 T4 N2 M0 mammary nodes by imaging); or pN2a in the presence of pN1b T3 N0 M0 Stage IIIC Any T N3 M0 pN3c Metastases in ipsilateral supraclavicular lymph nodes Stage IV M1 Any T Any N Notes: Note: (sn) and (f) suffixes should be added to the N category to denote 1. T1 includes T1mi. confirmation of metastasis by sentinel node biopsy or FNA/core needle 2. T0 and T1 tumors with nodal micrometastases (N1mi) are staged as Stage IB. biopsy respectively, with NO further resection of nodes 3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using Distant Metastasis (M) the N1 category. 4. M0 includes M0(i+). M0 No clinical or radiographic evidence of distant 5. The designation pM0 is not valid; any M0 is clinical. metastases* 6. If a patient presents with M1 disease prior to neoadjuvant systemic therapy, the cM0(i+) No clinical or radiographic evidence of distant stage is considered Stage IV and remains Stage IV regardless of response to metastases in the presence of tumor cells or deposits neoadjuvant therapy. no larger than 0.2 mm detected microscopically or by 7. Stage designation may be changed if postsurgical imaging studies reveal the molecular techniques in circulating blood, bone marrow, presence of distant metastases, provided the studies are performed within 4 or other nonregional nodal tissue in a patient without months of diagnosis in the absence of disease progression, and provided the symptoms or signs of metastases patient has not received neoadjuvant therapy. cM1 Distant metastases detected by clinical and radiographic 8. Staging following neoadjuvant therapy is designated with “yc” or “yp” prefix means to the T and N classification. There is no anatomic stage group assigned if pM1 Any histologically proven metastases in distant organs; there is a complete pathological response (pCR) to neoadjuvant therapy, for or if in non-regional nodes, metastases greater than 0.2 example, ypT0ypN0cM0. mm Continued Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. ST-3 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Table 2. AJCC Anatomic Stage Groups (continued) Histologic Grade (G) All invasive breast carcinomas should be assigned a histologic grade. The Nottingham combined histologic grade (Nottingham modification of the SBR grading system) is recommended and is stipulated for use by the College of American Pathologists (see www.cap.org). The grade for a tumor is determined by assessing morphologic features (tubule formation, nuclear pleomorphism, and calibrated mitotic count), assigning a value from 1 (favorable) to 3 (unfavorable) for each feature, and totaling the scores for all three categories. A combined score of 3–5 points is designated as grade 1; a combined score of 6–7 points is grade 2; a combined score of 8–9 points is grade 3. The use of subjective grading alone is discouraged. Invasive Cancer (Scarff-Bloom-Richardson [SBR] Grading System, Nottingham Modification) GX Grade cannot be assessed G1 Low combined histologic grade (favorable); SBR score of 3–5 points G2 Intermediate combined histologic grade (moderately favorable); SBR score of 6–7 points G3 High combined histologic grade (unfavorable); SBR score of 8–9 points Ductal Carcinoma in situ: Nuclear Grade The grade that should be used for ductal carcinoma in situ is nuclear grade (www.cap.org) GX Grade cannot be assessed G1 Low nuclear grade G2 Intermediate nuclear grade G3 High nuclear grade Continued Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. ST-4 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Histopathologic Type - WHO Classification 5th Edition (2019) In situ carcinomas Favorable Histologic Types Ductal carcinoma in situ (DCIS) (low nuclear grade, intermediate nuclear grade, and Tubular carcinoma high nuclear grade) Cribriform carcinoma Insitu papillary neoplasms (papillary DCIS, encapsulated papillary carcinoma, solid Mucinous carcinoma papillary carcinoma in situ) Adenoid cystic Invasive Carcinomas Low-grade adenosquamous carcinoma metaplastic carcinoma Invasive breast carcinoma of no special type (ductal and other special patterns) Low-grade fibromatosis-like metaplastic carcinoma Microinvasive carcinoma Invasive lobular carcinoma Tubular carcinoma Cribriform carcinoma Mucinous carcinoma Mucinous cystadenocarcinoma Invasive micropapillary carcinoma Invasive papillary carcinoma Invasive solid papillary carcinoma Carcinoma with apocrine differentiation Metaplastic carcinoma (spindle cell, squamous, with heterologous differentiation, low-grade adenosquamous carcinoma, low-grade fibromatosis-like and mixed metaplastic) Neuroendocrine tumor (NET) Neuroendocrine carcinoma (NEC) Salivary gland-type (acinic cell, adenoid cystic, secretory, mucoepidermoid, polymorphous adenocarcinoma) Tall cell carcinoma with reversed polarity Continued WHO Classification of Tumors Editorial Board, ed. WHO Classification of Tumors, 5th Edition – Breast Tumors. Lyon: International Agency for Research on Cancer 2019. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. ST-5 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Table 3. Clinical Prognostic Stage Clinical Prognostic Stage applies to ALL patients with breast cancer for clinical classification and staging. It uses clinical tumor (T), node (N) and metastases (M) information based on history, physical examination, any imaging performed (not necessary for clinical staging) and relevant biopsies. Genomic profile information is not included in Clinical Prognostic Stage as pathologic information from surgery is necessary to ascertain the prognosis using these tools. TNM Grade HER2 ER PR Stage TNM Grade HER2 ER PR Stage Tis N0 M0 Any Any Any Any 0 T0 N1** M0 Positive IB T1* N1** M0 Positive T1* N0 M0 Positive Negative Positive T2 N0 M0 Positive T0 N1mi M0 Negative Positive IIA T1* N1mi M0 Positive Negative Positive Negative Negative G1 Negative IA Positive IB G1 Positive Positive Negative Positive Negative Negative Positive IIA Negative Negative Positive Negative Negative Negative IB Positive IB Positive Positive Negative Positive Positive Negative Positive IIA Positive Negative Positive Negative Negative G2 Negative IA Positive IB G2 Positive Positive Negative Positive Negative IIA Negative Positive Negative Negative Positive Negative IIB Negative Negative IB Positive IB Positive Positive Negative Positive Positive Negative Positive Positive Negative IIA Positive IA Negative Negative G3 Negative Positive G3 Positive Positive Negative Positive Negative Negative Positive IIB Negative Negative Positive IB Negative Negative Negative Continued *T1 includes T1mi. **N1 does not include N1mi. T1 N1mi M0 and T0 N1mi M0 cancers are included for prognostic staging with T1 N0 M0 cancers of the same prognostic factor status. Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. ST-6 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Table 3. Clinical Prognostic Stage (continued) TNM Grade HER2 ER PR Stage TNM Grade HER2 ER PR Stage T2 N1*** M0 Positive IB T0 N2 M0 Positive IIA T3 N0 M0 Positive T1* N2 M0 Positive Negative Negative Positive IIA T2 N2 M0 Positive Positive T3 N1*** M0 Positive IIIA Negative T3 N2 M0 Negative Negative IIB Negative G1 G1 Positive IIA Positive IIA Positive Positive Negative Negative Negative Negative IIIA Positive IIB Positive Negative Negative Negative Negative IIIB Positive IB Positive IIA Positive Positive Negative Negative Positive IIA Positive Positive Positive IIIA Negative Negative Negative IIB Negative G2 G2 Positive IIA Positive IIA Positive Positive Negative Negative Negative IIB Negative IIIA Positive Positive Negative Negative Negative IIIB Negative IIIB Positive IB Positive IIB Positive Positive Negative Negative Positive Positive Positive Positive Negative IIB Negative IIIA Negative Negative G3 G3 Positive Positive Positive Positive Negative Negative Negative IIIA Negative IIIB Positive Positive Negative Negative Negative IIIB Negative IIIC Continued *T1 includes T1mi. ***N1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2 N1, T3 N1 and T4 N1, respectively. Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. ST-7 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Table 3. Clinical Prognostic Stage (continued) Notes: TNM Grade HER2 ER PR Stage 1. Because N1mi categorization requires evaluation of the entire node, and cannot T4 N0 M0 Positive IIIA be assigned on the basis of an FNA or core biopsy, N1mi can only be used T4 N1*** M0 Positive with Clinical Prognostic Staging when clinical staging is based on a resected Negative T4 N2 M0 Positive lymph node in the absence of resection of the primary cancer, such as the Any T N3 M0 Positive situation where sentinel node biopsy is performed prior to receipt of neoadjuvant Negative Negative chemotherapy or endocrine therapy. G1 IIIB 2. For cases with lymph node involvement with no evidence of primary tumor (e.g. Positive Positive T0 N1, etc.) or with breast ductal carcinoma in situ (e.g. Tis N1, etc.), the grade, Negative HER2, ER, and PR information from the tumor in the lymph node should be used Negative Positive for assigning stage group. Negative 3. For cases where HER2 is determined to be “equivocal” by ISH (FISH or CISH) Negative IIIC testing under the 2013 ASCO/CAP HER2 testing guidelines, the HER2 “negative” Positive IIIA category should be used for staging in the Clinical Prognostic Stage Group. Positive 4. The prognostic value of these Prognostic Stage Groups is based on populations Negative Positive of persons with breast cancer that have been offered and mostly treated with Positive appropriate endocrine and/or systemic chemotherapy (including anti-HER2 Negative Negative therapy). G2 IIIB Positive Positive Negative Negative Positive Negative Negative IIIC Positive Positive Negative Positive Positive IIIB Negative Negative G3 Positive Positive Negative Negative Positive IIIC Negative Negative Any T Any N M1 Any Any Any Any IV Continued ***N1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2 N1, T3 N1 and T4 N1, respectively. Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. ST-8 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Table 4. Pathological Prognostic Stage Pathological Prognostic Stage applies to patients with breast cancer treated with surgery as the initial treatment. It includes all information used for clinical staging plus findings at surgery and pathological findings from surgical resection. Pathological Prognostic Stage does not apply to patients treated with systemic or radiation prior to surgical resection (neoadjuvant therapy). TNM Grade HER2 ER PR Stage TNM Grade HER2 ER PR Stage Tis N0 M0 Any Any Any Any 0 T0 N1** M0 Positive IA T1* N1** M0 Positive T1* N0 M0 Positive Negative Positive T2 N0 M0 Positive IB T0 N1mi M0 Negative Positive T1* N1mi M0 Positive Negative Positive Negative IIA Negative G1 Negative Positive IA G1 Positive Positive Negative Positive Negative IB Negative Positive Negative Negative Positive Negative IIA Negative Negative IA Positive IA Positive Positive Negative Positive Positive IB Negative Positive Positive Negative Positive Negative IIA Negative G2 Negative Positive IA G2 Positive Positive Negative Positive Negative Negative Positive IIA Negative Negative Positive Negative Negative Negative IB Positive IA Positive Positive Negative Positive Positive Negative Positive IIA Positive Negative Positive Negative Negative G3 Negative IA Positive IB G3 Positive Positive Negative Positive Negative Negative Positive IIA Negative Negative Positive Negative Negative Negative IB Continued *T1 includes T1mi. **N1 does not include N1mi. T1 N1mi M0 and T0 N1mi M0 cancers are included for prognostic staging with T1 N0 M0 cancers of the same prognostic factor status. Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. ST-9 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Table 4. Pathological Prognostic Stage (continued) TNM Grade HER2 ER PR Stage TNM Grade HER2 ER PR Stage T2 N1*** M0 Positive IA T0 N2 M0 Positive IB T3 N0 M0 Positive T1* N2 M0 Positive Negative Negative Positive T2 N2 M0 Positive Positive IIB T3 N1*** M0 Positive IIIA Negative T3 N2 M0 Negative Negative Negative G1 G1 Positive IA Positive IB Positive Positive Negative Negative Negative Negative Positive IIB Positive IIIA Negative Negative Negative Negative Positive IB Positive IB Positive Positive Negative Negative Positive Positive Positive IIB Positive IIIA Negative Negative Negative Negative G2 G2 Positive IB Positive IB Positive Positive Negative Negative Negative Negative IIIA Positive IIB Positive Negative Negative Negative Negative IIIB Positive IB Positive IIA Positive Positive Negative Negative Positive Positive Positive IIB Positive IIIA Negative Negative Negative Negative G3 G3 Positive IIA Positive IIB Positive Positive Negative Negative Negative IIB Negative IIIA Positive Positive Negative Negative Negative IIIA Negative IIIC Continued *T1 Includes T1mi. ***N1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2 N1, T3 N1 and T4 N1, respectively. Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. ST-10 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion Table 4. Pathological Prognostic Stage (continued) Notes: TNM Grade HER2 ER PR Stage 1. For cases with lymph node involvement with no evidence of primary tumor (e.g. T4 N0 M0 Positive IIIA T0 N1, etc.) or with breast ductal carcinoma in situ (e.g. Tis N1, etc.), the grade, T4 N1*** M0 Positive HER2, ER and PR information from the tumor in the lymph node should be used Negative T4 N2 M0 Positive for assigning stage group. Any T N3 M0 Positive IIIB 2. For cases where HER2 is determined to be “equivocal” by ISH (FISH or CISH) Negative testing under the 2013 ASCO/CAP HER2 testing guidelines, HER2 “negative” Negative G1 category should be used for staging in the Pathological Prognostic Stage Group. Positive IIIA 3. The prognostic value of these Prognostic Stage Groups is based on populations Positive of persons with breast cancer that have been offered and mostly treated with Negative Negative appropriate endocrine and/or systemic chemotherapy (including anti-HER2 Positive IIIB therapy). Negative Negative Table 5. Genomic Profile for Pathologic Prognostic Staging Positive IIIA When Oncotype DX Score is Less than 11... Positive Negative TNM Grade HER2 ER PR Stage Positive Positive IIIB T1 N0 M0 Negative Any Negative Positive Any IA Negative T2 N0 M0 G2 Notes: Positive IIIA Positive 1. Obtaining genomic profiles is NOT required for assigning Pathological Negative Prognostic Stage. However genomic profiles may be performed for use in Negative IIIB Positive determining appropriate treatment. If the OncotypeDx® test is performed in cases Negative with a T1N0M0 or T2N0M0 cancer that is HER2-negative and ER-positive, and Negative IIIC the recurrence score is less than 11, the case should be assigned Pathological Positive Prognostic Stage Group IA. Positive 2. If OncotypeDx® is not performed, or if it is performed and the OncotypeDx® Negative score is not available, or is 11 or greater for patients with T1–2 N0 M0 HER2– Positive Positive IIIB negative, ER-positive cancer, then the Prognostic Stage Group is assigned based Negative on the anatomic and biomarker categories shown above. Negative G3 3. OncotypeDx® is the only multigene panel included to classify Pathologic Positive Prognostic Stage because prospective Level I data supports this use for patients Positive with a score less than 11. Future updates to the staging system may include Negative Negative results from other multigene panels to assign cohorts of patients to Prognostic Positive IIIC Stage Groups based on the then available evidence. Inclusion or exclusion in this Negative staging table of a genomic profile assay is not an endorsement of any specific Negative assay and should not limit appropriate clinical use of any genomic profile assay Any T Any N M1 Any Any Any Any IV based on evidence available at the time of treatment. ***N1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2 N1, T3 N1 and T4 N1, respectively. Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. ST-11 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion ABBREVIATIONS APBI accelerated partial breast LFTs liver function tests TNBC triple-negative breast cancer irradiation LVEF left ventricular ejection fraction BCS breast-conserving surgery LVI lymphovascular invasion WBRT whole breast radiation therapy CPS combined positive score NAC nipple-areolar complex ctDNA circulating tumor NST no special type deoxyribonucleic acid DCIS ductal carcinoma in situ OS overall survival ER estrogen receptor PBI partial breast irradiation EPC encapsulated papillary pCR complete pathological carcinoma response PR Progesterone Receptor FNA fine-needle aspiration RNI regional nodal irradiation HER2 human Epidermal Growth RS recurrence score Factor Receptor 2 HR hormone receptor SLN sentinel lymph node SLNB sentinel lymph node biopsy IBC inflammatory breast cancer SPC solid papillary carcinoma IBTR ipsilateral breast tumor recurrence SNRI selective serotonin reuptake inhibitors IHC immunohistochemistry SSRI serotonin and norepinephrine IMRT intensity modulated radiation reuptake inhibitors therapy ISH in situ hybridization ABBR-1 Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 NCCN Guidelines Index Table of Contents Breast Cancer Discussion NCCN Categories of Evidence and Consensus Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. All recommendations are category 2A unless otherwise indicated. NCCN Categories of Preference Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, Preferred intervention affordability. Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; intervention or significantly less affordable for similar outcomes. Useful in certain Other interventions that may be used for selected patient populations (defined with recommendation). circumstances All recommendations are considered appropriate. Version 5.2023, 12/05/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. CAT-1 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Discussion This discussion corresponds to the NCCN Guidelines for Breast Cancer. The section for DCIS and Locoregional Management of Invasive Breast Cancer was updated on May 7th, 2022. The update to the rest of the Discussion is in progress. Table of Contents Special Situation Overview Paget’s Disease ........................................................................ MS-76 Literature Search Criteria and Guidelines Update Methodology MS-2 Phyllodes Tumors of the Breast ................................................. MS-78 Ductal Carcinoma in Situ (Tis, N0, M0) Breast Cancer During Pregnancy .............................................. MS-79 Workup for DCIS .......................................................................... MS-3 Inflammatory Breast Cancer ...................................................... MS-81 Primary Treatment for DCIS ......................................................... MS-4 Stage T4d, N0- N3, M0 .......................................................... MS-81 Management of DCIS After Primary Treatment ............................. MS-8 Workup .................................................................................. MS-81 Invasive Breast Cancer Axillary Breast Cancer ............................................................... MS-84 Workup for Non-metastatic (M0) Invasive Breast Cancer ............ MS-10 References Locoregional Treatment of cT1–3, cN0 or cN+, M0 Disease ...... MS-13 Breast Reconstruction …………………………………………..MS-26 Systemic Therapies (Preoperative and Adjuvant) ....................... MS-30 Post-Therapy Surveillance and Follow-up .................................. MS-50 Recurrent/Stage IV Breast Cancer Staging and Workup for Recurrent and Stage IV Breast Cancer . MS-53 Management of Locally Recurrent Disease ................................ MS-54 Management of Recurrent or Stage IV Disease .......................... MS-55 Monitoring Metastatic Disease ................................................... MS-74 Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-1 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer The potential relevance of the PubMed search was examined. The data Overview from key PubMed articles selected by the panel for review during the Breast cancer is the most common malignancy in females in the United Guidelines update meeting as well as articles from additional sources States and is second only to lung cancer as a cause of cancer death. The deemed as relevant to these Guidelines and discussed by the panel have American Cancer Society has estimated that 290, 560 Americans will be been included in this version of the Discussion section. Recommendations diagnosed with breast cancer and 43, 780 will die of disease in the United for which high-level evidence is lacking are based on the panel’s review of States in 2022.1 The therapeutic options for patients with noninvasive or lower-level evidence and expert opinion. The complete details of the invasive breast cancer are complex and varied. These NCCN Clinical Development and Update of the NCCN Guidelines are available on the Practice Guidelines for Breast Cancer include up-to-date guidelines for NCCN webpage. clinical management of patients with carcinoma in situ, invasive breast cancer, Paget’s disease, phyllodes tumor, inflammatory breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multi-disciplinary panel of representatives from NCCN member institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. Literature Search Criteria and Guidelines Update Methodology Prior to the update, an electronic search of the PubMed database was performed to obtain key literature in Breast Cancer: Breast Cancer, Breast Neoplasms, DCIS, Inflammatory Breast Cancer OR Phyllodes. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.2 The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-2 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Ductal Carcinoma in Situ (Tis, N0, M0) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and The diagnosis of DCIS has increased since the introduction and increased Pancreatic. utilization of screening mammography. According to the American Cancer The role of MRI in management of DCIS remains unclear. MRI has been Society, over 50,000 cases of DCIS of the female breast will be diagnosed prospectively shown to have a sensitivity of up to 98% for high-grade in 2022 in United States.1 DCIS.10 In a prospective, observational study of 193 patients with pure Workup for DCIS DCIS who underwent both mammography and MRI imaging preoperatively; 93 (56%) patients were diagnosed by mammography and The recommended workup and staging of DCIS includes history and 153 (92%) were diagnosed by MRI (P < .0001). Of the 89 patients with physical examination; bilateral diagnostic mammography; pathology high-grade DCIS, 43 (48%) who were not diagnosed by mammography review; determination of tumor estrogen receptor (ER) status; and MRI, as were diagnosed by MRI alone.10 However, other studies suggest that MRI indicated. can overestimate the extent of disease.11 Therefore, the surgical decisions for performing a mastectomy for DCIS should not be solely based on MRI For pathology reporting, the NCCN Panel endorses the College of findings alone. If MRI findings suggest more extensive disease than is American Pathologists (CAP) Protocol for both invasive and noninvasive seen on mammography such that a markedly larger resection is required carcinomas of the breast.3 for complete excision, the findings should be verified histologically through The NCCN Panel recommends testing for ER status in order to determine MRI-guided biopsy of the more extensive enhancement. Studies the benefit of adjuvant endocrine therapy or risk reduction. This is in performed to determine whether the use of MRI reduces re-excision rates accordance with the American Society for Clinical Oncology (ASCO)/CAP and decreases local recurrence in patients with DCIS show conflicting guidelines,4 which recommend that ER testing of newly diagnosed DCIS to results. While several studies suggest no reduction in re-excision rates in determine potential benefit of endocrine therapies for breast cancer risk patients with pure DCIS undergoing breast-conserving surgery (BCS) reduction and progesterone receptor (PR) testing be considered optional. following MRI compared with those who did not undergo preoperative Although the tumor HER2 status is of prognostic significance in invasive MRI,12,13 some have demonstrated a reduction in re-excision rate with use cancer, its importance in DCIS has not been established. To date, studies of preoperative MRI for DCIS.14,15 One study showed an additional cancer have either found unclear or weak evidence of HER2 status as a detection rate of 6.2% with preoperative MRI15 Therefore, the use of prognostic indicator in DCIS,5-8 and no statistically significant benefit to the preoperative MRI remains controversial. The NCCN Panel recommends use of trastuzumab concurrently with radiation in HER2-amplified DCIS.9 only performing breast MRI for DCIS in select circumstances where The NCCN Panel has concluded that HER2 status for DCIS does not alter additional information is warranted during the initial workup, noting that the the management strategy and therefore is not recommended for DCIS. use of MRI has not been shown to increase likelihood of negative margins or decrease conversion to mastectomy for DCIS. Genetic counseling is recommended if the patient is considered to be at high risk for hereditary breast cancer as defined by the NCCN Guidelines Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-3 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Primary Treatment for DCIS In contrast, several population-based studies suggest beneficial effects of The goal of primary therapy for DCIS is to prevent progression to invasive WBRT for DCIS after BCS, for example, the use of WBRT in patients with breast carcinoma. Management strategies for DCIS treatment include higher-risk DCIS (eg, higher nuclear grade, younger age, larger tumor surgery (mastectomy or BCS), and/or radiation therapy (RT), followed by size) was demonstrated to be associated with a modest but statistically adjuvant endocrine therapy in eligible patients to reduce risk of recurrence. significant improvement in OS.27 In another observational study of the SEER database including 140,366 patients with DCIS, the 15-year breast The choice of local treatment does not impact overall disease-related cancer mortality rate was 1.7% for those treated with breast-conserving survival; therefore, the individual’s preferences for risk-reduction must be therapy (BCT) versus 2.3% for patients treated with BCS alone (HR, 0.77; considered. 95% CI, 0.67–0.88; P < .001), demonstrating a small but significant reduction in breast cancer mortality with BCS and WBRT compared with Several prospective randomized trials of pure DCIS have shown that the BCS alone.28 addition of whole breast radiation therapy (WBRT) after BCS decreases the rate of in-breast disease recurrence,16-23 but not distant metastasis-free RT Boost: The use of RT boost has been demonstrated to provide a small survival.24 A meta-analysis of four large multicenter randomized trials but statistically significant reduction in ipsilateral breast tumor recurrence confirmed the results of the individual trials, demonstrating that the (IBTR) risk (4% at 20 years) in all age groups for invasive breast addition of WBRT after BCS for DCIS provides a statistically and clinically cancers.29-32 significant reduction in ipsilateral breast events (hazard ratio [HR], 0.49; 95% confidence interval [CI]; 0.41–0.58, P < .00001).25 However, these A pooled analysis of patient-level data from 10 academic institutions trials did not show that the addition of RT has an overall survival (OS) evaluated outcomes of pure DCIS patients, all treated with BCS and benefit. The long-term follow-up of the NSABP B-17 showed that at 15 WBRT (n = 4131) who either received RT boost with a median dose of 14 years, RT resulted in a 52% reduction of ipsilateral invasive recurrence Gy (n = 2661) or received no boost (n = 1470). The median follow-up of compared with excision alone (HR, 0.48; 95% CI, 0.33–0.69, P < .001).22 patients was 9 years. A decrease in IBTR was seen in patients who The OS and cumulative all-cause mortality rates through 15 years were received a boost compared with those who did not at 5 years (97.1% vs. similar between the two groups (HR for death, 1.08; 95% CI, 0.79–1.48).22 96.3%), 10 years (94.1% vs. 92.5%), and 15 years (91.6% vs. 88.0%) (P = Similar findings were reported by a large observational study of the SEER .0389 for all). The use of RT boost was associated with significantly database that included 108,196 patients with DCIS.26 In a subgroup decreased IBTR across the entire cohort of patients (HR, 0.73; 95% CI, analysis at 10 years, of 60,000 patients treated with BCS, with or without 0.57–0.94; P = .01).33 In a multivariate analysis that took into account WBRT, a 50% reduction in the risk of ipsilateral recurrence (adjusted HR, factors associated with lower IBTR, including grade, ER positive status, 0.47 [95% CI, 0.42–0.53]; P < .001) was associated with the addition of use of adjuvant tamoxifen, margin status, and age, the benefit of RT boost WBRT. However, in this study, breast cancer-specific mortality was found still remained statistically significant (HR, 0.69; 95% CI, 0.53–0.91; P < to be similar (HR, 0.86 [95% CI, 0.67–1.10]; P = .22).26 .010).33 Even in patients considered very low risk based on negative margins status (defined as no ink on tumor as per National Surgical Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-4 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Adjuvant Breast and Bowel Project (NSABP) definition, or margins >2 mm BCS alone were 94% for patients with low-risk DCIS and 83% for patients as per Society of Surgical Oncology [SSO]/American Society for Radiation with both intermediate- and high-risk DCIS.36 In another retrospective Oncology [ASTRO]/ASCO definition), the RT boost remained statistically study of 215 patients with DCIS treated with BCS without RT, or systemic significant for decreasing the rate of local relapse. risk reduction therapy, the recurrence rates over 8 years were 0%, 21.5%, and 32.1% in patients with low-, intermediate-, or high-risk DCIS, Similar to invasive cancers, though RT boost was beneficial in all age respectively.37 The stratification for risk of recurrence in this retrospective groups studied, the magnitude of the absolute benefit of the boost was study was calculated using the modified Van Nuys Prognostic Index based greatest in younger patients. Two randomized phase III trials are studying on tumor grade, size, absence of comedo necrosis, margin width, and age whether an RT boost reduces recurrence in patients with DCIS at diagnosis.37 (ClinicalTrials.gov Identifiers: NCT00470236 and NCT00907868). These trials have completed accrual and are now in active follow-up. A A multi-institutional, non-randomized, prospective study of selected recent publication on the health-related quality of life (HRQOL) in patients patients with low-risk DCIS treated without radiation has also provided enrolled in the BIG 3-07/TROG 07.01 phase III trial (NCT00470236) some support for BCS alone without radiation.40 Patients were enrolled showed that after 2 years, the cosmetic status was impacted negatively onto one of two low-risk cohorts: 1) low- or intermediate-grade DCIS, with the boost versus no boost, suggesting the importance of informed tumor size 2.5 cm or smaller (n = 561); or 2) high-grade DCIS, tumor size shared decision-making regarding addition of boost until data related to 1 cm or smaller (n = 104). Protocol specifications included excision of the impact on local recurrence and OS are published.34 According to the 5- DCIS tumor with a minimum negative margin width of at least 3 mm. Only year data from this trial, presented at the 2021 annual San Antonio Breast 30% of the patients received tamoxifen. Of note, margins were Cancer Symposium (SABCS) meeting, 93% of patients in the group who substantially wider than the 3-mm protocol requirement in many patients did not receive a boost were free from local recurrence compared with (ie, the low-/intermediate-risk patient group margins were ≥5 mm in 62% of 97% in the group who received an RT boost (HR, 0.47; 95% CI, 0.31– patients and >10 mm or no tumor on re-excision in 48% of patients).40 0.72; P < .001).35 The peer-reviewed publication of these data is awaited. Although the rate of IBTR was acceptably low for the low-/intermediate- grade group at 5 years, at a median follow-up of 12.3 years, the rates of Breast Conserving Surgery Alone Without WBRT: RT adds to treatment developing an IBTR were 14.4% for low-/intermediate-grade and 24.6% cost and is accompanied by adverse effects. Therefore, in an attempt to for high-grade DCIS (P = .003). This suggests that IBTR events may be de-escalate treatment and limit morbidity and preserve quality of life delayed but not prevented in the seemingly low-risk population. (QOL), several trials have examined omission of RT in carefully selected low-risk patients. The RTOG 9804 trial investigated outcomes of RT omission in the setting of low-risk DCIS, randomizing 636 patients with low-risk disease to either There are retrospective series suggesting that selected patients have a RT or observation after surgery.23 In this study, low risk consisted of low- low risk of in-breast recurrence when treated with excision alone (without to intermediate-grade DCIS measuring less than 2.5 cm, with negative WBRT).36-39 For example, in one retrospective review, 10-year margins of greater than or equal to 3 mm. With a median follow-up of 7 disease-free survival (DFS) rates of 186 patients with DCIS treated with Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-5 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer years, a reduced risk of local recurrence was seen with use of RT A study retrospectively reviewed a database of 2996 patients with DCIS compared with observation (0.9% vs. 6.7%; HR, 0.11; 95% CI, 0.03–0.47). who underwent BCS to investigate the association between margin width No difference was seen in either DFS or OS. With a follow-up of 15 years, and recurrence, controlling all other characteristics.49 Wider margins were local recurrence rates were reduced by 50% with RT versus without RT significantly associated with a lower rate of recurrence only in patients who (7.1% vs. 15.1%; HR, 0.36; 95% CI, 0.20–0.66).41 did not receive RT (P < .0001), but not in those treated with radiation (P = .95).49 The available evidence from four randomized trials (NSABP B-39/RTOG 0413,42 OCOG-RAPID,43 University of Florence,44 and GEC-ESTRO45) of According to the DCIS Consensus Guideline on Margins by patients with breast cancer (tumors ≤3 cm) has shown that accelerated SSO/ASTRO/ASCO, the use of at least a 2-mm margin in DCIS treated partial breast irradiation (APBI) delivered with multi-catheter brachytherapy with WBRT is associated with low rates of IBTR.46 Additional factors to is non-inferior in local control compared with WBRT, with similar toxicity consider in assessing adequacy of excision for DCIS include presence of and breast cosmetic outcomes. Patients with DCIS constituted 25%,18%, residual calcifications, which margin is close (anterior against skin or 8.8%, and 6% of patients in the NSABP B-39/RTOG 0413, OCOG RAPID, posterior against muscle versus medial, superior, inferior, or lateral), and University of Florence, and GEC-ESTRO trials, respectively. Per the life expectancy of the patient. Notably, in situations where DCIS is ASTRO guideline for APBI, patients with screen-detected DCIS measuring admixed with invasive carcinoma, the SSO/ASTRO/ASCO Consensus less than 2.5 cm, with grade I or II disease, and with negative margins of 3 Guideline on Margins for invasive breast cancer should be utilized, which mm or more are “suitable’ candidates for APBI.46 supports “no tumor on ink” as an adequate margin applying to both the invasive and noninvasive components in this mixed tumor scenario. Margin Status After Breast-Conserving Therapy: Prospective randomized trials have not been carried out to analyze whether wider margins can Mastectomy: Patients with DCIS and evidence of widespread disease (ie, replace the need for RT for DCIS. Results from a retrospective study of disease involving two or more quadrants) on diagnostic mammography or 445 patients with pure DCIS treated by excision alone indicated that other imaging, physical examination, or biopsy may require mastectomy. margin width was the most important independent predictor of local recurrence, although the trend for decreasing local recurrence risk with For DCIS patients undergoing mastectomy, or for local excision in an increasing margin width was most apparent with margins less than 1 mm anatomic location that could compromise the lymphatic drainage pattern to compared to greater than or equal to 10 mm.47 In a meta-analysis of 4660 the axilla (eg, tail of the breast), a sentinel lymph node biopsy (SLNB) patients with DCIS treated with BCS and radiation, a surgical margin of procedure should strongly be considered at the time of definitive surgery less than 2 mm was associated with increased rates of IBTR compared to avoid necessitating a full axillary lymph node (ALN) dissection for with margins of 2 mm, although no significant differences were observed evaluation of the axilla.50-53 Since only a small proportion of patients (about when margins of greater than 2 mm to 5 mm or greater than 5 mm were 25%) with seemingly pure DCIS on initial biopsy will have invasive breast compared with 2-mm margins.48 cancer at the time of the definitive surgical procedure54 and will ultimately require ALN staging, ALN dissection (ALND) is not recommended unless Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-6 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer there is pathologically documented invasive cancer or ALN metastatic the absolute reduction of in-breast recurrence may not be large enough to disease in patients (by either biopsy or SNLB). justify the risks associated with RT. Therefore, according to the NCCN Panel, it may be reasonable to omit RT in such cases. NCCN Recommendations for Primary Treatment of DCIS Contraindications to BCT are listed in the algorithm (Special Trials are ongoing to determine if there might be a selected favorable Considerations to Breast Conservation Therapy Requiring RT). Patients biology DCIS subgroup where surgical excision is not required. Until such treated with mastectomy are appropriate candidates for breast time that definitive evidence regarding the safety of this non-surgical reconstruction (see Principles of Breast Reconstruction Following approach is demonstrated, the NCCN Panel continues to recommend Surgery). surgical excision for all DCIS. According to the NCCN Panel, complete resection should be documented According to the NCCN Panel, primary treatment options for patients with by analysis of margins and specimen radiography. Post-excision DCIS along with their respective categories of consensus are: mammography can be considered for any uncertainty about adequacy of 1) BCS plus WBRT with or without boost (category 1). While considering the excision remains (eg, the mass and/or microcalcifications are not RT boost for DCIS, the NCCN Panel recommends an individualized clearly within the specimen). Clips may be used to delineate the tumor bed approach based on patient preference and other factors such as longevity. and ensure adequate coverage with radiation, provide design of boost and The NCCN Panel notes that WBRT following BCS reduces IBTR rates in APBI fields, and provide markers should additional surgery be required DCIS by about 50% to 70%. For DCIS patients treated with BCS alone pending the pathologic margin status review. (without radiation), irrespective of margin width, the risk of IBTR is substantially higher than treatment with excision followed by WBRT (even For patients with pure DCIS treated by BCS and WBRT, a quantitative for predefined low-risk subsets of DCIS patients). description of any tumor close to margin is helpful as a resection width of 2) Total mastectomy, with or without SLNB with optional reconstruction at least 2 mm is associated with a reduced risk of IBTR relative to (category 2A). narrower negative margin widths. The routine practice of obtaining 3) BCS plus APBI in carefully selected cases (category 2A). According to margins greater than 2 mm to further improve outcomes is not supported the panel, select patients with low-risk DCIS may be considered suitable by the evidence. When there is only minimal or focal DCIS involvement for APBI if they meet all aspects of the definition of RTOG 9804 low-risk near the margin, clinical judgment should be utilized to weigh the risks of DCIS or ASTRO “suitable” DCIS for APBI. re-excision with risk of recurrence for an individual patient. 4) BCS alone (category 2B). The option of BCS alone should be considered only in cases where the patient and the physician view the For patients with DCIS treated with excision alone (no WBRT), regardless individual as having a low risk of disease recurrence. For patients with of margin width, there is a substantially higher rate of IBTR than treatment low-risk disease that has been fully resected with negative margins and with excision and WBRT, even in predefined, low-risk patients. Although particularly if they are ER-positive and will be receiving endocrine therapy, the optimal margin width for treatment with excision alone is unknown, it Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-7 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer should be at least 2 mm, with some evidence suggesting improved IBTR breast cancers in the ipsilateral breast, compared with 7.3% invasive and rates with margin widths wider than 2 mm. 7.2% noninvasive recurrences for those treated with placebo. The cumulative 10-year frequency of invasive and noninvasive breast cancer in For DCIS with microinvasion (DCIS-M), defined as an invasive focus 1 mm the contralateral breast was 6.9% and 4.7% in the placebo and tamoxifen or smaller in size, the optimal margin width should refer to the DCIS groups, respectively. No differences in OS were noted. A retrospective margin definition (≥2 mm), given that the majority of DCIS-M is comprised analysis of ER expression in NSABP B-24 suggests that increased levels of DCIS and the natural history and systemic therapy utilization for DCIS- of ER expression predict for tamoxifen benefit in terms of risk reduction for M more closely reflect the treatment pattern for pure DCIS than for ipsilateral and contralateral breast cancer development following BCT.59 invasive carcinoma. A phase III trial randomized patients with excised DCIS to receive WBRT Management of DCIS After Primary Treatment or no WBRT and tamoxifen versus no tamoxifen.21 The randomization was Tamoxifen: DCIS falls between atypical ductal hyperplasia (ADH) and independent for each of the two treatments (RT and tamoxifen). With 12.7 invasive ductal carcinoma within the spectrum of breast proliferative years of median follow-up, the use of tamoxifen decreased all new breast abnormalities. The Breast Cancer Prevention Trial performed by NSABP events (HR, 0.71; 95% CI, 0.58–0.88; P = .002). The use of tamoxifen showed a 75% reduction in the occurrence of invasive breast cancer in decreased ipsilateral and contralateral breast events in the subjects not patients with ADH treated with tamoxifen.55,56 These data also showed that given WBRT (ipsilateral HR, 0.77; 95% CI, 0.59–0.98; contralateral HR, tamoxifen led to a substantial reduction in the risk of developing invasive 0.27; 95% CI, 0.12–0.59), but not in those receiving WBRT (ipsilateral HR, breast disease.57 The Early Breast Cancer Trialists’ Collaborative Group 0.93; 95% CI, 0.50–1.75; P = .80; contralateral HR, 0.99; 95% CI, 0.39– (EBCTCG) overview analysis showed that, with 5 years of tamoxifen 2.49; P = 1.0). therapy, patients with ER-positive or receptor-unknown invasive tumors had a 39% reduction in the annual odds of recurrence of invasive breast The standard dose of tamoxifen is 20 mg/day for 5 years. The phase III cancer.58 TAM-01 trial studied a lower dose of tamoxifen (5 mg for 3 years) in 501 patients with breast intraepithelial neoplasia including DCIS, lobular Similarly, the NSABP B-24 trial found a benefit from tamoxifen for patients carcinoma in situ (LCIS), and ADH. The rate of recurrence of either with DCIS after treatment with breast conservation surgery and RT. In that intraepithelial neoplasia or invasive breast cancer was 5.7% among those study, patients with DCIS who were treated with BCT were randomized to receiving tamoxifen 5 mg daily versus 11.9% for those receiving placebo receive placebo or tamoxifen. At a median follow-up of 13.6 years, (HR, 0.48; 95% CI, 0.25–0.89) at a median follow-up of 5.1 years.60 The patients who received tamoxifen had a 3.4% absolute reduction in relative risk (RR) reduction with low-dose tamoxifen seen in the TAM-01 ipsilateral in-breast tumor recurrence risk (HR, 0.30; 95% CI, 0.21–0.42; P trials is consistent with that seen in trials that used a higher dose of < .001) and a 3.2% absolute reduction in contralateral breast cancers (HR, tamoxifen, but the rate of severe toxicity compared with placebo was less. 0.68; 95% CI, 0.48–0.95; P = .023).22 The patients receiving tamoxifen had a 10-year cumulative rate of 4.6% for invasive and 5.6% for noninvasive Anastrozole: In patients with ER-positive and/or PR-positive DCIS treated by wide local excision with or without RT, a large, randomized, Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-8 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer double-blind, placebo-controlled trial (IBIS-II) compared anastrozole (n = for postmenopausal patients with hormone receptor (HR)-positive DCIS 1471) with tamoxifen (n = 1509). The results demonstrated non-inferiority treated with BCS and RT, with a different toxicity profile. of anastrozole to tamoxifen.61 After a median follow-up of 7.2 years, 67 recurrences were reported with anastrozole versus 77 for tamoxifen (HR, Surveillance after treatment for DCIS helps early recognition of disease 0.89; 95% CI, 0.64–1.23). A total of 33 deaths were recorded for recurrences (either DCIS or invasive disease) and evaluation and anastrozole and 36 for tamoxifen (HR, 0.9393; 95% CI, 0.58–1.50; P = management of therapy-related complications. The majority of recurrences .78).61 Although the number of patients reporting any adverse event was of DCIS are in-breast recurrences after BCT, and recurrences mostly similar between anastrozole (n = 1323, 91%) and tamoxifen (n = 1379, occur in close proximity to the location of the prior disease. Overall, 93%), the side-effect profiles of the two drugs were different. There were approximately one-half of the local recurrences after initial treatment for a more fractures, musculoskeletal events, hypercholesterolemia, and pure DCIS are invasive in nature, whereas the remainder recur as pure strokes reported with anastrozole and more muscle spasms, gynecologic DCIS. cancers and symptoms, vasomotor symptoms, and deep vein thromboses NCCN Recommendations for Management of DCIS After Primary reported with tamoxifen. The NSABP B-35 study randomly assigned 3104 Treatment postmenopausal patients with hormone-positive DCIS treated with According to the NCCN Panel, in patients with ER-positive DCIS treated lumpectomy and radiation to either tamoxifen or anastrozole for 5 years. with BCT, endocrine therapy with tamoxifen (for premenopausal and Prior to being randomly assigned, patients were stratified by age—under postmenopausal patients) or an aromatase inhibitor (for postmenopausal 60 years or over 60 years. The primary endpoint was breast cancer-free patients, especially those < 60 years of age or in those with concerns of interval.62 Anastrozole treatment resulted in an overall statistically embolism) may be considered as a strategy to reduce the risk of ipsilateral significant decrease in breast cancer-free interval events compared with breast cancer recurrence (category 1 for those undergoing BCT followed tamoxifen (HR, 0.73; 95% CI, 0.56–0.96; P = .0234). The significant by RT; category 2A for those undergoing excision alone). The benefit of difference in breast cancer-free interval between the two treatments was endocrine therapy for ER-negative DCIS is not known. Low-dose apparent in the study only after 5 years of follow-up. The estimated tamoxifen (5 mg/day for 3 years) is an option only if the 20-mg standard- percentage of patients with a 10-year breast cancer-free interval was dose of tamoxifen is not tolerated (see DCIS-2). 89.1% in the tamoxifen group and 93.1% in the anastrozole group.62 In addition, anastrozole resulted in further improvement in breast cancer-free Follow-up of patients with DCIS includes interval history and physical interval in younger postmenopausal patients (<60 years of age). With examination every 6 to 12 months for 5 years and then annually, as well respect to adverse effects, the overall incidence of thrombosis or as yearly diagnostic mammography. In patients treated with BCT, the first embolism was higher in the tamoxifen group while the anastrozole group follow-up mammogram should be performed 6 to 12 months after the had slightly more cases of arthralgia and myalgia.62 completion of RT (category 2B) (see DCIS-2). Patients receiving endocrine therapy for risk reduction should be monitored as described in Results of the IBIS-II and the NSABP-B-35 studies indicate that the NCCN Guidelines for Breast Cancer Risk Reduction. anastrozole provides at least a comparable benefit as adjuvant treatment Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-9 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Invasive Breast Cancer review of the utility of MRI showed conflicting outcome results— one with Workup for Non-metastatic (M0) Invasive Breast Cancer benefit74 and another without.75 One systematic review66 documented that breast MRI staging altered surgical treatment in 7.8% to 33.3% of The recommended workup of localized invasive breast cancer (listed on patients;66 however, no differences in local recurrence or survival have BINV-1) includes a history and physical exam. Complete blood count been demonstrated. In addition, there is no evidence that use of breast (CBC) and liver function tests (LFTs) have no added benefit in the MRI increases rates of margin-negative resection.76,77 detection of underlying metastatic disease in patients with asymptomatic early-stage breast cancers.63 In addition, monitoring of disease relapse Breast MRI may assist with identification and management of clinically with any tumor markers is not recommended. occult primary tumors presenting with axillary nodal metastases.78 In patients with Paget disease not identifiable on mammography, breast MRI Imaging: Imaging with bilateral diagnostic mammography is may help determine the extent of disease.79,80 Breast MRI also has utility recommended; breast ultrasonography is recommended only if necessary. in screening patients with higher than average risk based on family The use of MRI in the workup remains controversial. Breast MRI history.81 advocates note its high sensitivity for evaluation of extent of disease, If breast MRI imaging is performed, a dedicated breast coil, an imaging particularly for invasive cancer and in dense breasts where team experienced with reading breast MRI and performing MRI-guided mammographically occult disease is more likely to elude preoperative biopsy, and multidisciplinary management are the standard of care. detection. MRI detractors note that MRI has a high percentage of false-positive findings, resulting in further diagnostic workup—including According to the NCCN Panel, the use of MRI is optional and is not MRI-guided biopsy—in many circumstances.64-66 MRI findings tend to universally recommended by experts in the field. Breast MRI may be used overestimate extent of disease,67 resulting in increased frequency of for staging evaluation to define extent of cancer, in the adjuvant or mastectomies.68-71 neoadjuvant setting, to detect the presence of multifocal or multicentric cancer in the ipsilateral breast, or as screening of the contralateral breast MRI findings alone are not sufficient to determine whether BCT is optimal, cancer at time of initial diagnosis. Additional indications for breast MRI as additional tissue sampling is needed to verify true malignant disease include: clinical axillary metastasis with an occult primary cancer; Paget warranting excision. MRI use may increase mastectomy rates by disease of the nipple with breast primary not identified by other breast identifying areas of mammographically occult disease that may have been imaging modalities or physical examination; follow-up screening of adequately treated with radiation after BCS had the disease remained patients with prior mammographically undetected breast cancers; and undiscovered without MRI.71 those whose lifetime risk of a second primary breast cancer is greater than Two prospective randomized studies have examined the utility of 20% (based on models largely dependent on family history). preoperative MRI in determining disease extent, and neither demonstrated Pathology Assessment: A central component of the treatment of breast improvement in rates of re-excision after initial BCS.72,73 Retrospective cancer is full knowledge of extent of disease and biologic features. Full Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-10 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer knowledge of extent of disease and biologic features is central to the use of the CAP protocols for reporting the pathologic analysis of all breast treatment of breast cancer. cancer specimens.4 The specimens should be oriented for the pathologist, and specific Genetic Counseling: For patients considered to be at high risk for requests for determination of biomarkers should be stated (eg, ER, PR, hereditary breast cancer as defined by the NCCN Guidelines for and HER2 status). The panel also recommends testing for Ki-67 if HR- Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, positive, HER2-negative, and considering adjuvant abemaciclib. genetic counseling is recommended. Accurate pathology reporting requires communication between the Distress Assessment: Levels of distress may vary in patients and should clinician and the pathologist relating to relevant patient history, prior breast be addressed individually. Psychological distress can be impacted by body biopsies, prior irradiation to the chest, pregnancy status, characteristics of image and other factors. Younger patients have higher rates of the abnormality biopsied (eg, palpable, mammographically detected psychosocial distress than patients diagnosed at older ages.82-86 The microcalcifications), clinical state of lymph nodes, presence of NCCN Breast Cancer Panel recommends assessing for distress in inflammatory change or other skin abnormality, and any prior treatment patients newly diagnosed with breast cancer using guidance from NCCN administered (eg, chemotherapy, radiation therapy). The specimens Guidelines for Distress Management. should be oriented for the pathologist, and specific requests for determination of biomarkers should be stated. The use of consistent, Fertility and Sexual Health: unambiguous standards for reporting is strongly encouraged. Data from The general considerations for fertility and sexual health/function outlined both national and local surveys show that as many as 50% of pathology for specific populations in NCCN Guidelines for Adolescent and Young reports for breast cancer are missing some elements critical to patient Adult (AYA) Oncology and NCCN Guidelines for Survivorship are management.12,13 Significant omissions include failure to orient and report applicable to all patients diagnosed with breast cancer. The panel surgical margins and failure to report tumor grade consistently. The recommends referring to those guidelines for guidance. College of American Pathologists (CAP) has developed pathology reporting protocols to promote complete and standardized reporting of Numerous epidemiologic studies have demonstrated that childbearing malignant specimens. CAP provides a protocol for each disease site that after treatment for invasive breast cancer does not increase rates of includes cancer case summaries (checklists) along with background recurrence or death from breast cancer.87 The offspring of pregnancies documentation. These checklists form the basis for a synoptic, after treatment for breast cancer do not have an increased rate of birth standardized reporting of pathologic findings. The checklists are available defects or other serious childhood illness. However, treatment for breast without charge through the CAP website at www.cap.org. Consistent, cancer, especially with cytotoxic agents, may impair fertility and fertility unambiguous, and complete pathology reporting is a cornerstone of may wane during the 5 to 10 years of adjuvant endocrine therapy. quality breast cancer care. The NCCN Breast Cancer Panel endorses the Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-11 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer While the potential to regain menstrual function within 2 years of with respect to the protective effects of GnRH agonists in fertility completing chemotherapy is possible, especially for those younger than preservation. age 35,88 resumption of menses does not correlate with fertility, and conversely, fertility may be preserved without menses. Therefore, all Patients should be informed of all the various modalities available to premenopausal patients should be informed about the potential impact of minimize gonadal damage and preserve ovarian function and future chemotherapy on fertility and offered the option of fertility preservation if fertility. The fertility specialist should discuss specifics of fertility future childbearing is desired. preservation options including hormonal interventions, ovarian stimulation, embryo or oocyte cryopreservation, and other investigational options, as Considerations for fertility preservation should incorporate patient well as the probability of successful gestation and childbirth.103,104 preference, tumor stage and biology, age of the patient, risk of premature ovarian failure based on anticipated type and duration of chemotherapy Combining the various modalities for a specific patient may increase the and/or endocrine therapy, as well as the timing and duration allowed for odds of preservation of future fertility. It is important for fetal safety that fertility preservation. patients actively avoid becoming pregnant during breast cancer treatment. Several studies report lower rates of fertility discussion among female Additional Diagnostic Workup patients with cancer89-91 despite the updated ASCO guidelines stating that The panel has reiterated that routine systemic imaging is not indicated for patients should not be excluded from consideration for discussion of patients with early-stage breast cancer in the absence of signs/symptoms fertility preservation for any reason, including parity, prognosis, age, and of metastatic disease. Recommendations for additional metastatic workup socioeconomic status.92 The NCCN Panel recommends that all treating should be performed for those patients with signs or symptoms suspicious physicians should have a discussion with their patients of childbearing for metastatic disease, based on lack of evidence to demonstrate any potential regarding the options for fertility preservation. Patients who benefits with metastatic workup in early-stage disease.105-107 In one study, desire to bear children after systemic therapy should be referred to a metastases were identified by bone scan in 5.1%, 5.6%, and 14% of fertility specialist prior to initiating systemic (chemotherapy or endocrine) patients with stage I, II, and III disease, respectively, and no evidence of therapy.92-98 metastasis was detected by liver ultrasonography or chest radiography in patients with stage I or II disease.105 For patients with stage III breast Randomized trials have demonstrated that GnRH agonists (such as cancer, the prevalence of a positive liver ultrasound and positive chest goserelin) administered prior to initiating chemotherapy and then x-ray was 6% and 7%, respectively.105 administered concurrently with adjuvant chemotherapy protect against ovarian failure and reduce the risk of early menopause.99-101 In one trial CBC, comprehensive metabolic panel, liver function, and alkaline goserelin improved the probability of pregnancy from 11% to 21% in phosphatase tests should be considered only if the patient is a candidate patients with HR-negative early-stage breast cancer.102 Smaller historical for preoperative or adjuvant systemic therapy (BINV-12). A bone scan or experiences in patients with HR-positive disease have conflicting results sodium fluoride PET/CT is indicated in patients presenting with localized bone pain or elevated alkaline phosphatase. Bone scan or sodium fluoride Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-12 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer PET/CT may not be needed if FDG PET/CT is performed and clearly refer to www.NCCN.org. Radiation is typically sequenced after definitive indicates bone metastasis, on both the PET and CT component. surgery and after systemic chemotherapy (if delivered). A diagnostic chest CT is indicated only if pulmonary symptoms (ie, cough Several randomized trials document that mastectomy is equivalent to or hemoptysis) are present. Likewise, abdominal and pelvic imaging using BCT, which includes BCS with WBRT with respect to OS as primary diagnostic CT or MRI is indicated if the patient has elevated alkaline treatment for the majority of patients with stage I and stage II breast phosphatase, abnormal results on LFTs, abdominal symptoms, or cancers (category 1).112-116 The optimal choice of surgery is based on a abnormal physical examination of the abdomen or pelvis. shared decision made by the patient and clinician after discussing benefits and risks of mastectomy versus BCT in regards to long-term survival, risk FDG PET/CT may be performed at the same time as diagnostic CT, and of local recurrence, and the impact on cosmetic outcome and overall QOL. may be helpful in situations where standard staging studies are equivocal or suspicious. FDG PET/CT may also be helpful in identifying unsuspected Breast Conserving Surgery regional nodal disease and/or distant metastases when used in addition to BCS allows patients to preserve their breast without sacrificing oncologic standard staging studies. The routine use of FDG PET/CT scanning is not outcome. BCS is contraindicated for patients who are pregnant and would recommended in the staging of clinical stage I, II, or operable III (T3,N1) require radiation during pregnancy; have diffuse suspicious or breast cancer, due to its high false-negative rate for the detection of malignant-appearing microcalcifications on mammography; have lesions that are small (<1 cm) and/or low-grade disease, the high rate of widespread disease that cannot be incorporated by local excision of a false-positive scans in patients without locally advanced disease, the low single region or segment of the breast tissue with a satisfactory cosmetic sensitivity for detection of axillary nodal metastases, and the low result; have diffusely positive pathologic margins; or have homozygous probability of these patients having detectable metastatic disease.108-111 (biallelic) inactivation for ATM mutation (category 2B). Relative contraindications to lumpectomy include previous RT to the breast or Locoregional Treatment of cT1–3, cN0 or cN+, M0 Disease chest wall; active connective tissue disease involving the skin (especially Surgery scleroderma and lupus); persistently positive pathologic margin; or in Patients with early-stage operable breast cancer initially undergo upfront those with a known or suspected genetic predisposition to breast cancer definitive surgery (BCS or mastectomy), and adjuvant systemic therapy, if who may have an increased risk of ipsilateral breast recurrence or indicated, based on primary tumor characteristics, such as tumor size, contralateral breast cancer with BCT or who may be considered for grade, lymph node involvement, ER/PR status, expression of HER2 prophylactic bilateral mastectomy for risk reduction as per the criteria in receptor, and tumor genomics. Some patients with early-stage operable the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, HER2-positive or triple-negative disease may be treated with preoperative Ovarian, and Pancreatic or may have known or suspected Li-Fraumeni systemic therapy first, followed by surgery. For NCCN Panel syndrome (category 2B). recommendations and consideration for preoperative systemic therapy, Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-13 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Several studies of patients with early-stage breast cancer treated with among all age, ER status, and cancer stage groups.131 Data from another BCS have identified young age as a significant predictor of an increased meta-analysis found no absolute reduction in risk of distant metastases likelihood of IBTRs after BCT.117-119 Risk factors, such as a family history with risk-reducing mastectomy.132 Furthermore, among patients with of breast cancer or a genetic predisposition for breast cancer (ie, BRCA1/2 unilateral breast cancer who have an increased familial/genetic risk, a or other cancer predisposing mutation), are more likely to exist in the decrease in metastatic contralateral breast cancer incidence was population of young patients with breast cancer, thereby confounding the observed in those who received risk-reducing contralateral mastectomy, independent contributions of age and treatment to clinical outcome.120 although no improvement was seen in OS of these patients.132 With respect to OS outcomes for young patients with breast cancer, BCT The panel recommends that patients with breast cancer who are less than or mastectomy are similar.114,115,121-123 Some studies have shown improved or equal to 35 years or premenopausal and carriers of a known BRCA1/2 survival124-126 and fewer post-surgical complications127 with BCS. mutation consider additional risk reduction strategies following appropriate risk assessment and counseling (see NCCN Guidelines for Breast Risk Mastectomy Reduction and NCCN Guidelines for Genetic/Familial High-Risk Mastectomy is indicated for patients who are not candidates for BCS or Assessment: Breast, Ovarian, and Pancreatic). This process should those who choose to undergo this procedure over BCS. involve multidisciplinary consultations prior to surgery, and should include a discussion of the risks associated with development of a contralateral Only limited data are available on the survival impact of risk-reducing breast cancer as compared with the risks associated with recurrent contralateral mastectomy in patients with a unilateral breast cancer.128 disease from the primary cancer. Except as specifically outlined in NCCN Analysis of patients included in the SEER database treated with Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, mastectomy for a unilateral breast cancer from 1998 to 2003 showed that and Pancreatic), risk reduction mastectomy of the contralateral breast to a contralateral risk-reducing mastectomy performed at the time of treatment known unilateral breast cancer treated with mastectomy or BCT is of a unilateral cancer was associated with a reduction in breast discouraged by the panel. cancer-specific mortality only in the population of young patients (18–49 years of age) with stage I/II, ER-negative breast cancer (HR, 0.68; 95% The NCCN Panel recommends referring to the NCCN Guidelines for Older CI, 0.53–0.88; P = .004).129 The 5-year breast cancer survival for this Adult Oncology for special considerations for this population. group was only slightly improved with contralateral risk-reducing mastectomy versus without (88.5% vs. 83.7%, difference = 4.8%).129 Margin Assessment: After surgical resection, a careful histologic These differences observed in retrospective analysis could be due to assessment of resection margins is essential. The NCCN Panel notes that selection bias among patients who chose risk-reducing contralateral benefit of BCS is predicated on achieving pathologically negative margins mastectomy.130 A statistical simulation of survival outcomes after risk- after resection. The NCCN Panel accepts the most recent definition reducing contralateral mastectomy among patients with stage I or II breast outlined in the guidelines established by the SSO/ASTRO as the standard cancer with no BRCA mutation found that the absolute 20-year survival for negative surgical margins for invasive cancer.133 benefit from risk-reducing contralateral mastectomy was less than 1% Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-14 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer For patients with stage I or II invasive cancers after BCS, a positive margin than WBRT. Individualized clinical judgment should be utilized on a case- is defined as “ink on tumor” (any invasive cancer or DCIS cells on ink). by-case basis, using postoperative mammography to identify residual Patients with positive margins generally require further surgery—either a calcifications and clinical-pathologic factors such as quantitative extent of re-excision to achieve a negative margin or a mastectomy. If re-excision is disease near margin, presence of extensive intraductal component (EIC), technically feasible to achieve “no ink on tumor,” this can be done with young age, or multiple close margins to assist in identifying patients who resection of the involved margin guided by the orientation of the initial may have an increased risk of ipsilateral recurrence and therefore may resection specimen or re-excision of the entire original excision cavity. benefit from re-excision. There may be select patients with stage III invasive cancers who may be eligible for BCS. For these patients, the margin status would be assessed Surgical Axillary Staging with similar definitions. If margins remain positive after further surgical Axillary status is important for planning systemic adjuvant treatment and re-excision(s), then mastectomy may be required for optimal local disease RT. The lymphatic pathways from the breast go to the ALNs, internal control. mammary, infraclavicular, and/or supraclavicular lymph nodes. In order to adequately assess margins following surgery, the panel Traditional level I and level II ALNDs require that at least 10 lymph nodes recommends that the surgical specimens be directionally oriented and that be provided for pathologic evaluation to accurately stage the axilla.134,135 the pathologist provide descriptions of the gross and microscopic margin ALND should be extended to include level III nodes only if gross disease is status and the distance, orientation, and type of tumor (invasive cancer or apparent in the level II and I nodes. In the absence of gross disease in pure DCIS) in relation to the closest margin. Marking the tumor bed with level II nodes, lymph node dissection should include tissue inferior to the clips facilitates accurate planning of the radiation boost field, where axillary vein from the latissimus dorsi muscle laterally to the medial border appropriate. of the pectoralis minor muscle (level I and II). For invasive breast cancers that have a component of DCIS, the negative Historically, ALND has been the standard of care for axillary staging.136 margin definition of “no ink on tumor” should be utilized based on the However, ALND is associated with lymphedema and other significant SSO/ASTRO Consensus Guideline on Margins unless it is DCIS with morbidities.137-139 This has been largely replaced with SLNB. microinvasion, which behaves more like pure DCIS and 2-mm margins are recommended. In this setting, “no ink on tumor” is recommended for either SLN mapping injections may be peritumoral, subareolar, or subdermal. DCIS or invasive cancer cells, primarily because the natural history, SLNs can be assessed for the presence of metastases by both treatment, and outcomes of these lesions are more similar to invasive hematoxylin and eosin (H&E) staining and cytokeratin cancer than DCIS. For specifically challenging cases, clinical judgment immunohistochemistry (IHC). The clinical significance of a lymph node that and discussion with the patient should precede routine re-excision. is negative by H&E staining but positive by cytokeratin IHC is not clear. Because the historical and clinical trial data on which treatment decisions The same margin recommendations cannot be applied directly to patients are based have relied on H&E staining, the panel does not recommend undergoing APBI, where data regarding local recurrence are more limited Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-15 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer routine cytokeratin IHC to define node involvement and believes that The ACOSOG Z0011 trial addressed the role of ALND in those with a current treatment decisions should be made based solely on H&E staining. clinically negative axilla but pathologically positive lymph nodes from an This recommendation is further supported by a randomized clinical trial SLNB. This trial randomized patients greater than or equal to 18 years of (ACOSOG Z0010) for patients with H&E negative nodes where further age with clinical T1/T2 tumors, fewer than 3 positive SLNs, undergoing examination by cytokeratin IHC was not associated with improved OS over BCS and WBRT, to SLNB alone (n = 436) or to a completion ALND (n = a median of 6.3 years.140 In the uncommon situation in which H&E staining 420). In this study, there was no difference in local recurrence, DFS, or OS is equivocal, reliance on the results of cytokeratin IHC is appropriate. between patients with positive SLN undergoing a completion ALND versus no ALND. Only ER-negative status, age less than 50, and lack of adjuvant Two randomized trials compared SLNB alone versus ALND. The Milan systemic therapy were associated with decreased OS.149 At a median trial (1998–1999) randomized 516 patients treated with BCS with tumors follow-up of 6.3 years, locoregional recurrences were noted in 4.1% of up to 2 cm to two arms, one receiving immediate axillary dissection and patients in the ALND group and 2.8% of patients in the SLNB group (P = the other receiving the dissection only if the sentinel node was involved.141 .11). Median OS was approximately 92% in each group.150 Long-term After 79 months follow-up, there was no difference in OS and DFS.142 follow-up (median 9.25 years) results of the ACOSOG Z0011 study showed no statistically significant difference in local recurrence-free Another similar study, (NSABP) B-32, conducted between 1999 and 2004, survival (RFS) between trial arms (P = .13).151 The cumulative incidence of randomized 5611 patients with invasive breast cancer up to 2 cm to either ipsilateral axillary recurrences at 10 years was 0.5% (2 patients) in those ALND or SLNB alone with ALND performed only if the SLN was who underwent ALND and 1.5% (5 patients) in those who underwent positive.143 After 95.6 months of follow-up, OS and DFS were similar in the SLNB alone (P = .28).151 The 10-year cumulative incidence of locoregional two groups. Results of a subgroup analysis of this study showed patients recurrences was 6.2% with ALND and 5.3% with SLNB alone (P = .36).151 with ALND had significantly higher arm morbidity and significantly more restricted work and social activity and impaired QOL.144,145 The results of the ACOSOG Z0011 trial demonstrate that there is no benefit to ALND in patients with early-stage breast cancer who have only The ALMANAC trial studied the QOL in patients with SLNB versus ALND one or two SLN metastases (minimal nodal burden) on SLNB after in 1031 patients.146 After 12 months, lymphedema and sensory loss were receiving WBRT as part of BCT. Mastectomy patients were not enrolled in higher in the ALND group. Operative time, drainage use, hospitalization, the ACOSOG Z0011 trial since these patients do not routinely receive and resumption of normal life were much longer in ALND compared to the radiation. SLNB group. The SNAC trial147 and the DBCCG trial148 also showed less morbidity with SLNB compared with ALND. Another randomized trial (IBCSG 23-01) was specifically designed to compare outcomes in patients with sentinel micrometastases (≤2 mm) Based on the results of the above studies, it was clarified that for negative treated with ALND versus no ALND.152 While the ACOSOG Z0011 trial sentinel nodes, ALND is not needed. was limited to those undergoing BCT, this trial included patients undergoing mastectomy (9%).152 Between the group treated with SLNB Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-16 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer plus ALND versus the group that had SLNB alone, there were no The OTOASAR trial was designed similarly to the AMAROS trial; patients differences in 5-year DFS (84.4%; 95% CI, 80.7%–88.1% vs. 87.8%; 95% (n = 2100) with tumors less than or equal to 3.0 cm who were clinically CI, 84.4%–91.2%); cumulative incidence of breast cancer events, node negative were randomized to receive either ALND or axillary RT if including local, regional, contralateral breast, and distant recurrence they had 1 to 2 positive SLNs.155 The results showed no difference in (10.8%; 95% CI, 7.6–14.0 vs. 10.6%; 95% CI, 7.5–13.8); or OS (97.6%; axillary recurrence with ALND compared with SLNB plus RT to the 95% CI, 96.0%–99.2% vs. 97.5%; 95% CI, 95.8%–99.1%).152 Regional axilla.155 recurrence was less than 1% for those who underwent ALND and 1% for those who did not undergo ALND.152 The results of this trial show that in In the setting of preoperative chemotherapy, the question that is being patients with micrometastases on SLNB, ALND is not needed. explored is whether ALND may be omitted in patients with complete pathologic response after preoperative therapy. The results of a trial by the European EORTC group (AMAROS) assessed whether axillary RT provides regional control with fewer side effects Several prospective studies have evaluated patients with positive lymph compared with ALND.153 This trial included patients (n = 4823) with T1 or nodes before preoperative systemic therapy who had clinical complete T2 breast cancer with positive SLNs randomized to an ALND or axillary response to preoperative therapy and underwent SLNB and ALND. The RT. One thousand four hundred twenty-five patients had positive SLNs results of these studies have shown that in those with node-positive (micrometastatic or macrometastatic), which included a small fraction of disease prior to preoperative systemic therapy, SLNB has a greater than patients (n = 248) treated with mastectomy (17%).153 The results reported 10% false-negative rate when performed after preoperative systemic no difference in 5-year OS or DFS for patients randomized to ALND therapy. In the SENTINA study,156 the overall false-negative rate was versus axillary radiation.153 The 5-year DFS was 86.9% (95% CI, 84.1– 14.2%. In the ACOSOG-Z1071 trial,157 the false-negative rate was 12.6% 89.3) in the ALND group and 82.7% (79.3–85.5) in the axillary RT group. and in the SN FNAC trial,158 the false-negative rate was 13.3%. The 5-year OS was 93.3% (95% CI, 91.0–95.0) in the ALND group and Subgroup analyses from studies have shown that 1) using dual-agent 92.5% (90.0–94.4) in the axillary RT group.153 At the end of 5 years, lymphatic mapping (radiotracer and blue dye); 2) identifying three or more lymphedema was less frequent in the group treated with axillary RT versus SLNs; and 3) marking the metastatic lymph node with a clip before ALND (11% vs. 23%).153 The 10-year follow-up results presented at the neoadjuvant therapy and then resecting it at the time of surgery reduces 2021 SABCS showed no significant differences between the two arms with false-negative rates to less than 10%. respect to OS (with ALND, OS was 84.6% vs. 81.4% with axillary RT), distant metastasis-free survival (with ALND was 81.7% vs. 78.2% with A subgroup analysis of the ACOSOG Z1071 trial showed lower false- axillary RT), or locoregional recurrence rate (3.59% with ALND vs. 4.07% negative rates in patients who had a clip placed in the positive lymph with axillary RT). The axillary recurrence with axillary RT was 1.8% versus nodes at the time of initial biopsy followed by removal of the clipped node 0.93% with ALND.154 during SLN surgery after preoperative systemic therapy.159 A another study of selective localization and removal of clipped nodes with SLN biopsy, known as targeted axillary dissection (TAD), showed false- Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-17 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer negative rates reduced to approximately 2% compared with 4% with negative axillae but 1 to 2 positive SLNs, the panel notes that axillary removal of the clipped lymph node alone.160 radiation may replace ALND for regional control of disease. Based on the results of the IBCSG 23-01 trial, the NCCN Panel recommends no ALND Several ongoing clinical trials are examining further de-escalation of for patients with positive SLNs when that disease is limited to only axillary surgery in those who have positive nodes after preoperative micrometastatic. According to the American Joint Committee on Cancer systemic treatment. The Alliance A011202/MAC19 trial (NCT01901094) is (AJCC) staging, micrometastatic nodal involvement is defined as a randomly assigning patients who have sentinel node–positive disease metastatic deposit or greater than 0.2 mm but less than or equal to 2.0 after neoadjuvant chemotherapy to ALND versus no further axillary mm.161 surgery. Both arms will receive regional nodal radiation. The SLNB alone arm will include axillary RT to the undissected axilla (levels I–III), whereas In patients with clinically suspicious (palpable) lymph nodes or 3 or more the ALND arm will not include RT to levels I or II axillae. suspicious lymph nodes on imaging, or if preoperative systemic therapy is being considered for patients with suspicious lymph nodes at diagnosis on NCCN Recommendations for Surgical Axillary Staging: If ALNs are exam or imaging, the panel recommends pathologic confirmation of clinically negative (no palpable nodes) at the time of diagnosis, 2 or fewer malignancy using ultrasound-guided fine-needle aspiration (FNA)162 or suspicious lymph nodes are found on imaging, or 2 or fewer positive core biopsy of suspicious nodes with clip placement. lymph nodes are confirmed by needle biopsy, the panel recommends SLN mapping. According to the NCCN Panel, the recommendation for ALND of level I and II nodes is limited to patients with biopsy-proven axillary metastases If SLN is negative, no further surgery is needed in these patients. If SLN is (in those who did not receive preoperative systemic therapy) or who have positive, based on the ACOSOG Z 0011 data, no further surgery is residual disease after preoperative chemotherapy. Highly selected recommended only if all of the following criteria are met: the patients have patients with biopsy-proven axillary metastases, who then converted to cT1-2, N0 tumors, have not received preoperative systemic therapy, only clinically node negative after preoperative systemic therapy, may undergo have 1 or 2 positive SLNs, and will undergo BCT (BCS + WBRT). If any of SLNB with removal of the clipped lymph node. This is a currently a the above criteria are not met, the panel recommends level I and II axillary category 2B recommendation as the rate of false negatives is high when dissection. SLN is performed after preoperative systemic therapy. Based on the AMAROS and OTASAR trial data, no further surgery is According to the NCCN Panel, based on available data, the false-negative recommended only if all of the following criteria are met: the patients have rate can be reduced by marking biopsied lymph nodes to document their cT1-2, N0 tumors, have not received preoperative systemic therapy, have removal, using dual tracer, and by removing 3 or more sentinel nodes 1 to 2 positive SLNs, and will undergo lumpectomy or mastectomy along (targeted ALND). When sentinel nodes are not successfully identified, the with adjuvant RT with intentional inclusion of undissected axilla at risk. If panel recommends level I and II axillary dissection be performed for any of the above criteria are not met, the panel recommends level I and II axillary staging. axillary dissection. In select patients undergoing mastectomy with clinically Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-18 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Radiation Therapy standard 50 Gy in single fractions of 2 Gy.168-171 The 10-year follow-up data from the START trials172 are consistent with the 10-year results of the Principles of Radiation Therapy Canadian trial,171 which reported that local tumor control and breast It is important to individualize RT planning and delivery. CT-based cosmesis were similar with a regimen of 42.5 Gy in 16 fractions over 3.2 treatment planning is encouraged to delineate target volumes and weeks compared with the standard dose of 50 Gy in 25 fractions over 5 adjacent organs at risk. Greater target dose homogeneity and sparing of weeks.171 The START trials reported radiation-related effects to normal normal tissues can be accomplished using compensators such as breast tissue such as breast shrinkage, telangiectasia, and breast edema wedges, forward planning using segments, and intensity-modulated RT as less common with the hypofractionated regimen.172 (IMRT). Respiratory control techniques including deep inspiration breath-hold and prone positioning may be used to try to further reduce Another randomized trial showed similar outcomes among patients dose to adjacent normal tissues, particularly the heart and lung.163 receiving a hypofractionated schedule (40 Gy in 15 fractions) compared Verification of treatment setup consistency is done with weekly imaging. with standard fractionation (50 Gy in 25 fractions) in patients (n = 1854) When using certain techniques (ie, prone breast), more frequent imaging with node-negative breast cancer (n = 1608) or DCIS (n = 246).173 The 9- may be appropriate. Standard utilization of daily imaging is not year risk of locoregional recurrence was 3.3% in the 50-Gy group and recommended. Radiation to the breast/chest wall and nodal regions is 3.0% in the 40-Gy group. The 9-year OS was 93.4% in the 50-Gy group generally delivered with single-energy or mixed-energy photons with or and 93.4% in the 40-Gy group. Radiation-associated cardiac and lung without electrons. Dose-volume histograms (DVHs) should be used to disease were comparable between the groups. evaluate dose constraints, evaluate dose to normal tissues (ie, heart, lung), and ensure adequate coverage to the intended planning target Other shorter schedules of delivering WBRT have also been studied with volumes (PTVs), including the breast/chest wall, supraclavicular fossa, similar results. The FAST trial compared patients over 50 years of age axillary levels I–III, and internal mammary nodes. with low-risk invasive breast carcinoma (pT1–2, pN0) randomly assigned to the standard schedule of 50 Gy in 25 fractions over 5 weeks or 30 Gy or Whole Breast Radiation Therapy 28.5 Gy in 5 fractions once weekly. After 10-year follow-up, there were no WBRT reduces the risk of local recurrence and has shown to have a significant differences reported in normal tissue effects for the standard 50 beneficial effect on survival.113,116 Randomized trials have demonstrated Gy in 25 fractions schedule versus a once-weekly schedule for 5 weeks decreased in-breast recurrences with an additional boost dose of radiation totaling 28.5 Gy, but normal tissue effects were higher with a weekly (by photons, brachytherapy, or electron beam) to the tumor bed.164,165 For schedule for 5 weeks totaling 30 Gy.174 greater homogeneity of target dose and to spare normal tissues using compensators such as tissue wedges, forward planning using segments The FAST Forward trial randomized patients with non-metastatic breast and IMRT may be used.166,167 cancer (n = 4096) after BCS or mastectomy to one of the following: 40 Gy in 15 fractions over 3 weeks; 27 Gy in 5 fractions over 1 week; or 26 Gy in Four randomized clinical trials have investigated hypofractionated WBRT 5 fractions over 1 week to either whole beast or chest wall.175 The 5-year schedules (39–42.9 Gy in single fractions of 2.6–3.3 Gy) compared to incidence of ipsilateral breast tumor relapse was 2.1% with the standard Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-19 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer 40 Gy in 15 fractions over 3 weeks versus 1.7% with 27 Gy in 5 fractions should be discussed with patients prior to its use. The panel also notes over 1 week (5.4 Gy per fraction; HR, 0.86; 95% CI, 0.51–1.44) and 1.4% that when using ultra-hypofractionated dosing, it is essential to utilize 3-D with 26 Gy in 5 fractions over 1 week (5.2 Gy per fraction; HR, 0.67; 95% planning to minimize inhomogeneity and exposure to heart and lung. CI, 0.38–1.16).175 The moderate or marked tissue effects in the breast or chest wall were 15% with 27 Gy, 12% with 26 Gy, and 10% with 40 Gy, Chest Wall Radiation: but differences between the 40 Gy and 26 Gy groups were not statistically The target includes the ipsilateral chest wall, mastectomy scar, and drain different.175 sites when indicated. Depending on whether the patient has had breast reconstruction, several techniques using photons and/or electrons are RT Boost to Tumor Bed: In patients with higher risk characteristics (such appropriate. Chest wall scar boost may be delivered with or without bolus as age <50 years, high-grade disease, or patients with focally positive using electrons or photons. margins) an RT boost has been shown to reduce local relapse.29,31,165,172,176-178 RT boost treatment in the setting of breast NCCN Recommendations for Chest Wall Radiation: The NCCN Panel conservation can be delivered using enface electrons, photons, or recommends a dose of 45 to 50.4 Gy in 25 to 28 fractions to the chest brachytherapy.179 wall. A boost at the scar of 1.8 to 2 Gy per fraction to a total dose of approximately 60 to 66 Gy may be considered in some cases based on NCCN Recommendations for WBRT: The panel has defined the target as risk. Special consideration should be given to the use of bolus material to breast tissue at risk. The NCCN Panel recommends a dose of 40 to 42.5 ensure that the skin dose is adequate, particularly in the case of Gy in 15 to 16 fractions for all patients getting whole breast radiation inflammatory breast cancer. without regional nodal radiation, based on its equivalence in efficacy and toxicity demonstrated in the moderately hypofractionated trials.172 While Regional Nodal Irradiation these abbreviated courses of RT of 40 to 42.5 Gy in 15 to 16 fractions are Two studies, MA.20 and EORTC 22922/10925, evaluated the addition of the NCCN Panel’s preferred fractionation schema for whole breast regional nodal irradiation (RNI) to the internal mammary nodes and the radiation, the conventionally fractionated regimen of 46 to 50 Gy in 23 to upper axillary nodes including the supraclavicular region, in addition to 25 fractions may be utilized in selected patients. The RT boost doses WBRT or chest wall irradiation after BCS or mastectomy, respectively. In MA.20, regional recurrences were reduced from 2.7% with breast intended to decrease rate of local recurrence are 10 to 16 Gy in 4 to 8 irradiation only to 0.7% with the addition of nodal irradiation.180 The distant fractions. recurrences were reduced from 17.3% to 13.4%.180 An improvement in Ultra-hypofractionated WBRT of 28.5 Gy delivered as 5 (once weekly) DFS was seen from 77% to 82% at 10 years in those who received RNI fractions may be considered in select patients with pTis/T1/T2/N0 aged compared to those who did not.180 In EORTC 22922/10925, regional RT greater than 50 years after BCS, though the optimal fractionation for the reduced the incidence of regional recurrences from 4.2% to 2.7% and decreased the rate of distant metastases from 19.6% to 15.9% at a boost delivery is unknown for this regimen. Alternatively, 26 Gy in 5 daily median follow-up of 10.9 years.181 Results of 15.7 years follow-up showed fractions over one week may be considered, though data beyond 5 years that breast cancer mortality (19.8% vs. 16%; 95% CI, 0.70–0.94) and for local relapse or toxicity are not yet available for this regimen and Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-20 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer breast cancer recurrence (27.1% vs. 24.5%; 95% CI, 0.77%–0.98%) were 15 once-daily fractions using reduced-size breast tangents and found less reduced with internal mammary and medial supraclavicular RT.182 breast firmness, less change in breast appearance, and lower average number of adverse events per person with partial breast irradiation.185,188 The independent contribution of internal mammary nodal RT as a The University of Florence compared WBRT with intensity-modulated component of RNI continues to be debated as it is associated with higher APBI (30 Gy in 5 fractions, delivered every other day), and 10-year results risk of cardiac and lung toxicity, and data regarding its benefits are have shown that APBI produced less acute and late toxicity and better conflicting (discussed in detail below). cosmetic outcomes.186 However, the RAPID trial found significantly higher NCCN Recommendation for RNI: When considering RNI, anatomic rates of fair/poor cosmetic outcome with 3-D conformal APBI delivered as variations across patients result in significant differences in prescription 38.5 Gy in 10 twice-daily fractions.43,189 The majority of APBI patients on depth and field design. The NCCN Panel therefore NSABP B-39 were treated with the same external beam regimen, and recommends contouring the individual nodal basins that are at-risk using treatment-related toxicities were not different for APBI versus WBRT as one of the various breast atlases, to ensure adequate RT coverage. 183,184 currently reported.42 Cosmetic outcome analysis, however, is pending. The recommended dose for RNI is 45 to 50.4 Gy in 25 to 28 fractions to NCCN Recommendation for APBI: The panel accepts the updated ASTRO the regional nodal fields. A supplemental RT boost can be delivered to APBI consensus statement for guidance on APBI use.190 The NCCN Panel grossly involved or enlarged lymph nodes (ie, internal mammary or recommends APBI for any BRCA-negative patient who meets the ASTRO clavicular) that have not been surgically addressed. 2016 “suitable” criteria defined as over age 50 years, ER-positive invasive ductal carcinoma measuring less than or equal to 2 cm (pT1 disease) with Accelerated Partial Breast Irradiation negative margin widths of greater than or equal to 2 mm, and no Several large, randomized trials have been published using various forms lymphovascular invasion (LVI), and also permits APBI in patients over the of APBI rather than WBRT after BCS. Most of these studies have found age of 50 with screen-detected low- or intermediate-grade DCIS that rates of local control in selected low-risk patients with early-stage measuring less than or equal to 2.5 cm, resected with greater than or breast cancer are equal to those treated with WBRT.43,45,185-187 In the equal to 3 mm margins. The panel prefers the APBI regimen and method NSABP B-39 trial, 10-year cumulative incidence of IBTR with APBI was followed in the trial by University of Florence (30 Gy/5 fractions QOD 4.6% compared with 3.9% with WBRT, yielding an absolute difference of delivered using IMRT).186 The panel encourages participation in clinical 0.7% with an HR of 1.22 (90% CI, 0.94–1.58) that did not meet the trials for patients who do not meet the above criteria. prespecified criteria for equivalence.42 However, given the small magnitude in IBTR differences between WBRT and APBI, it is not likely to Adjuvant Radiation Therapy After BCS be of clinical significance in appropriately selected patients. Those who have a positive lymph node have a high risk of recurrence. Therefore, after BCS WBRT is strongly recommended with or without QOL, toxicity, and cosmetic outcomes have generally been comparable or boost to tumor bed for node-positive disease (category 1 for those with slightly favored APBI in randomized trials. For example, the IMPORT-LOW positive nodes; category 2A for those with negative axillary nodes). This study compared WBRT with partial breast irradiation delivered as 40 Gy in Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-21 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer recommendation is supported by the results of a meta-analysis by the mammary nodes in patients (n = 3089) with positive nodes and early- EBCTCG showing reduction in 10-year risk of recurrence in those who stage breast cancer.192 In this study, RT to the internal mammary nodes received WBRT versus those who did not (19% vs. 35%; RR, 0.52; 95% was delivered to right-sided patients (n = 1,491), while no RT to internal CI 0.48-–0.56).116 In addition, a significant reduction in 15-year risk of mammary nodes was delivered to left-sided patients (n = 1,598). The breast cancer death (21% vs. 25%; RR, 0.82; 95% CI, 0.75–0.90) was study reported a 15-year improved OS rate of 60.1% with RT to internal also observed.116 mammary nodes compared to 55.4% with no RT to internal mammary nodes. Improvements were also seen with respect to risk of developing For patients with a pathologically confirmed, focally positive margin without distant recurrence and breast cancer-specific mortality favoring RT to EIC, who do not undergo re-excision after BCS, the use of a higher internal mammary nodes.192 radiation boost dose to the tumor bed may be considered, since generally a boost to the tumor bed is recommended for patients at higher risk of Clinical judgment is needed when determining inclusion of the internal recurrence. mammary nodes during RNI. Therefore, the NCCN Panel no longer specifies the fields that should be included for RNI and refers to it as Regional Nodal Irradiation After BCS comprehensive RNI. According to the panel, patient selection should The reduction in the risk of locoregional and distant recurrence and consider risks versus benefits including long-term organ (cardiac and lung) improvement in DFS seen in the MA.20 and EORTC 22922/10925 toxicities, comorbidities of the patient, age, and life expectancy. In trials,180,181 and the reduction in breast cancer mortality with 15-year follow- including RT to the internal mammary nodes, meticulous treatment up of the EORTC 22922 patients,182 support the importance of RNI after planning with normal tissue dose constraints is mandatory. BCS. RNI After BCS for Node-Negative Disease: The NCCN Panel As mentioned previously, routine inclusion of the internal mammary nodes recommends consideration of comprehensive RNI in patients with as a component of RNI remains somewhat controversial due to the central/medial tumors (in accordance with EORTC 22922 trial criteria) and associated cardiac and lung toxicities. A Korean trial KROG 08-06 studied in accordance with the MA.20 criteria: 3 tumors, as well as those with T2 independent effect on DFS of RT to internal mammary nodes after BCS or tumors who have undergone limited axillary dissection (<10 lymph nodes) mastectomy for node-positive disease,191 randomizing patients to RNI with and also have other risk factors, including high-grade histology, ER- internal mammary RT versus RNI without internal mammary RT. Radiation negative disease, or LVI.180 to the internal mammary nodes did not significantly improve the DFS in RNI After BCS for Node-Positive Disease: For those with 1 to 3 positive patients with node-positive breast cancer. However, there was a statistically significant benefit in outcomes with internal mammary nodal nodes, if a patient meets all of the following criteria—has cT1–T2, cN0; did not receive preoperative chemotherapy; and has 1 to 2 positive SLNs—the RT for patients with medially or centrally located tumors.191 Conflicting use of comprehensive RNI with or without the intentional inclusion of the data have arisen from the Danish Breast Cancer Cooperative Group that axilla is at the discretion of the radiation oncologist. If the patients do not recently reported 15-year follow-up of their study on RT to internal meet all the criteria listed, the NCCN Panel recommends WBRT with Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-22 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer inclusion of any portion of the undissected axilla at risk (category 1) with Randomized clinical trials have shown that a DFS and OS advantage is strong consideration of comprehensive RNI. conferred by the irradiation of chest wall and regional lymph nodes in patients with positive ALNs after mastectomy and ALN dissection.197-201 In For those with 4 or more positive nodes, the NCCN Panel recommends these trials, the ipsilateral chest wall and the ipsilateral locoregional lymph comprehensive RNI with inclusion of any portion of the undissected axilla nodes were irradiated. The results of EBCTCG meta-analyses show that at risk (category 1). RT after mastectomy and axillary node dissection reduced both recurrence and breast cancer mortality in the patients with 1 to 3 positive lymph nodes Radiation Therapy After BCS in Older Adults with ER-Positive Tumors even when systemic therapy was administered.181,202 According to the WBRT as a component of BCT does not affect breast cancer-specific NCCN Panel, post-mastectomy radiation to the chest wall is survival in selected patients over 70 years of age with more indolent recommended in all of these patients (category 1). Data from the EORTC disease. In a study of patients with clinical stage I, ER-positive breast 22922/10925 trial support the inclusion of RNI in patients undergoing post- cancer who were greater than or equal to 70 years of age at diagnosis, mastectomy radiation. The trial assessed the independent effects of patients were randomized to receive BCS with WBRT or BCS alone, both including RNI versus no RNI when treating the chest wall after with tamoxifen for 5 years. Locoregional recurrence rates were 1% in the mastectomy. Based on the benefits demonstrated in this trial, the NCCN BCS, radiation, and tamoxifen arm and 4% in the BCS plus tamoxifen arm. Panel recommends comprehensive RNI to include any undissected axilla There were no differences in OS, DFS, or need for mastectomy.193 These at risk (category 1 for 1 or more positive nodes). results were confirmed in an updated analysis of this study with a median follow-up of 12.6 years.194 At 10 years, a statistically significant reduction Post-Mastectomy RT for Node-Negative Disease: in IBTR was seen with RT with 90% of patients in the BCS and tamoxifen In patients with negative nodes, tumor less than or equal to 5 cm, and arm compared with 98% in the BCS plus radiation and tamoxifen arm.194 clear margins (≥1 mm), post-mastectomy RT is typically not Concordant results have been demonstrated in other studies of similar recommended. However, the panel has noted that it may be considered in design.195,196 Whether the increase in local relapse without RT is relevant subsets of these patients with high-risk features. Based on the inclusion for an individual patient should be individualized after a discussion of the criteria of node-negative patients enrolled onto the RNI trials (MA-20 and risks and benefits of RT and patient commitment to 5 years of endocrine EORTC 22922), any patients with the following high-risk features, therapy if RT omission is being considered. including central/medial tumors, T3 tumors, or tumors greater than or The NCCN Guidelines allow for the use of BCS (pathologically negative equal to 2 cm with fewer than 10 axillary nodes removed and at least one margin required) with 5 years of tamoxifen or an aromatase inhibitor, of the following: grade 3, ER-negative, or LVI, should be considered for without breast irradiation, for patients over 70 years of age with clinically PMRT with RNI to include any undissected axilla at risk. Features in negative lymph nodes and ER-positive, T1 breast cancers (category 1). node-negative tumors that predict a high rate of local recurrence include primary tumors greater than 5 cm or positive pathologic margins.203 Adjuvant Radiation Therapy After Mastectomy Post-Mastectomy RT for Node-Positive Disease Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-23 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer In patients with positive pathologic margin, if re-resection to negative benefit of RNI. Until the results of this trial become available, the existing margins is not possible, the panel recommends strongly considering chest data suggest that node-positive disease at presentation is at high risk for wall irradiation with the addition of comprehensive RNI including any locoregional recurrence and should be considered to receive portion of the axilla at risk. Chest wall irradiation should be considered with comprehensive RNI with inclusion of any portion of the undissected axilla addition of comprehensive RNI, including any portion of the axilla at risk in at risk. those with tumors greater than 5 cm. In patients with tumors less than or equal to 5 cm and negative margins but less than or equal to 1 mm, chest Patients who have clinically/radiographically positive nodes at diagnosis wall irradiation should be considered with consideration of comprehensive who convert to clinically/radiographically negative nodes after preoperative RNI including any portion of the undissected axilla at risk only in those with chemotherapy, but are found to have persistent nodal disease on SLNB, are candidates for the ALLIANCE 11202 trial assessing whether ALND high-risk features. can be safely replaced with axillary RT. ALND is the standard arm of this trial; however, in the event that a neoadjuvant therapy patient with node- Considerations for RT in Patients Receiving Preoperative Systemic positive disease (ypN1+) does not undergo a complete axillary dissection, Therapy all levels of the undissected axilla should be included with the radiation The panel recommends that decisions related to administration of adjuvant treatment. RT for patients receiving preoperative systemic chemotherapy should be made based on maximal stage (ie, clinical/anatomic stage, tumor RT After Preoperative Therapy and Mastectomy: characteristics) at diagnosis (before preoperative systemic therapy) and Those who have clinically positive nodes at diagnosis that respond to pathologic stage at definitive surgery (after preoperative systemic preoperative systemic therapy and become node-negative should be therapy). Data from numerous studies in patients with stage III disease strongly considered to receive RT to the chest wall and comprehensive suggest that postoperative RT improves local control even for patients RNI with inclusion of any portion of the undissected axilla at risk based on who have a pathologic complete response (pCR) to neoadjuvant the discussion above. chemotherapy.204-207 For those with positive nodes (ypN1+) after preoperative systemic therapy, RT After Preoperative Therapy and BCS: Those who have clinically negative nodes at diagnosis, that remain axillary dissection is the standard treatment arm of the ongoing Alliance pathologically node-negative at definitive surgery (after systemic therapy), 11202 trial; however, if RT is indicated it should include chest wall along should receive adjuvant RT to the whole breast with the addition of boost with comprehensive RNI with inclusion of any portion of the undissected to the tumor bed after SLNB. axilla at risk. Patients who have clinically/radiographically positive nodes at diagnosis Those who have node-negative disease at diagnosis and after and convert to clinically/radiographically node negative after preoperative preoperative systemic therapy and whose axilla was assessed by SLNB or chemotherapy are candidates for the NSABP B-51 trial assessing the axillary node dissection may forego RT. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-24 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Two prospective trials are ongoing and will prospectively evaluate the When adjuvant olaparib is used, the panel recommends that olaparib be benefit of RT in patients treated with neoadjuvant therapy (NSABP B- given after completion of RT. In the OlympiA trial,215 olaparib was not 51/RTOG 1304 [NCT01872975] and the Alliance A011202/MAC19 trial administered concurrently with RT and there are limited data on safety of [NCT01901094]). concurrent administration. Sequencing of RT and Systemic Therapy: Adjuvant HER2-targeted therapy may be delivered concurrently with RT. Data from clinical trials in the adjuvant setting do not suggest an increased If chemotherapy and radiation are indicated after surgery, adjuvant complication rate with the concurrent administration of HER2-targeted radiation is typically delivered after the completion of chemotherapy.208,209 therapies with adjuvant RT.216 This recommendation is based on results of the “Upfront-Outback” trial in which patients who had undergone BCS and axillary dissection were randomly assigned to receive chemotherapy following RT or RT following chemotherapy. The initial results showed an increased rate of local recurrence in the group with delayed RT at a median follow-up of 58 months;209 however, differences in rates of distant or local recurrence were not statistically significant when the two arms were compared at 135-month follow-up.208 While it is common for RT to follow chemotherapy when chemotherapy is indicated, based on data from prospective and retrospective studies, CMF (cyclophosphamide/methotrexate/fluorouracil) and RT may be given concurrently. Data from multiple studies of patients treated with endocrine therapy either before, during, or after RT suggest no difference in outcomes or toxicity.210-213 Therefore, according to the NCCN Panel, sequential or concurrent endocrine therapy with RT is acceptable. However, due to compounding side effects, initiating endocrine therapy at the completion of RT may be preferred. When adjuvant capecitabine214 is indicated, since it is a known radiosensitizing agent with potential to increase toxicity to normal tissue, it should be given after completion of adjuvant RT. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-25 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Breast Reconstruction Breast Reconstruction after Mastectomy Breast reconstruction may be an option for any woman receiving surgical Mastectomy results in loss of the breast for breastfeeding, loss of treatment for breast cancer. Therefore, all patients undergoing breast sensation in the skin of the breast and nipple-areolar complex (NAC), and cancer treatment should be educated about breast reconstructive options loss of the breast for cosmetic, body image, and psychosocial purposes. as adapted to their individual clinical situation and be offered an The loss of the breast for cosmetic, body image, and psychosocial issues opportunity to consult with a reconstructive plastic surgeon. Breast may be partially overcome through the performance of breast reconstruction should not interfere with the appropriate surgical reconstruction with or without reconstruction of the NAC. management. This may increase the risk of overall and cancer-related Those undergoing mastectomy should be offered consultation regarding death especially in those with late stage disease.217 Coordinating options and timing of breast reconstruction. consultation and surgical treatment with a reconstructive surgeon should be executed within a reasonable timeframe. Many factors must be considered in the decision-making about breast reconstruction. There are several different types of breast reconstruction Several reconstructive approaches are summarized for these patients in that include the use of implants, autogenous tissues, or both.223-225 the NCCN Guidelines for Breast Cancer under Principles of Breast Reconstruction with implants can be performed either by immediate Reconstruction Following Surgery. placement of a permanent subpectoral implant or initial placement of a The decision regarding type of reconstruction includes patient preference, subpectoral expander implant followed by gradual expansion of the body habitus, smoking history, comorbidities, plans for irradiation, and implant envelope with stretching of the pectoralis major muscle and expertise and experience of the reconstruction team. Smoking and obesity overlying skin followed by replacement of the expander with a permanent increase the risk of complications for all types of breast reconstruction implant. A wide variety of implants are available that contain saline, whether with implant or flap.218-222 Smoking and obesity are therefore silicone gel, or a combination of saline and silicone gel inside a solid considered a relative contraindication to breast reconstruction by the silicone envelope. NCCN Panel. Patients should be informed of increased rates of wound Autogenous tissue methods of reconstruction use various combinations of healing complications and partial or complete flap failure among smokers fat, muscle, skin, and vasculature from donor sites (i.e., abdomen, buttock, and obese patients. back) that may be brought to the chest wall with their original blood supply Reconstruction is an optional procedure that does not impact the (pedicle flap) or as free flaps with microvascular anastomoses to supply probability of recurrence or death, but it is associated with an improved blood from the chest wall/thorax.226 Several procedures using autologous quality of life for many patients. It is sometimes necessary to perform tissue are available including transverse rectus abdominis myocutaneous surgery on the contralateral breast (i.e., breast reduction, implantation) to flap, latissimus dorsi flap, and gluteus maximus myocutaneous flap achieve optimal symmetry between the ipsilateral reconstructed breast reconstruction. and the contralateral breast. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-26 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Composite reconstruction techniques use implants in combination with staged approach with immediate tissue expander placement followed by autogenous tissue reconstruction to provide volume and symmetry. implant placement. Immediate placement of an implant in patients Patients with underlying diabetes or who smoke tobacco have increased requiring postoperative radiation has an increased rate of capsular rates of complications following autogenous tissue breast cancer contracture, malposition, poor cosmesis, and implant exposure. Surgery to reconstruction, presumably because of underlying microvascular disease. exchange the tissue expanders with permanent implants can be performed prior to radiation or after completion of radiation therapy. Reconstruction can be performed either at the time of the mastectomy known as “immediate breast reconstruction” and under the same In a previously radiated patient, the use of tissue expanders/implants is anesthetic or in a delayed fashion any time, known as “delayed breast relatively contraindicated.230 Tissue expansion of irradiated skin can result reconstruction.” In many cases, breast reconstruction involves a staged in a significantly increased risk of capsular contracture, malposition, poor approach requiring more than one procedure such as surgery on the cosmesis, implant exposure, and failed reconstruction.231,232 If a patient contralateral breast to improve symmetry, revision surgery involving the has previously received radiation therapy to the breast, autologous tissue breast and/or donor site, and/or nipple and areola reconstruction and reconstruction is the preferred method of breast reconstruction. tattoo pigmentation. Skin-sparing Mastectomy Plans for post-mastectomy radiation therapy can impact decisions related Skin-sparing mastectomy procedures are appropriate for some patients to breast reconstruction since there is a significantly increased risk of and involve removal of the breast parenchyma including the NAC while implant capsular contracture following irradiation of an implant. preserving the majority of the original skin envelope, and are followed by Furthermore, postmastectomy irradiation may have a negative impact on immediate reconstruction with autogenous tissue, a prosthetic implant, or breast cosmesis when autologous tissue is used in immediate breast a composite of autogenous tissue and an implant. Skin-sparing reconstruction, and may interfere with the targeted delivery of radiation mastectomy involving preservation of the skin of the NAC has become the when immediate reconstruction is performed using either autologous subject of increased attention. Possible advantages of this procedure tissue or breast implants.227,228 Some studies, however, have not found a include improvements in breast cosmesis, body image, and nipple significant compromise in reconstruction cosmesis after radiation sensation following mastectomy, although the impact of this procedure on therapy.229 The preferred approach to breast reconstruction for irradiated these quality-of-life issues has not been well-studied.233-235 There are patients was a subject of controversy among the panel. While some limited data from surgical series, with short follow-up, that suggest that experienced breast cancer teams have employed protocols in which performance of NAC-sparing mastectomy in selected patients is immediate tissue reconstructions are followed by radiation therapy, associated with low rates of occult involvement of the NAC with breast generally radiation therapy is preferred to precede autologous cancer and local disease recurrence.234,236,237 NAC-sparing procedures reconstruction due to the reported loss in reconstruction cosmesis may be an option in patients who are carefully selected by experienced (category 2B). When implant reconstruction is planned in a post multidisciplinary teams. According to the NCCN Panel, when considering a mastectomy patient requiring radiation therapy, the NCCN Panel prefers a NAC-sparing procedure, assessment of nipple margins is mandatory. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-27 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Retrospective data support the use of NAC-sparing procedures for mastectomy following the same selection criteria as for standard patients with breast cancer with low rates of nipple involvement and low mastectomy. rates of local recurrence due to early-stage, biologically favorable (i.e., Breast Reconstruction after Lumpectomy Nottingham grade I or 2, node-negative, HER2-negative, no lymphovascular invasion) invasive cancers and/or DCIS that are Issues related to breast reconstruction also pertain to those who undergo peripherally located in the breast (>2 cm from nipple).238,239 or have undergone a lumpectomy, particularly in situations where the Contraindications for nipple preservation include evidence of nipple surgical defect is large and/or expected to be cosmetically unsatisfactory. involvement such as Paget’s disease or other nipple discharge associated An evaluation of the likely cosmetic outcome of lumpectomy should be with malignancy and/or imaging findings suggesting malignant performed prior to surgery. Oncoplastic techniques for breast conservation involvement of nipple and subareolar tissues. Several prospective trials can extend breast-conserving surgical options in situations where the are underway to evaluate NAC-sparing mastectomy in the setting of resection by itself would likely yield an unacceptable cosmetic outcome.246 cancer and enrollment in such trials is encouraged. The evolving field of oncoplastic surgery includes the use of “volume displacement” techniques performed in conjunction with a large partial Advantages of a skin-sparing mastectomy procedure include an improved mastectomy.247 Oncoplastic volume displacement procedures combine the cosmetic outcome resulting in a reduction in the size of the mastectomy removal of generous regions of breast tissue (typically designed to scar and a more natural breast shape, especially when autologous tissue conform to the segmentally distributed cancer in the breast) with is used in reconstruction,240 and the ability to perform immediate “mastopexy” techniques in which remaining breast tissues are shifted reconstruction. Although no randomized studies have been performed, together within the breast envelope to fill the resulting surgical defect and results of several mostly retrospective studies have indicated that the risk thereby avoid the creation of significant breast deformity. Volume of local recurrence is not increased when patients receiving skin-sparing displacement techniques are generally performed during the same mastectomies are compared with those undergoing non-skin–sparing operative setting as the breast-conserving lumpectomy by the same procedures. However, strong selection biases almost certainly exist in the surgeon who is performing the cancer resection.247,248 identification of patients appropriate for skin-sparing procedures.241-245 Reconstruction of the NAC may also be performed in a delayed fashion if Advantages of oncoplastic volume displacement techniques are that they desired by the patient. Reconstructed nipples are devoid of sensation. permit the removal of larger regions of breast tissue, thereby achieving According to the NCCN Panel, skin-sparing mastectomy should be wider surgical margins around the cancer, and at the same time better performed by an experienced breast surgery team that works in a preserve the natural shape and appearance of the breast than do standard coordinated, multidisciplinary fashion to guide proper patient selection for breast resections.249 skin- sparing mastectomy, determine optimal sequencing of the Limitations of oncoplastic volume displacement techniques include lack of reconstructive procedure(s) in relation to adjuvant therapies, and perform standardization among centers, performance at only a limited number of a resection that achieves appropriate surgical margins. Post-mastectomy sites in the United States, and the possible necessity for subsequent radiation should still be applied for patients treated by skin-sparing mastectomy if pathologic margins are positive when further Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-28 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer breast-conserving attempts are deemed impractical or unrealistic. Nevertheless, the consensus of the panel is that these issues should be considered prior to surgery for individuals who are likely to have a surgical defect that is cosmetically unsatisfactory. Those who undergo lumpectomy and are dissatisfied with the cosmetic outcome after treatment should be offered a consultation with a plastic surgeon to address the repair of resulting breast defects. Patients should be informed of the possibility of positive margins and potential need for secondary surgery, which could include re-excision segmental resection, or could require mastectomy with or without loss of the nipple. Oncoplastic procedures can be combined with surgery on the contralateral unaffected breast to minimize long-term asymmetry. Finally, decisions regarding breast reconstruction should primarily focus on treatment of the tumor, and such treatment should not be compromised. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-29 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Systemic Therapies (Preoperative and Adjuvant) patients with greater than or equal to T2, or greater than or equal to N1, Systemic Therapy Options HER2-positive, early-stage breast cancer. Chemotherapy: A number of chemotherapy regimens have activity in the Preoperative Systemic therapy preoperative setting. According to the NCCN Panel, those regimens recommended in the adjuvant setting may be considered in the Principles of Preoperative Systemic Therapy preoperative setting. In both settings, the underlying aim remains the The NCCN Panel has outlined the rationale, appropriate patient selection, same: eradication or control of undiscovered distant metastases. and response assessment for preoperative systemic therapy in a new section titled, Principles of Preoperative Chemotherapy. Endocrine Therapy: Neoadjuvant endocrine therapy alone may be offered to those with strongly HR-positive tumors.250-257 According to the NCCN Rationale for Preoperative Chemotherapy Panel, the endocrine therapy options include an aromatase inhibitor (with Randomized clinical trials have found no significant differences in ovarian suppression for premenopausal patients) or tamoxifen. The long-term outcomes when systemic chemotherapy is given before or after preferred endocrine therapy option for postmenopausal patients is an surgery.263,264 Historically, a primary advantage of administering aromatase inhibitor. preoperative systemic therapy has been to improve surgical outcomes. Preoperative systemic therapy can render inoperable tumors resectable HER2 Targeted Therapy: For patients with HER2-positive breast cancer, and also downstage patients with operable breast cancer desiring breast that are candidates for preoperative systemic therapy, chemotherapy and conservation.265 Results from large clinical trials and retrospective reviews trastuzumab-based therapy is recommended.258 Chemotherapy and dual indicate that breast conservation rates are improved with preoperative anti-HER2 blockade associated with trastuzumab plus pertuzumab has systemic therapy.264,266 Clinicians need to carefully consider the extent of shown significant improvements in the pCR rate when compared with disease in the breast and likelihood of adequate tumor response before chemotherapy and one anti-HER2 agent in the preoperative setting.259-261 recommending preoperative systemic therapy to improve the likelihood of In the Neosphere trial, the addition of pertuzumab to trastuzumab and successful breast conservation. docetaxel preoperatively led to a statistically significant increase in pCR in the breast (16.8% increase; 95% CI, 3.5–30.1; P = .0141).261 In the In addition, use of preoperative systemic therapy may provide important TRYPHAENA trial, preoperative therapy with pertuzumab and prognostic information based on response to therapy. Achieving a trastuzumab given along with anthracycline-containing or pathologic complete response (pCR) to neoadjuvant therapy is associated anthracycline-free standard chemotherapy regimens to patients with with favorable disease-free and OS in early-stage breast cancer. The operable, locally advanced, or inflammatory HER2-positive breast cancer correlation between pathologic response and long-term outcomes in showed pCR rates in all treatment arms ranging from 57% to 66%.262 The patients with early-stage breast cancer is strongest for patients with mean change in left ventricular ejection fraction was similar in all treatment triple-negative breast cancer, less so for HER2-positive disease, and least arms.262 The NCCN Panel supports the FDA-approved indication that a for hormone-positive disease.267-269 pertuzumab-containing regimen may be administered preoperatively to Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-30 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Other benefits of preoperative systemic therapy include allowing time for contralateral breast symmetry procedures are added to the appropriate genetic testing and for planning breast reconstruction in breast-conserving surgery to achieve optimal cosmetic outcomes. patients proceeding with mastectomy. For those with significant residual disease after standard preoperative systemic therapy, it may provide an The NCCN Panel cautions that preoperative systemic therapy is not opportunity to identify patients who are candidates for clinical trials of appropriate for certain patients. Preoperative systemic therapy should not novel agents in the adjuvant setting. To date, the tailoring of therapy be offered in patients with extensive in situ disease when the extent of based on poor response to standard preoperative chemotherapy has not invasive disease cannot be defined; in patients where the extent of the yet demonstrated improved outcomes. In addition, preoperative systemic tumor is poorly delineated; or in those whose tumors are not palpable or therapy also serves as an excellent research platform to test novel clinically assessable. The decision to utilize preoperative therapy should therapies and predictive biomarkers by providing tumor specimens and be made in the context of a coordinated and collaborative blood samples prior to and during systemic treatment. multi-disciplinary team. Selection of Patients for Preoperative Therapy Response Assessment During Preoperative Chemotherapy Not all patients are appropriate candidates for preoperative systemic The NCCN panel recommends that tumor response should be routinely therapy. According to the NCCN Panel, among those with inoperable assessed by clinical exam during the delivery of preoperative systemic breast tumors, preoperative systemic therapy is indicated in patients with therapy. Patients with operable breast cancer experiencing progression of locally advanced or inoperable breast cancer including those with disease while undergoing preoperative systemic therapy should be taken inflammatory breast cancer; those with N2 and N3 regional lymph node promptly to surgery. Imaging during preoperative systemic therapy should nodal disease; and T4 tumors. In patients with operable breast cancer who not be done routinely but may be considered if tumor progression is are clear candidates for adjuvant chemotherapy, preoperative systemic suspected. Imaging prior to surgery should be determined by a therapy may be considered if a patient desires breast-conserving surgery multi-disciplinary team. but the surgery is not possible due to the size of the tumor relative to that of the breast, with the hope that this will help obtain clear surgical margins at final resection. Preoperative systemic therapy may also be administered in patients with operable tumors if the patient’s breast cancer subtype is one associated with a high likelihood of response. When preoperative systemic therapy is used to improve the likelihood of successful breast conservation, the surgical plan should consider the possibility that clear surgical margins may not always be obtained, and a follow-up mastectomy may be required, with or without breast reconstruction. This consideration is especially important when oncoplastic breast reduction techniques or Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-31 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Adjuvant Systemic Therapy patient in their shared decision-making regarding the toxicities and After surgical treatment, adjuvant systemic therapy should be considered. benefits of systemic adjuvant therapy.273 In patients with early-stage breast cancer, systemic adjuvant therapy is administered to reduce risk of cancer recurrence. The decision is often Adjuvant Systemic therapy for hormone receptor-positive, based on individual risk of relapse and predicted sensitivity to a particular HER2-negative tumors treatment (eg, ER/PR and HER2 status). The decision to use systemic Patients with HR positive, HER2-negative tumors, receive adjuvant adjuvant therapy requires considering and balancing risk for disease endocrine therapy to reduce the risk of recurrence and those deemed at recurrence with local therapy alone, the magnitude of benefit from high risk for distant recurrence despite adjuvant endocrine therapy, applying adjuvant therapy, toxicity of the therapy, and comorbidity. The receive adjuvant chemotherapy. The incremental benefit of adding decision-making process requires collaboration between the health care adjuvant chemotherapy to endocrine therapy in patients with low clinical team and patient. risk of recurrence such as those with very small, low grade, lymph node-negative tumors is relatively small.274 The decision whether or not to Stratification for Systemic Adjuvant Therapy administer adjuvant chemotherapy in patients with HR-positive, The NCCN Guidelines stratify patients with breast cancer based on their HER2-negative tumors is based on many factors including lymph node HR- status and HER2 expression. Patients are then further stratified status, size, grade, lymphovascular invasion, age, comorbid conditions based on risk of disease recurrence based on anatomic and pathologic and/or the results of a gene expression profile test using multigene characteristics (ie, tumor grade, tumor size, ALN status, angiolymphatic assays. invasion). Multigene Assays Several commercially-available gene-based assays are useful in Estimating Risk of Relapse or Death and Benefits of Systemic Treatment determining prognosis by predicting distant recurrence, local recurrence, Several prognostic factors predict for future recurrence or death from or survival. Of these, only one, the 21-gene assay (Oncotype Dx) has breast cancer. The strongest prognostic factors are patient age, been clinically validated for predicting the benefit of adding adjuvant comorbidity, tumor size, tumor grade, number of involved ALNs, and chemotherapy to further reduce the risk of recurrence. possibly HER2 tumor status. Algorithms have been published estimating rates of recurrence,270 and a validated, computer-based model (Adjuvant! 21-gene assay (Oncotype DX) in Node-negative, HR-positive, Online; www.adjuvantonline.com) is available to estimate 10-year DFS HER2-negative disease: The 21-gene recurrence score (RS) is one of the and OS that incorporates all of the above prognostic factors except for most validated multigene assays. The RS is helpful in determining the HER2 tumor status.271,272 These tools aid the clinician in objectively prognosis in patients with HR-positive, HER2-negative tumors treated with estimating outcome with local treatment only, and also assist in estimating endocrine therapy alone by predicting locoregional and distant the absolute benefits expected from systemic adjuvant endocrine therapy recurrence.275-277 This assay has also been validated to predict the benefit and chemotherapy. These estimates may be utilized by the clinician and from adding adjuvant chemotherapy to adjuvant endocrine therapy for Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-32 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer patients with HR-positive, HER2-negative, node-negative breast recurrence in patients with a RS of <18, treated with endocrine therapy cancer.278-280 alone was 2.7%.283 These results suggest that in patients with limited nodal disease (1-3 positive lymph nodes) and a low RS, the absolute Among patients with T1b/c and T2, lymph node-negative, HR-positive, benefit from chemotherapy is likely to be very small.283,284 HER2-negative tumors with RS between 0-10, the risk of distant recurrence is low and these patients derive no incremental benefit from There is a clear benefit from adjuvant chemotherapy in patients with node the addition of adjuvant chemotherapy to endocrine therapy.279,281 At the positive, HR-positive, HER2-negative tumors, if the RS is high (≥ 31). In a other end of the spectrum, patients with lymph node-negative, secondary analysis of the SWOG 8814 trial of patients with HR-positive, HR-positive, HER2-negative cancers with high RS (≥ 31) have a higher lymph node-positive tumors, high RS (≥31) was predictive of risk of distant recurrence and secondary analyses of prospective studies chemotherapy benefit. This study evaluated breast cancer specimens from demonstrate a clear benefit from adjuvant chemotherapy.279,281 node-positive, HR-positive postmenopausal patients (n= 367) randomized to endocrine therapy with tamoxifen alone or chemotherapy with CAF For those with intermediate RS (11-25), the recently reported TAILORx followed by tamoxifen.278 Compared with tamoxifen alone, treatment with trial of postmenopausal patients (n= 6711) with lymph node-negative, CAF among patients with a high RS (≥31) resulted in improved 10-year HR-positive, HER-2 negative breast cancer, showed similar disease-free DFS (55% vs. 43%; HR 0.59, 95% CI 0.35-1.01) and OS (73% vs. 54%; survival rates at 9-years in those who received adjuvant chemotherapy HR 0.56, 95% CI 0.31-1.02).278 followed by endocrine therapy compared with endocrine therapy alone.281 However, in a subset analysis, patients 50 years of age or younger with The absolute benefit of chemotherapy in patients with limited lymph node RS 16-25 had significantly lower rates of distance recurrence with the involvement and a RS <25 remains to be determined. The ongoing addition of adjuvant chemotherapy to endocrine therapy.281 The cutoff for Southwest Oncology Group (SWOG) S1007 RxPONDER trial,285 assigned low, intermediate, and high RS was different in TAILORx versus NSABP patients with 1-3 lymph node-positive nodes, HR-positive, HER2-negative B-20. The NSABP-B20 was the first trial to validate the 21-gene assay breast cancer and a RS ≤ 25 to standard endocrine therapy with or without both as a prognostic as well as a predictive tool and identified RS cut-offs adjuvant chemotherapy. The results of this trial are expected to determine to predict the magnitude of chemotherapy benefit in patients with the benefit (if any) for chemotherapy in this group of patients. node-negative, HR-positive breast cancer.7 70-gene assay (MammaPrint): Results from the randomized MINDACT 21-gene assay (Oncotype DX) in Node- positive, HR-positive, trial,286 demonstrated that the 70-gene assay can identify a subset of HER2-negative disease: In the West German Plan B study, patients (n = patients who have a low likelihood of distant recurrence despite high-risk 110) with lymph node-positive, HR-positive, HER2-negative tumors, and clinical features (based on tumor size, grade, nodal status). In this trial, a RS of ≤11, were found to have a 5-year disease-free survival was 79% had lymph node-negative disease and 21% had 1-3 positive lymph 94.4% when treated with endocrine therapy alone.282 In a secondary nodes and all patients underwent risk assessment by clinical criteria (using analysis of a prospective registry of patients with HR-positive, Adjuvant! Online) and genomic risk assessment by the 70-gene assay. HER2-negative, lymph node-positive tumors, the 5-year risk of distant Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-33 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Patients with low-risk disease according to both clinical criteria and 1-3 positive lymph nodes, the rates of survival without distant metastases genomic assay results did not receive adjuvant chemotherapy, whereas were 96.3% (95% CI, 93.1 to 98.1) in those who received adjuvant patients categorized as high-risk by both assessments received chemotherapy versus 95.6 (95% CI, 92.7 to 97.4) in those who did not chemotherapy. Patients with discordant results (i.e., either high clinical receive adjuvant chemotherapy.286 These data suggest that the additional risk/low genomic risk or low clinical risk/high genomic risk) were benefit of adjuvant chemotherapy in patients with high-clinical risk/low randomized to the chemotherapy group or the no-chemotherapy group on genomic risk is likely to be small. the basis of either the clinical result or the genomic result. The primary outcome of the study was met with the demonstration that among those 50-gene assay (PAM50): The 50-gene assay (PAM-50) risk of recurrence with high clinical risk/low genomic risk, the 5-year rate of survival without (ROR) score stratifies patients with HR-positive disease into high, distant metastasis in those did not receive adjuvant chemotherapy was medium, and low risk groups. Several studies have demonstrated the 94.7% (95% CI, 92.5 to 96.2).286 prognostic value of ROR score in estimating risk of disease recurrence.287- 289 In the intention-to-treat population, among patients at high clinical risk/low genomic risk by the 70-gene assay, the 5-year rate of survival with no In a study from the Danish Breast Cancer Cooperative Group database, distant metastasis in those who received chemotherapy was 95.9% (95% patients with lymph node node-negative tumors and low ROR had a CI, 94.0 to 97.2) versus 94.4% (95% CI, 92.3 to 95.9) in those who did not distant recurrence risk of 5.0% (95% CI, 2.9% to 8.0%) whereas tumors receive chemotherapy (adjusted HR for distant metastasis or death with with high ROR had a distant recurrence risk of 17.8% (95% CI, 14.0% to chemotherapy vs.no chemotherapy 0.78; 95% CI, 0.50 to 1.21)286 Among 22.0%).288 Based on these analyses, patients with T1 and T2, patients at low clinical risk/ high genomic risk, 5-year survival with no HR-positive, HER2- negative, lymph node-negative tumors, a ROR score distant metastasis was 95.8% with chemotherapy (95% CI, 92.9 to 97.6), in the low range, regardless of tumor size, places the individual into the compared with a rate of 95.0% (95% CI, 91.8 to 97.0%) without same prognostic category as those with T1a–T1b, N0, M0 tumors.288 chemotherapy (adjusted HR for distant metastasis or death with In patients with 1-3 lymph-node positive, HR-positive, HER2-negative chemotherapy vs. no chemotherapy,1.17; 95% CI, 0.59 to 2.28). These disease with low-risk of recurrence score, the distant recurrence risk was data suggest that the results of the 70-gene signature do not provide less than 3.5% at 10 years with endocrine therapy alone. 288 In evidence for making recommendations regarding chemotherapy for TransATAC study, no distant recurrence was seen at 10 years in a similar patients at low clinical risk.286 group.289 In a subgroup analysis by nodal status, among node-negative patients 12-gene assay (EndoPredict): This assay utilizes 12-genes to calculate a with high clinical risk/low genomic risk, the 5-year rate of survival with no prognostic score. This assay appears to be useful in identifying a distant metastasis was 95.7% (95% CI, 93.0 to 97.4) in those who subgroup of patients with ER-positive, HER2-negative tumors with very received adjuvant chemotherapy compared with 93.2% (95% CI, 90.1 to low risk of recurrence without adjuvant chemotherapy and helpful in 95.4) in those who did not receive chemotherapy.286 Among patients with identifying patients at low risk for a late recurrence.290 Based on results of Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-34 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer two Austrian Breast Cancer Study Group trials- ABCSG-6 and ABCSG-8, implications based on risk scores and nodal status. The Panel notes that patients with HR-positive, HER-2 negative, and lymph-node node-negative the multigene assays provide prognostic and therapy-predictive disease with a low-risk score by the 12-gene assay had risk of distant information that complements TNM and biomarker information. recurrence of 4% at 10 years.290 The prognostic value of the risk score rom the 12-gene assay was found to be independent of conventional Use of Multigene Assays in Axillary Lymph Node-Negative HR-Positive, HER2-Negative Tumors clinicopathological factors. Patients with T1 and T2 HR-positive, HER2-negative, and lymph node-negative tumors, a 12-gene low-risk Small tumors (up to 0.5 cm in greatest diameter) that do not involve the score, regardless of T size, places the tumor into the same prognostic lymph nodes have a favorable prognosis so adjuvant chemotherapy is category as T1a–T1b, N0, M0. not recommended. According to the NCCN Panel, adjuvant endocrine therapy may be considered in this group of patients to reduce the risk for In TransATAC study, patients with 1-3 positive nodes in the low-risk group a second contralateral breast cancer, as well as the small benefit in had a 5.6% risk of distant recurrence at 10 years,289 suggesting that reducing the risk of local/regional and distant recurrence.(Category 2B). chemotherapy would be of limited benefit in these patients. For patients with invasive ductal or lobular tumors greater than 0.5 cm in Breast Cancer Index: The Breast Cancer Index (BCI) is a combination of diameter and no lymph node involvement (lymph node node-negative), two profiles, the HOXB13-to-IL17BR expression ratio (H:I ratio) and the the NCCN panel recommends strongly considering the 21-gene RT-PCR Molecular Grade Index (MGI). Compared with clinical prognostic factors assay to help estimate likelihood of recurrence and benefit from (eg, age, tumor size, tumor grade, and lymph node status), the H:I ratio chemotherapy (category 1). The panel has noted that on an exploratory has been shown to be prognostic in the setting of adjuvant tamoxifen analysis from the TAILORx study,281 adjuvant chemotherapy may be monotherapy.291,292 The addition of MGI to H:I was determined provide considered in patients 50 years of age or younger with a 21-gene RS of additional prognostic discrimination, leading to the BCI assay.291 In a 16-25. Also, patients with T1b tumors with low grade histology should be secondary analysis of the ATAC trial, BCI was prognostic in node negative considered for endocrine monotherapy, as the TAILORx study281 did not breast cancer for both early (years 0-5) and late (years 5-10) distant include patients with such tumors. recurrence.293 For patients with T1 and T2 HR-positive, HER2-negative, and lymph node-negative tumors, a BCI in the low-risk range, regardless The panel notes that other prognostic multigene assays may be of T size, places the tumor into the same prognostic category as T1a-T1b, considered to help estimate risk of recurrence but these assays have not N0, M0. There are limited data as to the role of BCI in HR-positive, been validated to predict the benefit of systemic chemotherapy. Also, HER2-negative, and lymph node-positive breast cancer. amongst the other assays, the panel has listed the 70-gene assay as a category 1 option based on the results of the prospective MINDACT286 trial NCCN Recommendations for Use of Multigene Assays: Considering the demonstrating the ability of the 70-gene assay to identify a good genomic ability of the multigene assays to predict benefit of adjuvant systemic risk population despite a high clinical risk, in whom chemotherapy may be chemotherapy and ability to determine prognosis by predicting risk of omitted without a detrimental effect. High clinical risk in the MINDACT trial distant recurrence, the NCCN Panel has summarized the treatment Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-35 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer was defined for grade 1 tumors as >3 cm N0 or T2N1, for grade 2 tumors to be predictive for adjuvant chemotherapy benefit, they are prognostic T2N0-1, and for grade 3 tumors T1c-2N0-1. and can be used to identify low-risk patients who are likely to derive little or no absolute benefit from addition of adjuvant chemotherapy to adjuvant urthermore, given no difference in outcomes with or without chemotherapy endocrine therapy. While a secondary analysis of the prospective SWOG in the discordant low clinical risk/high genomic risk group, the MINDACT 8814 trial demonstrated no benefit for chemotherapy for patients with 1-3 study suggests that the 70-gene panel is not useful guiding systemic involved ipsilateral axillary lymph nodes and a low RS, there was benefit chemotherapy decisions in this subgroup of patients. for the addition of adjuvant chemotherapy in those with high-RS (≥ 31) from the 21-gene assay,278 At this time, the optimal RS cut-off (< 11 vs < Since results of different assays may not be concordant with each other 18) to withhold chemotherapy for HR-positive, HER2-negative, 1-3 lymph and these assays have not been compared head-to-head prospectively, node-positive tumors is still unknown. The results of the RxPONDER clinicians should only order one of the available assays for a specific trial,285 are expected determine the benefit (if any) of chemotherapy goog. patient and tumor. In the MINDACT trial, among patients with 1-3 positive nodes who had a Use of Multigene Assays in Axillary Lymph Node-Positive HR- Positive, high clinical risk of recurrence but low risk by the 70-gene assay, the rates HER2-Negative Tumors of survival were similar between those who received adjuvant For patients with four or more involved nodes the panel recommends chemotherapy in addition to adjuvant endocrine therapy versus those systemic adjuvant chemotherapy followed by endocrine therapy (category received adjuvant endocrine therapy alone, suggesting that chemotherapy 1). could be omitted in this group.286 Other multigene assays have not proven to be predictive of benefit from chemotherapy. Patients with less than four involved nodes or with pN1mi and less than or equal to 2 mm axillary node metastasis, are most often candidates for For those who are candidates for systemic adjuvant chemotherapy based chemotherapy in addition to endocrine therapy. The panel recommends on clinical characteristics, tumor stage, and pathology, if multigene assay that clinical decision making for adjuvant chemotherapy be based on is not available, the panel recommends systemic adjuvant chemotherapy elements of clinical risk stratification such as clinical characteristics, tumor followed by endocrine therapy (category 1). stage, pathology and comorbid conditions. If the patient is not a candidate Adjuvant Endocrine Therapy for chemotherapy, the panel recommends adjuvant endocrine therapy alone (category 2A). The NCCN Guidelines call for the determination of ER and PR content in all primary invasive breast cancers.294 Patients with invasive breast For those who are candidates for systemic adjuvant chemotherapy based cancers that are ER- or PR- positive should be considered for adjuvant on clinical characteristics, tumor stage, and pathology, the panel endocrine therapy regardless of patient age, lymph node status, or recommends consideration of multigene assays to assess prognosis as a whether adjuvant chemotherapy is to be administered.295 Selected studies tool to assist with treatment decision making. The panel notes in those suggest that HER2-positive breast cancers may be less sensitive to some with N1mi and N1 tumors, while multigene assays have yet to be proven endocrine therapies, although other studies have failed to confirm this Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-36 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer finding.296-304 A retrospective analysis of tumor blocks collected in the ATLAS trial after with 10 years of tamoxifen treatment were an increased ATAC trial indicated that HER2 amplification is a marker of relative risk for endometrial cancer and pulmonary embolism.309 The results of the endocrine resistance independent of type of endocrine therapy.305 aTTom trial confirm the significant reduction in recurrence and death from However, given the favorable toxicity profile of the available endocrine breast cancer seen in the ATLAS trial with 10 versus 5 years of tamoxifen therapies, the panel recommends the use of adjuvant endocrine therapy in therapy.310 the majority of patients with HR-positive breast cancer regardless of menopausal status, age, or HER2 status of the tumor. In patients who are premenopausal at diagnosis, the NCCN Panel recommends tamoxifen treatment with or without ovarian Tamoxifen: The most firmly established adjuvant endocrine therapy is suppression/ablation. Ovarian ablation may be accomplished by surgical tamoxifen for both premenopausal and postmenopausal patients.58 In oophorectomy or by ovarian irradiation. Ovarian suppression utilizes patients with ER-positive breast cancer, adjuvant tamoxifen decreases the luteinizing hormone-releasing hormone (LHRH) agonists that result in annual odds of recurrence by 39% and the annual odds of death by 31% suppression of luteinizing hormone (LH) and release of follicle-stimulating irrespective of the use of chemotherapy, patient age, menopausal status, hormone (FSH) from the pituitary and reduction in ovarian estrogen or ALN status.58 In patients receiving both tamoxifen and chemotherapy, production. Available LHRH agonists in the United States include chemotherapy should be given first, followed by sequential tamoxifen.306 goserelin and leuprolide dosed monthly or every 3 months. Prospective randomized trials have demonstrated that 5 years of tamoxifen is more effective than 1 to 2 years of tamoxifen.307,308 The EBCTCG performed a meta-analysis of randomized studies of ovarian ablation or suppression alone versus no additional systemic adjuvant The ATLAS trial randomly allocated pre- and postmenopausal patients to therapy for early-stage breast cancer. Analysis of ovarian suppression 5 or 10 years (extended therapy) of tamoxifen. The outcome analyses of versus no adjuvant therapy did not demonstrate significant reduction in 6846 patients with ER-positive disease showed that by extending adjuvant recurrence (HR 0.72; 95% CI, 0.49–1.04) or death (HR 0.82; 95% CI, treatment to 10 years, the risk of relapse and breast cancer-related 0.47–1.43).311 In addition, data on ovarian suppression with tamoxifen, mortality was reduced.309 The risk of recurrence during years 5 to 14 was chemotherapy, or both showed no significant reduction in recurrence or 21.4% for patients receiving tamoxifen versus 25.1% for controls (absolute death. recurrence reduction 3.7%). Patients who received tamoxifen for 10 years had a greater reduction in risk of progression, possibly due to a “carryover Studies in premenopausal patients of ovarian ablation or suppression effect.” The reduction in risk of recurrence was 0.90 (95% CI, 0.79–1.02) alone versus CMF (cyclophosphamide/methotrexate/fluorouracil) during 5 to 9 years of tamoxifen treatment and 0.75 (0.62–0.90) after 10 chemotherapy alone generally demonstrate similar antitumor efficacy in years of treatment. There were decreases in the incidence of contralateral patients with HR-positive tumors and superior outcomes with CMF in breast cancer as well. Furthermore, reduced mortality was also apparent patients with HR-negative tumors.311-319 There is also the suggestion that after completion of 10 years of treatment with tamoxifen. With regards to the benefits of ovarian suppression/ablation may be greater in the younger toxicity, the most important adverse effects noted in all patients in the premenopausal group. Studies in premenopausal patients of ovarian Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-37 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer ablation/suppression plus tamoxifen versus chemotherapy alone generally hormone-receptor breast cancer were randomized to tamoxifen alone, demonstrate no difference in rates of recurrence or survival.320-322 tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression for 5 years. In the primary analysis, tamoxifen plus ovarian A large intergroup study in premenopausal patients with HR-positive, suppression was not superior to tamoxifen alone for DFS. After 67 months node-positive breast cancer studied adjuvant CAF of median follow-up, the DFS rate at 5 years was 86.6% in the tamoxifen– (cyclophosphamide/doxorubicin/5-fluorouracil) chemotherapy versus CAF ovarian suppression group and 84.7% in the tamoxifen alone group (HR plus ovarian suppression with goserelin (CAF-Z) versus CAF-Z plus 0.83; 95% CI, 0.66–1.04; P = .10).325 In a subgroup analysis, patients at tamoxifen (CAF-ZT).312 The results demonstrated no improvement in time high risk of recurrence, who received prior chemotherapy, had improved to recurrence or OS comparing CAF with CAF-Z. There was improvement outcomes with ovarian suppression. Their chance of remaining in time to recurrence (HR, 0.73; 95% CI, 0.59–0.90; P < .01) but not OS disease-free at 5 years was 78% with tamoxifen alone, 82.5% with with CAF-Z compared with CAF-ZT (HR, 0.91; 95% CI, 0.71–1.15; P = tamoxifen and ovarian suppression, and 85.7% with exemestane and .21). This study did not include a CAF plus tamoxifen arm, so the ovarian suppression.325 In the subgroup of patients with no prior contribution of the goserelin to the improved time to recurrence in the chemotherapy, no meaningful benefit was seen from ovarian suppression, CAF-ZT arm cannot be assessed. The addition of ovarian as patients who received tamoxifen alone demonstrated a 95% chance of suppression/ablation has also been subjected to meta-analysis by the remaining disease-free for 5 years.324 The OS data from these trials is still EBCTCG.320 They identified no statistically significant reduction in annual pending because the overall follow-up is relatively short in the context of rates of recurrence or death with the addition of ovarian suppression or endocrine-sensitive disease. ablation to chemotherapy in patients less than 40 years or 40 to 49 years of age. Based on the results of the SOFT and TEXT trials, the NCCN Panel has included ovarian suppression plus an aromatase inhibitor for 5 years as an In two randomized trials (TEXT and SOFT), premenopausal patients with adjuvant endocrine therapy option for premenopausal patients with HR-positive early-stage breast cancer were assigned to receive hormone-receptor–positive breast cancer at higher risk of recurrence (eg, exemestane plus ovarian suppression or tamoxifen plus ovarian young age, high-grade tumor, lymph-node involvement). suppression for a period of 5 years.323 Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing Aromatase inhibitors: Several studies have evaluated aromatase inhibitors hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The DFS in the treatment of postmenopausal patients with early-stage breast was 92.8% in the exemestane plus ovarian suppression group, as cancer. These studies have utilized the aromatase inhibitors as initial compared with 88.8% in the tamoxifen plus ovarian suppression group adjuvant therapy, as sequential therapy following 2 to 3 years of (HR for recurrence, 0.66; 95% CI, 0.55–0.80; P < .001).323 The OS did not tamoxifen, or as extended therapy following 4.5 to 6 years of tamoxifen. differ significantly between the two groups (HR for death in the The aromatase inhibitors are not active in the treatment of patients with exemestane plus ovarian suppression group, 1.14; 95% CI, 0.86–1.51; P functioning ovaries and should not be used in patients whose ovarian = .37).323 In the SOFT trial,324 premenopausal patients with Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-38 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer function cannot reliably be assessed owing to treatment-induced combined tamoxifen and anastrozole group gained no benefit over those amenorrhea. in the tamoxifen group, suggesting a possible deleterious effect from the weak estrogenic effect of tamoxifen in patients with near complete The results from two prospective, randomized, clinical trials have provided elimination of endogenous estrogen levels.332 ATAC trial sub-protocols evidence of an OS benefit for patients with early-stage breast cancer show a lesser effect of anastrozole compared with tamoxifen on receiving initial endocrine therapy with tamoxifen followed sequentially by endometrial tissue;333 similar effects of anastrozole and tamoxifen on anastrozole (HR, 0.53; 95% CI, 0.28–0.99; P = .045) or exemestane (HR, quality of life, with most patients reporting that overall quality of life was 0.83; 95% CI, 0.69–1.00; P = .05 [excluding patients with ER-negative not significantly impaired;334 a greater loss of bone mineral density with disease]) when compared with tamoxifen as the only endocrine anastrozole;335 a small pharmacokinetic interference of anastrozole in the therapy.326,327 In addition, the NCIC-CTG MA-17 trial demonstrated a presence of tamoxifen of unclear significance;336 and no evidence for an survival advantage with extended therapy with letrozole compared with interaction between prior chemotherapy and anastrozole.337 placebo in patients with ALN-positive (but not lymph node-negative), ER-positive breast cancer.328 However, no survival differences have been BIG 1-98 is a randomized trial testing the use of tamoxifen alone for 5 reported for patients receiving initial adjuvant therapy with an aromatase years, letrozole alone for 5 years, or tamoxifen for 2 years followed inhibitor versus first-line tamoxifen.329,330 Tamoxifen and aromatase sequentially by letrozole for 3 years, or letrozole for 2 years followed inhibitors have different side effect profiles. Both contribute to hot flashes sequentially by tamoxifen for 3 years. An early analysis compared and night sweats and may cause vaginal dryness. Aromatase inhibitors tamoxifen alone versus letrozole alone, including those patients in the are more commonly associated with musculoskeletal symptoms, sequential arms during their first 2 years of treatment only.330 With 8010 osteoporosis, and increased rate of bone fracture, while tamoxifen is patients included in the analysis, DFS was superior in the letrozole-treated associated with an increased risk for uterine cancer and deep venous patients (HR, 0.81; 95% CI, 0.70–0.93; log rank P = .003). No interaction thrombosis. between PR expression and benefit was observed. No difference in OS was observed. A comparison of the cardiovascular side effects in the Two studies have examined initial adjuvant endocrine treatment with either tamoxifen and letrozole arms of the BIG 1-98 trial showed that the overall tamoxifen or an aromatase inhibitor. The ATAC trial demonstrated that incidence of cardiac adverse events was similar (letrozole, 4.8%; anastrozole is superior to tamoxifen or the combination of tamoxifen and tamoxifen, 4.7%). However, the incidence of grade 3 to 5 cardiac adverse anastrozole in the adjuvant endocrine therapy of postmenopausal patients events was significantly higher in the letrozole arm, and both the overall with HR-positive breast cancer.331,332 With a median of 100 months incidence and incidence of grade 3 to 5 thromboembolic events was follow-up, results in 5216 postmenopausal patients with HR-positive, significantly higher in the tamoxifen arm.338 In addition, a higher incidence early-stage breast cancer enrolled in the ATAC trial demonstrated fewer of bone fracture was observed for patients in the letrozole arm compared recurrences (HR for DFS, 0.85; 95% CI, 0.76–0.94; P = .003) with with those in the tamoxifen arm (9.5% vs. 6.5%).339 After a longer anastrozole compared with tamoxifen.329 No difference in survival has follow-up (median 71 months) no significant improvement in DFS was been observed (HR, 0.90; 95% CI, 0.75–1.07; P = .2). Patients in the noted with either tamoxifen followed by letrozole or the reverse sequence Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-39 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer as compared with letrozole alone (HR for tamoxifen followed by letrozole, 0.66; 95% CI, 0.44–1.00; P = .049) and OS (HR, 0.53; 95% CI, 0.28–0.99; 1.05; 99% CI, 0.84–1.32; HR for letrozole followed by tamoxifen, 0.96; P = .045).327 A meta-analysis of ABCSG 8, ARNO 95, and ITA studies 99% CI, 0.76–1.21).340 showed significant improvement in OS (HR, 0.71; 95% CI, 0.52-0.98; P = .04) with a switch to anastrozole.345 Five trials have studied the use of tamoxifen for 2 to 3 years followed sequentially by a third-generation aromatase inhibitor versus continued The TEAM trial compared treatment of exemestane alone versus tamoxifen in postmenopausal patients. The Italian Tamoxifen Anastrozole sequential therapy of tamoxifen for 2.5 to 3.0 years followed by (ITA) trial randomized 426 postmenopausal patients with breast cancer exemestane to complete 5 years of hormone therapy.346 At the end of 5 who had completed 2 to 3 years of tamoxifen to either continue tamoxifen years, 85% of patients in the sequential group versus 86% in the or to switch to anastrozole to complete a total of 5 years of endocrine exemestane group were disease free (HR, 0.97; 95% CI, 0.88–1.08; P = therapy.341 The HR for relapse strongly favored sequential treatment with .60). This is consistent with the data from the BIG 1-98 trial,340 in which anastrozole (HR, 0.35; 95% CI, 0.18–0.68; P = .001) with a trend towards tamoxifen followed by letrozole or the reverse sequence of letrozole fewer deaths (P = .10).341 Updated results from this study show the HR for followed by tamoxifen was not associated with significant differences in relapse-free survival as 0.56 (95% CI, 0.35–0.89; P = .01); P value for OS efficacy versus letrozole monotherapy after a median follow-up of 71 analysis remained at 0.1.342 The IES trial randomized 4742 months. postmenopausal patients with breast cancer who had completed a total of 2 to 3 years of tamoxifen to either continue tamoxifen or to switch to The NCCN panel finds no compelling evidence that there is meaningful exemestane to complete a total of 5 years of endocrine therapy.343 The efficacy or toxicity differences between the available aromatase inhibitors: results at a median of 55.7 months of follow-up demonstrated the anastrozole, letrozole, and exemestane. All three have shown similar superiority of sequential exemestane in DFS (HR, 0.76; 95% CI, 0.66– anti-tumor efficacy and toxicity profiles in randomized studies in the 0.88; P = .0001) with a significant difference in OS in only patients with adjuvant settings. ER-positive tumors (HR, 0.83; 95% CI, 0.69–1.00; log rank P = .05). A Duration of adjuvant endocrine therapy prospectively planned, combined analysis of 3224 patients enrolled in the Adjuvant endocrine therapy is recommended for a minimum of 5 years. A ABCSG 8 trial and the ARNO 95 trial has also been reported.344 Patients recent retrospective analysis by the Oxford University studied risk of in this combined analysis had been randomized following 2 years of recurrence for years 5 through 20 after 5 years of endocrine therapy. 347 tamoxifen to complete 5 years of adjuvant tamoxifen or 3 years of These data showed a considerable risk of recurrence between years 5 anastrozole. With 28 months of median follow-up available, event-free and 20 in these patients treated with initial 5 years of endocrine therapy.347 survival was superior with crossover to anastrozole (HR, 0.60; 95% CI, Data has now emerged showing benefit of extended endocrine therapy in 0.44–0.81; P = .0009). No statistically significant difference in survival has improving DFS. been observed. An analysis of the ARNO 95 trial alone after 58 months of median follow-up demonstrated that switching from tamoxifen to anastrozole was associated with significant increases in both DFS (HR, Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-40 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Data from the ATLAS trial (discussed above)309 and the aTTom trial In the extension study of ABCSG trial 6, HR-positive postmenopausal confirm greater reduction in recurrence and death from breast cancer with patients received 5 years of adjuvant tamoxifen and were randomized to 3 10 versus 5 years of tamoxifen therapy.310 years of anastrozole or no further therapy.355 At a median follow-up of 62.3 months, patients who received anastrozole (n = 387) were reported to For those treated initially with adjuvant tamoxifen, there is evidence for have a statistically significantly reduced risk of recurrence compared with benefit from extended adjuvant endocrine therapy from several patients who received no further treatment (n = 469; HR, 0.62; 95% CI, randomized trials. Results of the MA-17 trial in 5187 patients who had 0.40–0.96; P = .031).355 completed 4.5 to 6 years of adjuvant tamoxifen demonstrated that extended therapy with letrozole provides benefit in postmenopausal The differences in design and patient populations among the studies of the patients with HR-positive, early-stage breast cancer.328,348 With a median aromatase inhibitors do not allow for the direct comparison of the results of follow-up of 64 months, letrozole was associated with improved DFS (HR these studies. A meta-analysis of adjuvant trials of aromatase inhibitors 0.52, 95% CI 0.45-0.61) and an improved OS (HR 0.61, 95% CI 0.52-0.71) versus tamoxifen alone versus after 2 or 3 years of tamoxifen documented compared with placebo.349 lower recurrence rates with the aromatase inhibitor-containing regimen, with no clear impact on OS.356 It is not known whether initial, sequential, or In a separate cohort analysis of the MA-17 trial, the efficacy of letrozole extended use of adjuvant aromatase inhibitors is the optimal strategy. versus placebo was evaluated after un-blinding of the study in the 1579 patients who had been randomly assigned to placebo after 4.5 to 6 years In patients initially treated with an AI, a randomized phase III trial of tamoxifen.350,351 The median time since completion of tamoxifen was 2.8 (MA17.R) evaluated the effects of extending adjuvant AI therapy from 5 to years. Both DFS and distant DFS were significantly improved in the group 10 years.357 Postmenopausal patients who had completed 4.5 to 6 years receiving letrozole, thereby providing some evidence for the efficacy of of therapy with an AI (with a median duration of prior tamoxifen of 5 letrozole in patients who had received 4.5 to 6 years of tamoxifen therapy years), were randomized to letrozole or placebo for an additional 5 followed by no endocrine therapy for an extended period. A formal years.357 Improvement was seen in five-year DFS in those receiving quality-of-life analysis demonstrated reasonable preservation of quality of letrozole compared to those who received placebo (95% [95% CI life during extended endocrine therapy, although patients may experience 93 - 96%] vs. 91% [95% CI 89 -93%]). The annual rate of contralateral ongoing menopausal symptoms and loss of bone mineral density.352,353 No breast cancer reported was lower with letrozole (0.49% vs. 0.21%; HR data are available regarding use of aromatase inhibitors for more than 5 0.42, 95% CI 0.22-0.81%). However, longer duration of AI resulted in more years or long-term toxic effects from extended treatment. In addition, the frequent bone-related adverse effects compared with those who received ATLAS trial data do not provide clear direction for treatment of placebo and no improvement was observed with respect to OS. postmenopausal patients.354 There are no data available to suggest that Bone-related adverse effects included bone pain (18% vs. 14%), fractures an aromatase inhibitor for 5 years is better for long-term benefit than 10 (14% vs. 9%), and new-onset osteoporosis (11% vs. 6%).357 years of tamoxifen. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-41 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer NCCN Recommendations for Adjuvant Endocrine Therapy for remain premenopausal after the initial 5 years of tamoxifen, the panel Postmenopausal Patients: The NCCN Guidelines for Breast Cancer recommends considering continuing up to 10 years of tamoxifen therapy. recommend the following adjuvant endocrine therapy options for patients with early-stage breast cancer who are postmenopausal at diagnosis: an Response to Adjuvant Endocrine Therapy: The measurement of the aromatase inhibitor as initial adjuvant therapy for 5 years (category 1); and nuclear antigen, Ki-67 by IHC, gives an estimate of the tumor cells in the tamoxifen for 2 to 3 years followed by one of the following options: an proliferative phase (G1, G2, and M phases) of the cell cycle. Studies have aromatase inhibitor to complete 5 years of adjuvant endocrine therapy demonstrated the prognostic value of Ki-67 as a biomarker and its (category 1) or 5 years of aromatase inhibitor therapy (category 2B); or usefulness in predicting response and clinical outcome.360 One small study tamoxifen for 4.5 to 6 years followed by 5 years of an aromatase inhibitor suggests that measurement of Ki-67 after short-term exposure to (category 1) or consideration of tamoxifen for up to 10 years. In endocrine treatment may be useful to select patients with tumors resistant postmenopausal patients, the use of tamoxifen alone for 5 years (category to endocrine therapy and those who may benefit from additional 1) or up to 10 years is limited to those who decline or who have a interventions.361 However, these data require larger analytic and clinical contraindication to aromatase inhibitors. validation. In addition, standardization of tissue handling and processing is required to improve the reliability and value of Ki-67 testing. At this time, NCCN Recommendations for Adjuvant Endocrine Therapy for there is no conclusive evidence that Ki-67 alone, especially baseline Ki-67 Premenopausal Patients: If premenopausal at diagnosis, the NCCN as an individual biomarker, helps to select the type of endocrine therapy Guidelines for Breast Cancer recommend 5 years of tamoxifen (category for an individual patient. Therefore, the NCCN Breast Cancer Panel does 1) with or without ovarian suppression (category 1) or ovarian suppression not currently recommend assessment of Ki-67. plus an aromatase inhibitor for 5 years (category 1). Patients who are premenopausal at diagnosis and who become amenorrheic with The cytochrome P-450 (CYP450) enzyme, CYP2D6, is involved in the chemotherapy may have continued estrogen production from the ovaries conversion of tamoxifen to endoxifen. Individuals with wild-type without menses. Serial assessment of circulating LH, FSH, and estradiol CYP2D6 alleles are classified as extensive metabolizers of tamoxifen. to assure a true postmenopausal status is mandatory if this subset of Those with one or two variant alleles with either reduced or no activity patients is to be considered for therapy with an aromatase inhibitor.358,359 are designated as intermediate metabolizers and poor metabolizers, respectively. A large retrospective study of 1325 patients found that time After 5 years of initial endocrine therapy, for patients who are to disease recurrence was significantly shortened in poor metabolizers of postmenopausal at that time (including those who have become tamoxifen.362 However, the BIG 1-98 trial reported on the outcome based postmenopausal during the 5 years of tamoxifen therapy), the NCCN on CYP2D6 genotype in a subset of postmenopausal patients with Panel recommends considering extended therapy with an aromatase endocrine-responsive, early invasive breast cancer.363 The study found no inhibitor for up to 5 years (category 1) or based on the data from the correlation between CYP2D6 allelic status and disease outcome or ATLAS trial considering tamoxifen for an additional 5 years. For those who between CYP2D6 allelic status and tamoxifen-related adverse effects.363 A genetic analysis of the ATAC trial found no association between CYP2D6 Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-42 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer genotype and clinical outcomes.364 Given the limited and conflicting breast cancer.370 With bisphosphonate therapy, the greatest improvement evidence at this time,365 the NCCN Breast Cancer Panel does not was seen in bone recurrence (RR=0.83, P = .004) and bone fractures recommend CYP2D6 testing as a tool to determine the optimal adjuvant (RR=0.85, P = .02). No effect was seen on distant recurrence outside endocrine strategy. This recommendation is consistent with the ASCO bone (RR =0.98, P =0.69).370 In premenopausal patients, bisphosphonate Guidelines.366 When prescribing a selective serotonin reuptake inhibitor therapy did not seem to have a significant effect on bone recurrence. (SSRI), it is reasonable to avoid potent and intermediate CYP2D6 However, in postmenopausal patients, zoledronic acid significantly inhibiting agents, particularly paroxetine and fluoxetine, if an appropriate reduced bone recurrence (3.4% vs. 4.5%, RR=0.73, 99% CI 0.53 to 1.00); alternative exists. the difference in breast cancer mortality was not statistically significant (7.1% vs. 7.9%, RR=0.88, 99% CI 0.69 to 1.11).370 Adjuvant bisphosphonate therapy The antiresorptive agents (bisphosphonates and denosumab) have an Denosumab: In the adjuvant setting, the ABCSG-18 trial studied the effect established role as preventative and therapeutic agents for the of denosumab in postmenopausal patients treated with adjuvant AIs and management of osteoporosis, hypercalcemia of malignancy, and bone showed a reduction in clinical fractures (HR 0.5, P < .0001), which was the metastases. primary endpoint of this study.371 Subsequently in an interim analysis, an improvement in DFS, a secondary end point of the trial was reported.372 Bisphosphonates: In the Austrian Breast and Colorectal Cancer Study However unlike the bisphosphonates which have demonstrated an OS Group trial-12 (ABCSG-12) trial, for patients over 40 years, zoledronic acid benefit when used as adjuvant therapy, there is no available data showing significantly reduced the risk of recurrence by 34% (HR, 0.66; P=.014) and an OS benefit with denosumab. Results of the ABCSG-18 and the ongoing the risk of death by 49% (HR, 0.51; P=.020). However, no improvement D-CARE373 trials may provide evidence for use of denosumab in the was seen in either DFS or OS in this post hoc analysis among patients adjuvant setting. under 40 years.367 In a planned subgroup analysis of the AZURE trial, zoledronic acid improved DFS in patients who were more than 5 years NCCN recommendations for use of bisphosphonates as adjuvant therapy: since menopause at trial entry.368 A meta-analysis of data from seven Based on the EBTCG metaanalysis.370, the panel recommends adjuvant bisphosphonate trials (AZURE, ABCSG-12, ZO-FAST, Z-FAST, considering adjuvant bisphosphonate therapy for postmenopausal (natural EZO-FAST, NSABP-B34, GAIN), including only those known to be over 50 or induced) patients receiving adjuvant endocrine therapy. years, postmenopausal, or with ovarian suppression, showed a significant benefit for the use of adjuvant bisphosphonates in patients with a Adjuvant Cytotoxic Chemotherapy low-estrogen state and early-stage breast cancer.369 More recently, the Several combination chemotherapy regimens are appropriate to consider Early Breast Cancer Trialists' Collaborative Group (EBTCG) conducted a when adjuvant cytotoxic chemotherapy is utilized. All adjuvant meta-analysis of all randomized adjuvant bisphosphonate studies (26 chemotherapy regimens listed in the NCCN Guidelines have been studies) and reported convincing evidence that adjuvant bisphosphonates evaluated in phase III clinical trials, and the current version of the adjuvant provide benefits to postmenopausal (natural or induced) patients with chemotherapy guidelines does not distinguish between options for chemotherapy regimens by ALN status. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-43 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer The adjuvant chemotherapy guidelines also include specific representative The ECOG E1199 study was a four-arm trial that randomized 4950 doses and schedules for the recommended adjuvant chemotherapy patients to receive AC chemotherapy followed by either paclitaxel or regimens. The regimens have been categorized as “preferred” or “other.” docetaxel given by either an every-3-week schedule or a weekly schedule.378-380 At a median 63.8 months of follow-up, no statistically The purpose of distinguishing the adjuvant chemotherapy regimens as significant differences in DFS or OS were observed when comparing preferred and other adjuvant chemotherapy regimens is to convey the paclitaxel to docetaxel or weekly versus every-3-week administration. In a sense of the panel regarding the relative efficacy and toxicity of the secondary series of comparisons, weekly paclitaxel was superior to regimens.374 Factors considered by the panel include the efficacy, toxicity, every-3-week paclitaxel in DFS (HR, 1.27; 95% CI, 1.03–1.57; P = .006) and treatment schedules of the regimens. Summarized below are clinical and OS (HR, 1.32; 95% CI, 1.02–1.72; P = .01), and every-3-week trial results focusing on treatment efficacy. docetaxel was superior to every-3-week paclitaxel in DFS (HR, 1.23; 95% CI, 1.00–1.52; P = .02) but not in OS.380 Based on these results, as well as Preferred Regimens the findings from the CALGB trial 9741 that showed dose-dense AC Regimens listed as preferred include: dose-dense doxorubicin and followed by paclitaxel every 2 weeks to have a survival benefit when cyclophosphamide (AC) with dose-dense sequential paclitaxel; compared with the regimen of AC followed by every-3-week paclitaxel,377 dose-dense AC followed by sequential weekly paclitaxel; and docetaxel the every-3-week paclitaxel regimen has been removed from the plus cyclophosphamide (TC). guidelines. The results of two randomized trials comparing AC chemotherapy with or Combination TC was compared with AC chemotherapy in a trial that without sequential paclitaxel chemotherapy in patients with axillary randomized 1016 patients with stage I to III breast cancer.381 At a median node-positive breast cancer suggest improved disease-free rates, and follow-up of 7 years, overall DFS (81% vs. 75%; HR, 0.74; 95% CI, 0.56– results from one of the trials showed an improvement in OS, with the 0.98; P = .033) and OS (87% vs. 82%; HR, 0.69; 95% CI, 0.50–0.97; P = addition of paclitaxel.375,376 On retrospective analysis, the apparent .032) were significantly improved with TC compared with AC. advantage of the paclitaxel-containing regimen appears greater in patients with ER-negative breast cancers. Other Regimens Other regimens included in the guidelines are: AC; epirubicin and A randomized trial evaluated the use of concurrent versus sequential cyclophosphamide (EC); CMF; AC with sequential docetaxel administered chemotherapy (doxorubicin followed by paclitaxel followed by every 3 weeks; AC with sequential weekly paclitaxel; FEC/CEF followed cyclophosphamide vs. doxorubicin plus cyclophosphamide followed by by docetaxel or weekly paclitaxel; FAC followed by weekly paclitaxel; and paclitaxel) given either every 2 weeks with filgrastim support or every 3 docetaxel, doxorubicin, and cyclophosphamide (TAC). weeks. The results show no significant difference between the two chemotherapy regimens, but demonstrate a 26% reduction in hazard of The AC regimen for four cycles has been studied in randomized trials, recurrence (P = .01) and a 31% reduction in the hazard of death (P = .013) resulting in relapse-free survival and OS equivalent to CMF for the dose-dense regimens.377 Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-44 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer chemotherapy.382,383 No benefit from dose escalation of either doxorubicin The NSABP B-36 phase III trial data compared six cycles of 5-fluorouracil, or cyclophosphamide was shown.375,384 epirubicin, and cyclophosphamide (FEC) with four cycles of AC, both given every 3 weeks as adjuvant therapy in patients with node-negative Studies of CMF chemotherapy versus no chemotherapy have shown DFS breast cancer. The rationale for the trial was to determine whether DFS and OS advantages with CMF chemotherapy.58,385 Studies using FAC/CAF improved with extra cycles of treatments.394 Patient and tumor chemotherapy have shown that the use of full-dose chemotherapy characteristics were equally distributed between both arms (<50 years of regimens is important.386 In the EBCTCG overview of polychemotherapy, age: 40%, lumpectomy: 68%, and hormone positivity: 65%).394 The results comparison of anthracycline-containing regimens with CMF showed a reported that DFS after eight years was not greater for those patients who 12% further reduction in the annual odds of recurrence (P = .006) and an had been on the longer FEC chemotherapy treatment and that the patients 11% further reduction in the annual odds of death (P = .02) with on the FEC experienced greater side effects. Combined grade 3 and 4 anthracycline-containing regimens.385 Based on these data, the panel toxicities with a significant difference of 3% or more between AC and FEC qualified the appropriate chemotherapy regimens by the statement that arms included fatigue 3.55% versus 8.45%, febrile neutropenia 3.70% anthracycline-containing regimens are preferred for node-positive patients. versus 9.42%, and thrombocytopenia 0.74% versus 4.41%, respectively.394 Five deaths resulted from the toxicity of FEC treatment, The EBCTCG analysis, however, did not consider the potential interaction compared to the death of two patients on the AC treatment.394 between HER2 tumor status and efficacy of anthracycline-containing versus CMF chemotherapy regimens. Retrospective analysis has The quality-of-life impact and menstrual history of patients on the NSABP suggested that the superiority of anthracycline-containing chemotherapy (NRG) B-36 was also investigated in a phase III trial.395 Patients on FEC may be limited to the treatment of those breast cancers that are treatment experienced a worse quality of life at six months and higher rate HER2-positive.301,387-392 The retrospective finding across several clinical of post-chemotherapy amenorrhea.395 trials that anthracycline-based chemotherapy may be more efficacious in patients whose tumors are HER2-positive has led to a footnote stating that Based on the results of the NSABP B-36 trial, the NCCN Panel has now anthracycline-based chemotherapy may be superior to excluded the FEC/CEF and FAC/CAF regimens as options for adjuvant non-anthracycline-containing regimens in the adjuvant treatment of such therapy. patients. Two randomized prospective trials of FEC chemotherapy in ALN-positive A trial compared 2 dose levels of EC chemotherapy with CMF breast cancer are available. In one trial, premenopausal patients with chemotherapy in patients with node-positive breast cancer.393 This study node-positive breast cancer were randomized to receive classic CMF showed that higher-dose EC chemotherapy was equivalent to CMF therapy versus FEC chemotherapy using high-dose epirubicin. Both chemotherapy and superior to moderate-dose EC in event-free survival 10-year relapse-free survival (52% vs. 45%; P = .007) and OS (62% vs. and OS. 58%; P = .085) favored the FEC arm of the trial.396 The second trial compared FEC given intravenously every 3 weeks at 2 dose levels of epirubicin (50 mg/m2 vs. 100 mg/m2) in premenopausal and Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-45 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer postmenopausal patients with node-positive breast cancer. Five-year DFS Estimated 5-year DFS was 75% with TAC and 68% with FAC (HR, 0.72; (55% vs. 66%; P = .03) and OS (65% vs. 76%; P =.007) both favored the 95% CI, 0.59–0.88; P =.001); survival was 87% with TAC and 81% with epirubicin 100 mg/m2 arm.397 Another randomized trial in patients with FAC (HR, 0.70; 95% CI, 0.53–0.91; P = .008). DFS favored TAC in both ALN-positive breast cancer compared 6 cycles of FEC with 3 cycles of ER-positive and ER-negative tumors. At a median follow-up of 73 months, FEC followed by 3 cycles of docetaxel.321 Five-year DFS (78.4% vs. results from the 3-arm randomized NSABP B-30 trial comparing TAC 73.2%; adjusted P = .012) and OS (90.7% vs. 86.7%; P = .017) were versus AT versus AC followed by docetaxel (AC followed by T) superior with sequential FEC followed by docetaxel. However, no demonstrated that AC followed by T had a significant advantage in DFS significant DFS differences were seen in a large randomized study (HR, 0.83; P = .006) but not in OS (HR, 0.86; P = .086) when compared comparing adjuvant chemotherapy with 4 cycles of every-3-week FEC with TAC. In addition, both DFS (HR, 0.080; P = .001) and OS (HR, 0.83; followed by 4 cycles of every-3-week docetaxel with standard P = .034) were significantly increased when AC followed by T was anthracycline chemotherapy regimens (eg, FEC or epirubicin followed by compared with AT, with AT demonstrating non-inferiority compared with CMF) in patients with node-positive or high-risk, node-negative, operable TAC.402 breast cancer.398 Several retrospective studies have evaluated the potential interaction of The addition of weekly paclitaxel after FEC was shown to be superior to chemotherapy benefit and ER status.58,274 These studies assessed the FEC alone in a randomized study of 1246 patients with early-stage breast effect of chemotherapy on the risk of breast cancer recurrence in patients cancer.399 The former regimen was associated with a 23% reduction in the with ER-positive tumors receiving adjuvant endocrine therapy when risk of relapse compared with FEC (HR, 0.77; 95% CI, 0.62–0.95; P = compared with patients with ER-negative tumor status not undergoing .022), although no significant difference in OS was seen when the two adjuvant endocrine therapy. These analyses suggest that the benefits of arms were compared at a median follow-up of 66 months. chemotherapy are significantly greater in patients with ER-negative disease. For example, the results of Berry et al demonstrated that 22.8% The phase III E1199 trial compared patients with node-positive or high-risk more patients with ER-negative tumors survived without disease for 5 node-negative breast cancer who received 4 cycles of AC every 3 weeks, years if they received chemotherapy; this benefit was only 7% for patients followed by either paclitaxel or docetaxel, either weekly or every 3 weeks. with ER-positive tumors receiving chemotherapy.274 The 10-year updated results of this trial showed that incorporation of weekly paclitaxel and docetaxel every 3 weeks was associated with For patients greater than 70 years of age, the consensus of the panel is significant improvements in DFS, and marginal improvements in OS, that there are insufficient data to make definitive chemotherapy compared with paclitaxel given every 3 weeks. Among patients with recommendations. Although AC or CMF has been shown to be superior to triple-negative disease, the10-year DFS rate with weekly paclitaxel was capecitabine in a randomized trial of patients aged greater than or equal to 69% and the 10-year OS rate was 75%.400 65 years with early-stage breast cancer,403 the enrollment in that study was discontinued early.403 Therefore, there is also a possibility that Final results from a randomized trial of TAC versus FAC chemotherapy in AC/CMF is not superior to any chemotherapy in this cohort. The panel ALN-positive breast cancer demonstrated that TAC is superior to FAC.401 Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-46 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer recommends that treatment should be individualized for patients in this in patients receiving treatment regimens containing trastuzumab ranged age group, with consideration given to comorbid conditions. from 0% (FinHer trial) to 4.1% (NSABP B-31 trial).405,407,409,411,414,415 The Adjuvant HER2-Targeted Therapy frequency of cardiac dysfunction appears to be related to both age and The panel recommends HER2-targeted therapy in patients with baseline left ventricular ejection fraction. An analysis of data from N9831 HER2-positive tumors (see Principles of HER2 Testing in the NCCN showed the 3-year cumulative incidence of CHF or cardiac death to be Guidelines for Breast Cancer). Trastuzumab is a humanized monoclonal 0.3%, 2.8%, and 3.3% in the arms of the trial without trastuzumab, with antibody with specificity for the extracellular domain of HER2.404Results of trastuzumab following chemotherapy, and with trastuzumab initially several randomized trials testing trastuzumab as adjuvant therapy have combined with paclitaxel, respectively.414 The acceptable rate of significant been reported.405-413 cardiac toxicity observed in the trastuzumab adjuvant trials in part reflects rigorous monitoring for cardiac dysfunction. Furthermore, concerns have NSABP B-31 patients with HER2-positive, node-positive breast cancer been raised regarding the long-term cardiac risks associated with were randomly assigned to 4 cycles of AC every 3 weeks followed by trastuzumab therapy based on results of follow-up evaluations of cardiac paclitaxel for 4 cycles every 3 weeks or the same regimen with 52 weeks function in patients enrolled in some of these trials.416,417 of trastuzumab commencing with paclitaxel. In the NCCTG N9831 trial, patients with HER2-positive breast cancer that was node-positive, or A third trial (HERA) (N = 5081) tested trastuzumab for 1 or 2 years node-negative, with primary tumors greater than 1 cm in size if ER- and compared to none following all local therapy and a variety of standard PR-negative or greater than 2 cm in size if ER- or PR-positive, were chemotherapy regimens in patients with node-positive disease or similarly randomized except that paclitaxel was given by a low-dose node-negative disease with tumor greater than or equal to 1 cm.407 At a weekly schedule for 12 weeks and a third arm delayed trastuzumab until median follow-up of one year, a 46% reduction in the risk of recurrence the completion of paclitaxel. was reported in those who received trastuzumab compared with those who did not (HR, 0.54; 95% CI, 0.43–0.67; P < .0001), there was no The B-31 and NCCTG N9831 trials have been jointly analyzed with the difference in OS, and acceptable cardiac toxicity was reported. The 2-year merged control arms for both trials compared with the merged arms using data indicate that 1 year of trastuzumab therapy is associated with an OS trastuzumab begun concurrently with paclitaxel. There were 4045 patients benefit when compared with observation (HR for risk of death = 0.66; 95% included in the joint analysis performed at 3.9 years median follow-up. A CI, 0.47–0.91; P = .0115).418 After this initial analysis, patients randomized 48% reduction in the risk of recurrence (HR, 0.52; 95% CI, 0.45–0.60; P < to chemotherapy alone were allowed to cross over to receive trastuzumab. .001) and a 39% reduction in the risk of death (HR, 0.61; 95% CI, 0.50– Intent-to-treat analysis including a crossover patient was reported at 0.75; log-rank P = .001) were documented.412 Similar significant effects on 4-year median follow-up.413 The primary endpoint of DFS continued to be DFS were observed when results of the NSABP B-31 and NCCTG N9831 significantly higher in the trastuzumab-treated group (78.6%) versus the trials were analyzed separately. Cardiac toxicity was increased in patients observation group (72.2; HR, 0.76; 95% CI, 0.66–0.87; P < .0001). At a treated with trastuzumab.409,414,415 In the adjuvant trastuzumab trials, the median follow-up of 8 years, the study reported no significant difference in rates of grade III/IV congestive heart failure (CHF) or cardiac-related death DFS, a secondary endpoint, in patients treated with trastuzumab for 2 Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-47 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer years compared with 1 year.408 Therefore, 1 year of adjuvant trastuzumab 0.83; P = .01). No statistically significant differences in OS (HR, 0.41; 95% remains the current standard of treatment. CI, 0.16–1.08; P = .07) or cardiac toxicity were observed with the addition of trastuzumab.405 At 5-year follow-up, a comparison of the two arms (ie, The BCIRG 006 study randomized 3222 patients with HER2-positive, chemotherapy with and without trastuzumab) demonstrated that the HRs node-positive, or high-risk node-negative breast cancer to AC followed by for distant DFS (HR, 0.65; 95% CI, 0.38–1.12; P = .12) and OS (HR, 0.55; docetaxel; AC followed by docetaxel plus trastuzumab for one year; or 95% CI, 0.27–1.11; P = .094) were higher relative to those reported at 3 carboplatin, docetaxel, and trastuzumab for one year.411 At 65-month years.406 follow-up, patients receiving AC followed by docetaxel with trastuzumab (AC-TH) had an HR for DFS of 0.64 (P < .001) when compared with the All of the adjuvant trials of trastuzumab have demonstrated clinically group of patients in the control arm receiving the same chemotherapy significant improvements in DFS, and the combined analysis from the regimen without trastuzumab (AC-T). The HR for DFS was 0.75 (P = .04) NSABP B31 and NCCTG N9831 trials, and the HERA trial, showed when patients in the carboplatin/docetaxel/ trastuzumab (TCH)-containing significant improvement in OS with the use of trastuzumab in patients with arm were compared to patients in the control arm. No statistically high-risk, HER2-positive breast cancer. Therefore, regimens from each of significant difference in the HR for DFS was observed between the two these trials are included as trastuzumab-containing adjuvant regimen trastuzumab-containing arms. An OS advantage was reported for patients choices in the guideline. The benefits of trastuzumab are independent of in both trastuzumab-containing arms relative to the control arm (HR for ER status.409,410 In the FNCLCC-PACS-04 trial, 528 patients with AC-TH vs. AC-T = 0.63; P = .001; HR for TCH vs. AC-T = 0.77; P = .04). HER2-positive, node-positive breast cancer were randomly assigned to Cardiac toxicity was significantly lower in the TCH arm (9.4% patients with receive trastuzumab or observation after completion of adjuvant >10% relative decline in left ventricular ejection fraction) compared with anthracycline-based chemotherapy with or without docetaxel.419 No the AC-TH arm (18.6%; P < .0001). CHF was also more frequent with statistically significant DFS or OS benefit was observed with the addition AC-TH than TCH (2% vs. 0.4%; P < .001). Analysis of this trial by critical of trastuzumab. These results suggest that the sequential administration of clinical event revealed more distant breast cancer recurrences with TCH trastuzumab following chemotherapy is not as efficacious as a schedule (144 vs. 124) but fewer cardiac events with TCH compared with AC-TH (4 involving concomitant chemotherapy and trastuzumab. The NCCN vs. 21).411 In the FinHer trial, 1010 patients were randomized to 9 weeks of Guidelines recommend a total of 12 months of adjuvant trastuzumab as vinorelbine followed by 3 cycles of FEC chemotherapy versus docetaxel the standard of care. Shorter than 12-month duration has not been found for 3 cycles followed by 3 cycles of FEC chemotherapy.405 Patients (n = to be as effective420 and longer than 12 months duration does not have 232) with HER2-positive cancers that were either node-positive or any added benefit; it has been found to be as effective as the 12 months node-negative and greater than or equal to 2 cm and PR-negative were of trastuzumab therapy.421 further randomized to receive or not receive trastuzumab for 9 weeks during the vinorelbine or docetaxel portions of the chemotherapy only. Retrospective analyses of low-risk patients with small tumors demonstrate With a median follow-up of 3 years, the addition of trastuzumab was that in T1a-bN0 breast cancers, HER2 overexpression added a 15% to associated with a reduction in risk of recurrence (HR, 0.42; 95% CI, 0.21– Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-48 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer 30% risk for recurrence.422-425 These risks rates are substantially higher The NCCN Panel suggests trastuzumab and chemotherapy be used for than seen among similarly sized HER2-negative tumors. patients with HER2-positive, node-negative tumors measuring 0.6 to 1.0 cm (ie, T1b) and for smaller tumors that have less than or equal to 2 mm A recent single-arm, multicenter trial studied the benefit of axillary node metastases (pN1mi). Some support for this recommendation trastuzumab-based chemotherapy in patients with HER2-positive, comes from studies showing a higher risk of recurrence for patients with node-negative tumors less than or equal to 3 cm. All patients received HER2-positive, node-negative tumors less than or equal to 1 cm trastuzumab and weekly paclitaxel for 12 weeks, followed by completion of compared to those with HER2-negative tumors of the same size.422 a year of trastuzumab monotherapy.426 Fifty percent of patients enrolled Ten-year breast cancer-specific survival and 10-year recurrence-free had tumors less than or equal to 1.0 cm and 9% of patients had tumors survival were 85% and 75%, respectively, in patients with tumors that were between 2 and 3 cm. The endpoint of the study was DFS. The characterized as HER2-positive, ER-positive tumors, and 70% and 61%, results presented at the 2013 Annual San Antonio Breast Cancer respectively, in patients with HER2-positive, ER-negative tumors. Two Symposium demonstrated that the 3-year DFS rate in the overall more retrospective studies have also investigated recurrence-free survival population was 98.7% (95% CI, 97.6–99.8; P < .0001). in this patient population. None of the patients in these two retrospective studies received trastuzumab. In the first study, 5-year recurrence-free Dual anti-HER2 blockade associated with trastuzumab plus lapatinib and survival rates of 77.1% and 93.7% (P < .001) were observed for patients trastuzumab plus pertuzumab has shown significant improvements in the with HER2-positive and HER2-negative T1a-bN0M0 breast tumors, pCR rate when compared with chemotherapy associated with one respectively, with no recurrence-free survival differences seen in the anti-HER2 agent in the neoadjuvant setting.259,260,262 HER2-positive group when hormonal receptor status was considered.423 In However, in the adjuvant setting, the results of the ALTTO trial failed to the other retrospective study of patients with small HER2-positive tumors, demonstrate a significant improvement in DFS with dual anti-HER2 the risk of recurrence at 5 years was low (99% [95% CI; 96%–100%] for therapy compared with trastuzumab alone.427 After a median follow-up of HER2-negative disease and 92% [95% CI; 86%–99%] for HER2-positive 4.5 years, the DFS rates were 86% for patients who received trastuzumab disease).428 Subgroup analyses from several of the randomized trials have alone; 88% for participants treated with trastuzumab and lapatinib shown consistent benefit of trastuzumab irrespective of tumor size or concurrently; and 87% for patients who received trastuzumab followed by nodal status.411,429,430 lapatinib.427 NCCN-Recommended HER-Targeted Regimens NCCN Recommendation for Adjuvant HER2-Targeted Therapy The panel recommends AC followed by paclitaxel with trastuzumab for 1 Based on these studies, the panel has designated use of trastuzumab with year commencing with the first dose of paclitaxel as a preferred chemotherapy as a category 1 recommendation in patients with HER2-targeting adjuvant regimen. The TCH regimen is also a preferred HER2-positive tumors greater than 1 cm. regimen, especially for those with risk factors for cardiac toxicity, given the results of the BCIRG 006 study that demonstrated superior DFS in Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-49 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer patients receiving TCH or AC followed by docetaxel plus trastuzumab and accuracy of the ER and/or HER2 determination should be reviewed if compared with AC followed by docetaxel alone. a tubular breast cancer is ER-negative and/or HER2-positive, or if a tumor with an ER- and PR-negative status is grade 1.294 Should a breast cancer Other trastuzumab-containing regimens included in the NCCN Guidelines be histologically identified as a tubular or mucinous breast cancer and be are: AC followed by docetaxel and trastuzumab,411 and docetaxel plus confirmed as ER-negative, then the tumor should be treated according to trastuzumab followed by FEC405 (see Preoperative /Adjuvant Systemic the guideline for the usual histology, ER-negative breast cancers. The Therapy in NCCN Guidelines for Breast Cancer for a complete list of panel acknowledges that prospective data regarding systemic adjuvant regimens). therapy of tubular and mucinous histologies are lacking. Considering the unprecedented improvement in OS in the metastatic Post-Therapy Surveillance and Follow-up for T0-3, N1, M0 and T1-3, setting431 and the significant improvement in pCR seen in the neoadjuvant N0-1, M0 tumors setting,260,262 the NCCN Panel considers it reasonable to incorporate Post-therapy follow-up is optimally performed by members of the pertuzumab into the above adjuvant regimens, if the patient did not treatment team and includes the performance of regular history/physical receive pertuzumab as a part of neoadjuvant therapy. An ongoing study is examinations every 4 to 6 months for the first 5 years after primary therapy evaluating pertuzumab and trastuzumab with standard chemotherapy and annually thereafter. Mammography should be performed annually. regimens in the adjuvant setting.432,433 Regarding frequency of mammograms after breast-conserving surgery The NCCN Panel has included paclitaxel and trastuzumab as an option for followed by radiation, the NCCN Panel agrees with ASTRO’s “Choosing patients with low-risk, HER2-positive, stage 1 tumors. This is based on a Wisely’ list of recommendations released in 2014.435 The trial that studied this combination in 406 patients with small, recommendations state that “annual mammograms are the appropriate node-negative, HER2-positive tumors. The results showed that the 3-year frequency for surveillance of breast cancer patients who have had rate of DFS was 98.7% (95% CI, 97.6–99.8) and the risk of serious toxic breast-conserving surgery and radiation therapy with no clear advantage effects with this regimen was low (incidence of heart failure reported was to shorter interval imaging. Patients should wait 6 to 12 months after the 0.5%).434 completion of radiation therapy to begin their annual mammogram Adjuvant Therapy for Tumors of Favorable Histologies surveillance. Suspicious findings on physical examination or surveillance The guidelines provide systemic treatment recommendations for the imaging might warrant a shorter interval between mammograms.” favorable histology of invasive breast cancers, such as tubular and The NCCN panel notes that any imaging of reconstructed breast is not mucinous cancers, based on tumor size and ALN status. If used, the indicated. treatment options for endocrine therapy, chemotherapy, and sequencing of treatment with other modalities are similar to those of the usual According to the NCCN Panel, in the absence of clinical signs and histology of breast cancers. The vast majority of tubular breast cancers symptoms suggestive of recurrent disease, laboratory or imaging studies are both ER-positive and HER2-negative. Thus, the pathology evaluation to screen for metastasis are not necessary. The routine performance of Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-50 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer alkaline phosphatase tests and LFTs are not included in the guidelines.436- Symptom management for patients on adjuvant endocrine therapies often 438 In addition, the panel notes no evidence to support the use of “tumor requires treatment of hot flashes and the treatment of concurrent markers” for breast cancer, and routine bone scans, CT scans, MRI scans, depression. Venlafaxine, a serotonin-norepinephrine reuptake inhibitor PET scans, or ultrasound examinations in the asymptomatic patient (SNRI) has been studied and is an effective intervention in decreasing hot provide no advantage in survival or ability to palliate recurrent disease and flashes.444-447 There is evidence suggesting that concomitant use of are, therefore, not recommended.109,439 tamoxifen with certain SSRIs (eg, paroxetine, fluoxetine) may decrease plasma levels of endoxifen, an active metabolite of tamoxifen.448,449 These The use of breast MRI in follow-up of patients with prior breast cancer is SSRIs/SNRIs may interfere with the enzymatic conversion of tamoxifen to undefined. It may be considered as an option in patients with high lifetime endoxifen by inhibiting a particular isoform of CYP2D6. However, the mild risk (greater than 20% based on models largely dependent on family CYP2D6 inhibitors such as citalopram, escitalopram, sertraline, and history) of developing a second primary breast cancer. Rates of venlafaxine appear to have no or only minimal effect on tamoxifen contralateral breast cancer after either breast-conserving therapy or metabolism.358,450,451 mastectomy have been reported to be increased in patients with BRCA1/2 mutations when compared with patients with sporadic breast cancer.440-442 Follow-up also includes assessment of patient adherence to ongoing medication regimens such as endocrine therapies. Predictors of poor The panel recommends that patients with intact uteri who are taking adherence to medication include the presence of side effects associated adjuvant tamoxifen should have yearly gynecologic assessments and with the medication, and incomplete understanding by the patient of the rapid evaluation of any vaginal spotting that might occur because of the benefits associated with regular administration of the medication.452 The risk of tamoxifen-associated endometrial carcinoma in postmenopausal panel recommends the implementation of simple strategies to enhance patients.443 The performance of routine endometrial biopsy or patient adherence to endocrine therapy, such as direct questioning of the ultrasonography in the asymptomatic woman is not recommended. Neither patient during office visits, as well as brief, clear explanations on the value test has demonstrated utility as a screening test in any population of of taking the medication regularly and the therapeutic importance of longer patients. The vast majority of patients with tamoxifen-associated uterine durations of endocrine therapy. carcinoma have early vaginal spotting. Lymphedema is a common complication after treatment for breast If an adjuvant aromatase inhibitor is considered in patients with cancer. Factors associated with increased risk of lymphedema include amenorrhea following treatment, baseline levels of estradiol and extent of axillary surgery, axillary radiation, infection, and patient gonadotropin followed by serial monitoring of these hormones should be obesity.453,454 The panel recommends educating the patients on performed if endocrine therapy with an aromatase inhibitor is initiated.358 lymphedema, monitoring for lymphedema, and referring for lymphedema Bilateral oophorectomy assures postmenopausal status in young patients management as needed. with therapy-induced amenorrhea and may be considered prior to initiating therapy with an aromatase inhibitor in a young woman. Many young patients treated for breast cancer maintain or regain premenopausal status following treatment for breast cancer. For these © © Version 5.2023 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-51 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer patients, the NCCN Panel discourages the use of hormonal birth control Evidence suggests that a healthy lifestyle may lead to better breast cancer methods, regardless of the HR status of the tumor.455 Alternative birth outcomes. A nested case control study of 369 patients with ER-positive control methods are recommended, including intrauterine devices, barrier methods, and, for those with no intent of future pregnancy, tubal ligation or tumors who developed a second primary breast cancer compared with vasectomy for the partner. Breastfeeding during endocrine or 734 matched control patients who did not develop a second primary tumor chemotherapy treatment is not recommended by the NCCN Panel showed an association between obesity (body mass index [BMI] ≥30), because of risks to the infant. Breastfeeding after breast-conserving smoking, and alcohol consumption and contralateral breast cancer.458 A treatment for breast cancer is not contraindicated. However, lactation from prospective study of 1490 patients diagnosed with stage I–III breast an irradiated breast may not be possible, or may occur only with a cancer showed an association between high fruit and vegetable diminished capacity.455,456 consumption, physical activity, and improved survivorship, regardless of obesity.459 There is emerging evidence that obesity is associated with The panel recommends that patients on an adjuvant aromatase inhibitor or poorer outcomes for certain subtypes of breast cancers. The study by the who experience ovarian failure secondary to treatment should have Women’s Intervention Nutrition group randomized early-stage breast monitoring of bone health with a bone mineral density determination at cancer patients to an intervention group and a control group. The baseline and periodically thereafter. The use of estrogen, progesterone, or intervention consisted of eight one-on-one visits with a registered dietitian selective ER modulators to treat osteoporosis or osteopenia in patients who had been trained on a low-fat eating plan. OS analysis showed no with breast cancer is discouraged. The use of a bisphosphonate is significant difference between the two study arms (17% for the intervention generally the preferred intervention to improve bone mineral density. A vs. 13.6% without); however, subgroup analysis showed that those with single phase 3 study, ABCSG12, demonstrated improved outcomes with ER- and PR-negative disease who were part of the intervention group saw the addition of zoledronic acid in premenopausal patients receiving a 54% improvement in OS.460 endocrine therapy with ovarian suppression.457 Use of bisphosphonates in such patients and in other subgroups remains controversial. Denosumab The NCCN Panel recommends an active lifestyle and ideal body weight has shown to significantly reduce fractures in postmenopausal patients (BMI 20–25) for optimal overall health and breast cancer outcomes as receiving adjuvant therapy aromatase inhibitors, and improves bone there are reports of proven benefits of exercise and active lifestyle during mineral density.371 and after treatment.461-463 Optimal duration of bisphosphonate therapy has not been established. For management of issues related to survivorship including late/long-term Factors to consider for duration of anti-osteoporosis therapy include bone effects of cancer and its treatment, see the NCCN Guidelines for mineral density, response to therapy, and risk factors for continued bone Survivorship. loss or fracture. Patients treated with a bisphosphonate should undergo a dental examination with preventive dentistry prior to the initiation of therapy, and should take supplemental calcium and vitamin-D. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-52 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer The section on management of recurrent/Stage IV breast cancer was updated on 03/06/20. allows for biomarker determination and selection of appropriate treatment. Soft tissue tumor biopsy is preferred over bone sites unless a portion of Recurrent/Stage IV Breast Cancer the biopsy can be protected from harsh decalcification solution to preserve Staging and Workup for Recurrent and Stage IV Breast Cancer more accurate assessment of biomarkers. The staging evaluation of patients who present with recurrent or stage IV breast cancer includes history and physical exam; the performance of a Determination of HR status (ER and PR) and HER2 status should be complete blood count, liver function tests, chest diagnostic CT, bone scan, repeated in all cases when diagnostic tissue is obtained. ER and PR and radiographs of any long or weight-bearing bones that are painful or assays may be falsely negative or falsely positive, and there may be appear abnormal on bone scan; diagnostic CT of the abdomen (with or discordance between the primary and metastatic tumors.466,467 The without diagnostic CT of the pelvis) or MRI scan of the abdomen; and reasons for the discordance may relate to change in biology of disease, biopsy documentation of first recurrence if possible. The NCCN Panel differential effect of prior treatment on clonal subsets, tumor heterogeneity, generally discourages the use of sodium fluoride PET or PET/CT scans for or imperfect accuracy and reproducibility of assays.467 Discordance the evaluation of patients with recurrent disease. There is limited evidence between the receptor status of primary and recurrent disease has been (mostly from retrospective studies) to support the use of PET/CT scanning reported in a number of studies. The discordance rates are in the range of to guide treatment planning through determination of the extent of disease 3.4% to 60% for ER-negative to ER-positive; 7.2% to 31% for ER-positive in select patients with recurrent or metastatic disease.109,110,464,465 In to ER-negative; and 0.7% to 11% for HER2.468-477 general, the non-diagnostic CT scans used for PET under-evaluate the The NCCN Panel recommends that re-testing the receptor status of lungs and the liver compared with contrast-enhanced diagnostic CT scans. recurrent disease be performed, especially in cases when it was The panel considers biopsy of equivocal or suspicious sites to be more previously unknown, originally negative, or not overexpressed. For likely than PET/CT scanning to provide accurate staging information in this patients with clinical courses consistent with HR–positive breast cancer, or population of patients. with prior positive HR results, the panel has noted that a course of The consensus of the NCCN Panel is that FDG PET/CT is optional and endocrine therapy is reasonable, regardless of whether the receptor assay most helpful in situations where standard imaging results are equivocal or is repeated or the result of the most recent HR assay. suspicious. The NCCN Panel recommends bone scan or sodium fluoride Genetic counseling is recommended if the patient is considered to be at PET/CT (category 2B) to detect bone metastases. However, if the FDG high risk for hereditary breast cancer, as defined by the NCCN Guidelines PET results clearly indicate bone metastasis, these scans can be omitted. for Genetic/Familial High-Risk Assessment: Breast and Ovarian. The NCCN Panel recommends that metastatic disease at presentation or Genetic testing: In the metastatic setting, results from genetic testing may first recurrence of disease should be biopsied as a part of the workup for have therapeutic implications. Germline mutations in BRCA1/2 have patients with recurrent or stage IV disease. This ensures accurate proven clinical utility and therapeutic impact. Therefore, germline BRCA1/2 determination of metastatic/recurrent disease and tumor histology, and mutations should be assessed in all patients with recurrent or metastatic Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-53 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer breast cancer to identify candidates for poly adenosine diphosphate ribose previously treated or if additional radiation therapy may be safely polymerase (PARP)-inhibitor therapy. administered). The use of surgical resection in this setting implies the use of limited excision of disease with the goal of obtaining clear margins of Management of Locally Recurrent Disease resection. Unresectable chest wall recurrent disease should be treated Patients with local recurrence only are divided into 3 groups: those who with radiation therapy if no prior radiation has been given. had been treated initially by mastectomy alone, those who had been treated initially by mastectomy plus radiation therapy, and those who had In patients with a local breast recurrence after breast-conserving surgery received breast-conserving therapy plus radiation therapy. and radiation therapy who had a prior sentinel lymph node (SLN) biopsy, a repeat SLN biopsy may be considered although the accuracy of repeat In one retrospective study of local recurrence patterns in patients with SNB is unproven, and the prognostic significance of repeat SNB after breast cancer who had undergone mastectomy and adjuvant mastectomy is unknown and its use is discouraged.480,481 On the other chemotherapy without radiation therapy, the most common sites of local hand, the prognostic significance of repeat SLN biopsy after mastectomy recurrence were at the chest wall and the supraclavicular lymph nodes.478 is unknown and its use is discouraged. The consensus recommendation of The recommendations for treatment of the population of patients the panel for most patients with a local recurrence following experiencing a local recurrence only are supported by analyses of a breast-conserving therapy and SLN biopsy is mastectomy and a level I/II combined database of patients from the EORTC 10801 and Danish Breast axillary dissection. Cancer Cooperative Group 82TM trials. The analyses compared breast-conserving therapy with mastectomy in patients with stage I and The results of the CALOR trial found that after complete resection in stage II disease. The 133 (approximately 8%) patients experiencing a local patients with isolated locoregional recurrence, adjuvant chemotherapy recurrence as an initial event were approximately equally divided between improves both DFS and OS.482 After median follow-up of 4.9 years, the those who had undergone mastectomy and those who had received overall DFS was 69% in the chemotherapy group versus 57% in the group breast-conserving therapy as initial treatment for breast cancer. Of those that did not receive chemotherapy (HR = 0.59, P = .046).482 Five-year OS in the former group, 51 (76%) were able to undergo radiation therapy with in all patients in the study was also significantly improved with or without surgery as treatment for local disease recurrence. No difference chemotherapy (88% vs. 76%, P = .024).482 The benefit of adjuvant in survival emerged between patients receiving treatment after initial chemotherapy was mostly seen in patients with ER-negative disease. treatment with mastectomy or breast-conserving therapy; approximately Among patients with ER-negative disease, 5-year DFS was 67% versus 50% of both groups were alive at 10-year follow-up.479 35% (HR, 0.32; 95% CI, 0.14–0.73) and in those ER-positive disease, the 5-year DFS was 70% versus 69% (HR, 0.94; 95% CI, 0.47–1.89).482 According to the NCCN Panel, mastectomy-treated patients should However these patients received endocrine therapy. undergo surgical resection of the local recurrence (if it can be accomplished with limited morbidity) and involved-field radiation therapy to According to the NCCN Panel, after local treatment, patients with local the chest wall and supraclavicular area (if the chest wall was not recurrences only should be considered for limited duration systemic chemotherapy or endocrine therapy similar to that outlined in the adjuvant Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-54 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer chemotherapy section. The panel emphasized the importance of prospective trial, patients (n =350) with de-novo metastatic breast cancer individualizing treatment strategies in patients with a recurrence of disease who achieved a partial or complete response to anthracycline-based limited to a local site. chemotherapy were randomly assigned to either surgery of the primary tumor plus adjuvant radiation versus no locoregional treatment.490 There Management of Recurrent or Stage IV Disease was no difference in the overall survival (OS) between the group that From the time of diagnosis of recurrent/stage IV metastatic disease, received surgery and the group that did not (19.2 vs. 20.5 months, hazard patients should be offered appropriate supportive care and ratio [HR] 1.04, 95% CI 0.81-1.34).490 In a separate multiple center symptom-related interventions as a routine part of their care. NCCN prospective registry study patients who responded to first-line systemic believes that the best management of any patient with cancer is in a therapy were randomized to management of the primary tumor by surgery clinical trial. Patients should be encouraged to participate in clinical trials or not. 492 Preliminary data showed no difference in OS between the two whenever clinical trials are available. groups 492 Surgery for Recurrent or Stage IV Disease However, another trial by the Turkish Federation, MF07-01 of patients The primary treatment approach recommended by the NCCN Panel for (n=274) with de-novo metastatic breast cancer randomized to local patients with metastatic breast cancer and an intact primary tumor is management (mastectomy, or BCS with radiation) followed by systemic systemic therapy, with consideration of surgery after initial systemic therapy versus systemic therapy only, observed a benefit with surgery.493 treatment for those requiring palliation of symptoms or with impending While no difference in survival was seen at 36 months, at 40 months, complications, such as skin ulceration, bleeding, fungation, and pain.483 patients treated with local management showed an improvement in Generally such surgery should be undertaken only if complete local survival with locoregional treatment (46.4% vs. 26.4%; HR 0.66, 95% CI clearance of tumor may be obtained and if other sites of disease are not 0.49-0.88). 493 The design of this trial is different from the other the first immediately threatening to life. Alternatively, radiation therapy may be being two prospective studies described above in which patients were considered as an option to surgery. Often such surgery requires included only if they had experienced a response to systemic therapy. collaboration between the breast surgeon and the reconstructive surgeon Second, randomization in the Turkish trial was not balanced. Patients who to provide optimal cancer control and wound closure. received surgery had lower rates of triple-negative disease (7% vs. 17%), visceral metastases (29% vs. 45%), and many had solitary bone Retrospective studies suggest a potential survival benefit from complete metastases only (33% vs. 20%).493 In an unplanned subgroup analysis, excision of the in-breast tumor in select patients with metastatic breast patients who appeared to derive the greatest OS benefit from local cancer.484-487 Substantial selection biases exist in all of these studies and management included those with HR-positive disease, (HR 0.63; 95% CI are likely to confound the study results.488,489 0.44–0.89; P = .008); HER2-negative disease (HR 0.64; 95% CI 0.45– 0.91; P = .01); those younger than 55 years HR 0.57; 95% CI 0.38–0.86; P Two prospective, randomized studies assessed whether or not surgery on = .007; and those with solitary bone metastases (HR 0.47; 95% CI 0.23– the primary tumor in the breast is necessary for patients who are 0.98; P = 0.04). 493 diagnosed with metastatic/stage IV breast cancer.490,491 In the first Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-55 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer The panel recognizes the need for more data from randomized clinical present, expected survival is ≥3 months. Patients should undergo a dental trials that will address the risks and benefits of local therapy for patients examination with preventive dentistry prior to initiation of this therapy. The with stage IV disease while eliminating selection biases. Though the bisphosphonates and denosumab are associated with a risk of available data does not support broadly considering local therapy with development of osteonecrosis of the jaw (ONJ). Poor baseline dental surgery and/or RT, this may be reasonable in select patients responding to health or dental procedures during treatment are known risk factors for initial systemic therapy. In such clinical scenarios, patient engagement in ONJ. Thus, a dental examination with preventive dentistry intervention is the decision is encouraged. recommended prior to treatment with intravenous bisphosphonate or denosumab, and dental procedures invasive of gum or bone during Guideline Stratification for Systemic Therapy for Stage IV/Recurrent treatment should be avoided if at all possible. Additional risk factors for the Disease development of ONJ include administration of chemotherapy or The systemic treatment of breast cancer recurrence or stage IV disease corticosteroids and poor oral hygiene with periodontal disease and dental prolongs survival and enhances quality of life (QOL) but is not curative. abscess.495 Therefore, treatments associated with minimal toxicity are preferred. Thus, the use of the minimally toxic endocrine therapies is preferred to the use of Bisphosphonates cytotoxic therapy whenever reasonable.494 Guidance for treatment of There are extensive data from randomized trials in support of the use of patients with breast cancer and brain metastases is included the NCCN bisphosphonates for patients with metastatic disease to bone. The Guidelines for Central Nervous System. randomized clinical trial data include the use of zoledronic acid and pamidronate in the United States and ibandronate and clodronate in Patients with recurrent or stage IV breast cancer at diagnosis are initially European countries.496-503 In metastatic bone disease, bisphosphonate stratified according to whether bone metastases is present. These two treatment is associated with fewer SREs, fewer pathologic fractures, and patient subsets (those with and without bony metastases) are then less need for radiation therapy and surgery to treat bone pain. stratified further by tumor HR and HER2 status. The use of bisphosphonates in metastatic disease is a palliative care Therapy for Bone Metastases measure. No impact on OS has been observed in patients treated with Complications from bone metastases include pain, decreased bisphosphonates. performance status, and decreased QOL, as well as skeletal-related events (SREs), which are defined as the need for radiation or surgery to The data indicate that zoledronic acid and pamidronate may be given on a bone, pathologic fractures, spinal cord compression, and hypercalcemia of 3- to 4-week schedule in conjunction with antineoplastic therapy (i.e., malignancy. endocrine therapy, chemotherapy, biologic therapy) or every 12 weeks. Three randomized trials have compared zoledronic acid dosed every 4 The NCCN Panel recommends treatment with a bone modifying agent weeks versus every 12 weeks.504-506 Data from these trials show that such as zoledronic acid, pamidronate or denosumab (category 1) in among patients with breast cancer and bone metastases zoledronic acid addition to chemotherapy or endocrine therapy if bone metastasis is administered once every 12 weeks versus once every four weeks does not Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-56 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer compromise efficacy and has similar rates of SREs.504,505,507 In the ZOOM of zoledronic acid every 4 weeks, and a subcutaneous placebo. In this trial trial,504 the rate of skeletal morbidities was 0.22 (95% CI, 0.14 to 0.29) in with non-inferiority as the primary endpoint, denosumab was shown to those receiving zoledronic acid every 4 weeks versus and 0.26 (95% CI, significantly delay time to first SRE by 18% as compared with zoledronic 0.15 to 0.37) those receiving zoledronic acid every 12 weeks. In the acid (HR, 0.82; 95% CI, 0.71–0.95; P < .001 for non-inferiority; P = .01 for CALGB 70604 trial,505 the rate of SRE rate in the 4-week arm was 29.5% superiority) and time to first and subsequent SREs (rate ratio, 0.77; 95% versus 28.6% in the 12-week arm. In OPTIMIZE-2 trial,506 the rate of SREs CI, 0.66–0.89; P = .001). No difference in time to progression or OS was was 22% of the in the 4-week arm and 23.2% in the 12-week arm.506 The observed.509 Dosing of denosumab outside of every 3-6 weeks has not NCCN Panel recommends an optimal dosing of every 12 weeks. been studied. Systemic Therapy for Stage IV or Recurrent Metastatic HR- Positive, The use of bisphosphonates should be accompanied by calcium and HER2-Negative Breast Cancer vitamin D supplementation with daily doses of calcium of 1200 to 1500 mg Patients with Stage IV or recurrent disease characterized by tumors that and vitamin D3 of 400 to 800 IU. Recommended agents for use in the are HR-positive, HER2-negative tumors with no visceral crisis are treated United States are pamidronate 90 mg intravenously over 2 hours or with endocrine therapy alone or endocrine therapy in combination with zoledronic acid 4 mg intravenously over 15 minutes. The original studies targeted agents. continued treatment for up to 24 months; however, there are limited long-term safety data indicating treatment can continue beyond that Patients whose disease progresses after a year from the end of adjuvant time.499,501,508 The risk of renal toxicity necessitates monitoring of serum endocrine-based therapy and those who present with de novo Stage creatinine prior to administration of each dose and dose reduction or IV/metastatic breast cancer are eligible for first-line endocrine therapies. discontinuation if renal function is reduced. Current clinical trial results support the use of bisphosphonates for up to 2 years. Longer durations of Many premenopausal and postmenopausal patients with HR-positive bisphosphonate therapy may provide additional benefit, but this has not breast cancer benefit from sequential use of endocrine therapies at yet been tested in clinical trials. disease progression. Therefore, patients with breast cancers who respond to an endocrine-based therapy with either shrinkage of the tumor or Denosumab long-term disease stabilization (clinical benefit) should receive additional Patients with metastatic breast cancer to bone who are candidates for endocrine therapy at disease progression. For disease progression on or bisphosphonate therapy may also be considered for treatment with within 12 months of completing adjuvant endocrine or for disease denosumab. This recommendation is based on the results of a single progression on first-line endocrine therapy for metastatic disease are randomized trial comparing denosumab to zoledronic acid.509 All trial eligible for second-line endocrine therapy either as monotherapy or in patients were recommended to supplement with vitamin D and calcium. combination with a targeted agent. The optimal sequence for endocrine Patients on the experimental arm were given 120 mg of denosumab therapy is not well defined. The choice would depend on previous, injected subcutaneously every 4 weeks plus intravenous placebo versus tolerance of treatment, and patient preference. the control arm where patients were given an intravenous infusion of 4 mg Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-57 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Many trials in HR-positive patients have not included premenopausal compared with letrozole alone.511 Grade 3 or 4 adverse events were more patients. The NCCN Panel that recommends patients with HR-positive common with the combination included neutropenia (62% vs. 1.2%), disease should have adequate ovarian suppression/ablation and then be leukopenia (21.3% vs. 0.9%), and abnormal liver function tests (10.2% vs. treated in the same way as post-menopausal patients. The NCCN panel 2.4%).511 has outlined endocrine-based therapies that would be used in the first-line versus second- and subsequent-line settings. The phase III MONARCH trial studied the combination of abemaciclib with either an AI (letrozole or anastrozole) versus AI monotherapy as first-line Preferred First Line therapy for HR- Positive, HER2-Negative Breast treatment of patients with advanced HR-positive, HER2-negative breast Cancer cancer. The combination of abemaciclib with the AI improved PFS, Aromatase inhibitor in combination with CDK 4/6 inhibitor: In compared with AI alone (median not reached versus 14.7 months, postmenopausal patients or premenopausal patients receiving ovarian respectively; HR 0.54, 95% CI 0.41-0.72).512 The ORR was higher with the ablation or ovarian function suppression with an LHRH agonist, combination compared with AI monotherapy (59% vs. 44 %).512 The most combinations of aromatase inhibitors (AI) with CDK 4/6 inhibitors frequent grade 3 or higher adverse events for abemaciclib versus placebo (palbociclib, ribociclib, or abemaciclib) have demonstrated improved PFS included diarrhea (9.5% vs.1.2%), neutropenia (21.1% vs. 1.2%), relative to an AI alone. leukopenia (8% vs. 0.6%) and fatigue (2% versus 0%).512 Palbociclib in combination with letrozole was studied in a phase III study Most trials studying CDK 4/6 inhibitor with an AI have mainly included that included postmenopausal patients (n =666) with metastatic, postmenopausal patients and only a small subset of premenopausal HR-positive, HER2-negative breast cancer who had not received prior patients on ovarian suppression. However, in the phase III treatment for advanced disease.510 An improvement in PFS (24.8 vs. 14.5 MONALEESA-7 trial, 672 pre- or perimenopausal patients with months; hazard ratio [HR] 0.58, 95% CI 0.46-0.72) and objective response HR-positive, HER2-negative, advanced breast cancer were randomly rate (ORR; 42 vs. 35 percent) was seen with the combination of assigned to first-line treatment with ribociclib or placebo with goserelin palbociclib and letrozole compared with letrozole alone.510 Grade 3 and 4 plus either a non-steroidal AI or tamoxifen.513 An improvement in PFS was adverse effects seen with the combination of palbociclib and letrozole seen with the addition of ribociclib (median PFS, 24 versus 13 months; HR included neutropenia (66.5% vs. 1.4%), leukopenia (24.8% vs. 0%), 0.55, 95% CI 0.4-0.69).513 anemia (5.4% vs. 1.8%) and fatigue (1.8% vs. 0.5%).510 At 3.5 years, an improvement in OS was reported with ribociclib (70% vs. Ribociclib in combination with letrozole was also studied as first-line 46%; HR 0.71, 95% CI 0.54-0.95).514 Grade 3 and 4 adverse events therapy in a phase III study of postmenopausal patients (n=668) with reported in greater than 10% of patients in either group included HR-positive, HER2-negative recurrent/Stage IV breast cancer. At a neutropenia (61% vs. 4%) and leukopenia (14% vs. 1%).513 median follow-up of 26.4 months, an improvement in PFS (25.3 vs. 16.0 months; HR for progression or death was 0.56, 95% CI 0.45-0.70) and Based on the above data, the NCCN panel has included AI in combination improved ORR of 43% vs. 29% was seen with ribociclib plus letrozole with CDK 4/6 inhibitors as a category 1 first-line option for Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-58 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer postmenopausal patients and premenopausal patients with ovarian death 0.797, 95% CI 0.637-0.999).520 The QOL outcomes were similar ablation/suppression with HR-positive, HER2-negative recurrent/stage IV between the two groups, with the most common adverse effects being breast cancer. arthralgia (17% vs. 10%) and hot flashes (11% vs. 10%) for fulvestrant and anastrozole, respectively.520 Single agent fulvestrant: Fulvestrant is an estrogen receptor (ER) antagonist and was originally approved as a monthly intramuscular Fulvestrant + CDK 4/6 inhibitor: In the phase III trial MONALEESA-3, injection (250 mg per month); higher dose has been proven to be more patients (n = 726) with advanced HR-positive breast cancer who had no effective in subsequent randomized trials. In the first-line setting, prior endocrine therapy or had disease progression on prior therapy, the fulvestrant was found to be as effective as anastrozole in terms of ORR combination of ribociclib with fulvestrant showed improved in PFS versus (36.0% vs. 35.5%; odds ratio, 1.02; 95% CI, 0.56 –1.87).515 An improved fulvestrant alone (21 vs. 13 months; HR 0.59, 95% CI 0.48-0.73).521 The time to progression was seen with fulvestrant compared to anastrozole PFS benefits were consistent across patients with and without prior (median time to progression was 23.4 months for fulvestrant versus 13.1 endocrine treatment. In a subsequent analysis, a significant improvement months for anastrozole; HR, 0.63; 95% CI, 0.39– 1.00; P = .0496).516 This in OS was observed.522 At 42 months the estimated OS was 57.8% (95% study also used a higher loading dose of 500 mg every 2 weeks for 3 confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% doses and then maintenance dose of 500 mg monthly.515 The median OS (95% CI,36.9 to 54.5) in the placebo group.522 was observed to be longer in the fulvestrant group than in the anastrozole group (54.1 months vs. 48.4 months; HR, 0.70; P = .041).517 Comparison across multiple trials, including those in the second-line settings studying combination of fulvestrant with palbociclib or abemaciclib A separate phase III randomized study in postmenopausal patients with have shown statistically significant improvement in PFS. Based on the metastatic HR-positive breast cancer compared fulvestrant 500 mg every results of the Monaleesa-3 trial and extrapolation results from the 2 weeks for 3 doses followed by 500 mg monthly versus fulvestrant 250 second-line setting, the NCCN Panel has included fulvestrant in mg monthly. The PFS was superior with the fulvestrant 500 mg regimen combination with CDK 4/6 inhibitors as a category 1 first-line option for (HR, 0.80; 95% CI, 0.68–0.94; P = .006),518 indicating an increased postmenopausal patients and premenopausal patients with ovarian duration of response with the higher dose of fulvestrant. The final analyses ablation/suppression with HR-positive, HER2-negative recurrent/stage IV demonstrated an increase in median OS (4.1 months) and reduced risk of breast cancer. death (19%) with a dose of 500 mg compared with 250 mg. Median OS was 26.4 versus 22.3 months (HR, 0.81; 95% CI, 0.69–0.96; P = .02).519 Fulvestrant + non-steroidal AI: Combination of two endocrine agents as first-line treatment in postmenopausal patients with HR-positive, Results from another phase III trial (FALCON) of first-line treatment with metastatic breast cancer has been reported from studies comparing fulvestrant compared with anastrozole in endocrine therapy-naive patients single-agent anastrozole versus anastrozole plus fulvestrant. with metastatic ER-positive breast cancer, demonstrated improved PFS with fulvestrant (at the higher dose, 500 mg) over anastrozole at a median In one study (FACT), combination of fulvestrant with anastrozole was not follow-up of 25.0 months (16.6 vs. 13.8 months, HR for progression or superior to single-agent anastrozole (time to progression HR, 0.99; 95% Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-59 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer CI, 0.81–1.20; P = .91).523 In a second phase III trial (SoFEA), the effect of The NCCN Panel has included an AI and fulvestrant as first-line therapy fulvestrant alone or in combination with anastrozole or exemestane was (category 1) for postmenopausal patients based on the above data. studied in patients with advanced breast cancer with acquired resistance to an non-steroidal AI.524 An AI had been given as adjuvant treatment to Monotherapy with endocrine agents: In postmenopausal patients there is 18% of patients for a median of 27.9 months, and to 82% of patients for evidence supporting the use of an AI as first-line therapy for their recurrent locally advanced/metastatic disease for a median of 19.3 months. Median disease.527,528 PFS was 4.8 months, 4.4 months, and 3.4 months for patients treated with Prospective randomized trials comparing the AI head-to-head have fulvestrant alone, anastrozole plus fulvestrant, and fulvestrant plus demonstrated that all AI’s are the same.529 Tamoxifen is the commonly exemestane, respectively. No differences were observed for ORR, clinical used SERM for premenopausal patients.530 In postmenopausal patients, benefit rate, and OS. AI monotherapy has been shown to have superior outcome compared with In the trial by the Southwest Oncology Group (SWOG), S0226, PFS (HR, tamoxifen, although the differences are modest.531-535 A randomized phase 0.80; 95% CI, 0.68–0.94; stratified log-rank P = .007) and OS (HR, 0.81; III trial comparing tamoxifen with exemestane as first-line endocrine 95% CI, 0.65–1.00; stratified P = .049) were superior with combination therapy for postmenopausal patients with metastatic breast cancer anastrozole plus fulvestrant.525 In a subgroup analysis in this trial showed no significant differences PFS or OS between the two arms.533 suggested that patients without prior adjuvant tamoxifen experienced the NCCN recommendations for first-line therapy: For postmenopausal greatest OS benefit with combination therapy compared with monotherapy patients with HR-positive, HER2-negative recurrent/stage IV breast (median, 52.2 months vs.40.3 months, respectively; hazard ratio, 0.73; cancer, NCCN category 1, preferred regimens include a cyclin-dependent 95% CI, 0.58 to 0.92).526 kinase (CDK) 4/6 inhibitor with an aromatase inhibitor (AI); fulvestrant with The reasons for the divergent outcomes in the above trials is not very or without a CDK 4/6 inhibitor; Fulvestrant with a non-steroidal AI. The clear. The three trials discussed above had slightly different patient NCCN category 2A, preferred regimen includes non-steroidal AI populations- there were more cases of patients with no prior endocrine (anastrozole, letrozole); steroidal aromatase inhibitor (exemestane), and exposure (with de novo stage IV metastatic disease) in the SWOG S0226 selective estrogen receptor modulator (tamoxifen or toremifene). For trial compared with the FACT trial. The FACT trial included a more premenopausal patients, first-line endocrine treatment includes ovarian heterogeneous population of both premenopausal and postmenopausal suppression/ablation and endocrine therapy listed above for patients with locally advanced and metastatic disease. The SoFEA trial postmenopausal patients or alternately with a selective estrogen- receptor only enrolled patients with acquired endocrine resistance (who had modulator (SERM) alone. disease progression while they were receiving an aromatase inhibitor). Preferred regimens for Second and Subsequent Lines of therapy for Further studies are needed to confirm the results of the SWOG S0226 HR- Positive, HER2-Negative Breast Cancer trial. Fulvestrant containing regimens Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-60 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Fulvestrant + CDK 4/6 inhibitors: Fulvestrant in combination with a CDK recurrent/stage IV breast cancer. The panel notes if there is disease 4/6 inhibitor may be offered to patients who experienced disease progression while on CDK4/6 inhibitor therapy, there are limited data to progression during prior treatment with AIs with or without one line of prior support an additional line of therapy with another CDK4/6 chemotherapy (category 1), because PFS was improved compared with inhibitor-containing regimen. fulvestrant alone in a phase III trial (PALOMA-3).536 The NCCN panel notes that treatment should be limited to those without prior exposure to Fulvestrant monotherapy: Fulvestrant monotherapy appears to be at least CDK 4/6 inhibitors as effective as anastrozole in patients whose disease progressed on previous tamoxifen.540,541 A randomized phase II study compared The phase III trial (PALOMA-3) compared the combination of palbociclib anastrozole versus fulvestrant in over 200 patients with advanced breast and fulvestrant to fulvestrant in pre- or post-menopausal HR-positive, cancer.515,516 In the initial analysis, fulvestrant was as effective as HER2-negative advanced breast cancer patients, whose disease anastrozole in terms of ORR (36.0% vs. 35.5%; odds ratio, 1.02; 95% CI, progressed on prior endocrine therapy. Pre- or peri-menopausal patients 0.56 –1.87; P = .947) in evaluable patients (n = 89 for fulvestrant and n = also received goserelin. The median PFS was 9.5 months for the 93 for anastrozole).515 An improved time to progression was seen with combination compared to 4.6 months for fulvestrant (HR 0.46, P < fulvestrant compared to anastrozole (median time to progression was 23.4 .000001)537 Grade 3/4 adverse events of palbociclib and fulvestrant were months for fulvestrant vs. 13.1 months for anastrozole; HR, 0.63; 95% CI, mainly confined to neutropenia (in 65% of patients). 0.39– 1.00; P = .0496).516 This study used a higher 500 mg loading dose every 2 weeks for 3 doses and then 500 mg monthly.515 The median OS In the MONARCH 2 phase III trial, patients who had disease progression was observed to be longer in the fulvestrant group than in the anastrozole while receiving endocrine therapy were randomly assigned to fulvestrant group (54.1 months vs. 48.4 months; HR, 0.70; P = .041).517 with or without abemaciclib.538 Those receiving combination therapy experienced an improved PFS relative to those receiving fulvestrant alone A phase II study of fulvestrant in postmenopausal patients with advanced (16.4 versus 9.3 months; HR 0.55, 95% CI 0.45-0.68). The ORR was breast cancer and disease progression following aromatase inhibitor higher in those receiving abemaciclib and fulvestrant (48% vs. 21%).538 In therapy documented a partial response rate of 14.3% with an additional addition, am improvement was seen in OS with abemaciclib plus 20.8% of patients achieving stable disease for at least 6 months.542 The fulvestrant compared with fulvestrant alone (46.7 versus 37.3 months; HR clinical benefit rates of exemestane versus fulvestrant observed in a phase 0.757 95% CI 0.606-0.945).539 III trial of postmenopausal patients with HR-positive advanced breast cancer who experienced disease progression on prior nonsteroidal Based on the above data that shows addition of a CDK 4/6 inhibitor to aromatase inhibitor therapy were comparable (32.2% vs. 31.5%; P = fulvestrant in patients previously exposed to prior endocrine therapy, .853).543 In that study, fulvestrant was administered as a 500 mg loading provides a significant improvement in median PFS, the NCCN Panel has dose followed by doses of 250 mg on day 14, day 28, and then monthly.543 included fulvestrant in combination with a CDK 4/6 inhibitor as a category 1 option for postmenopausal patients and premenopausal patients with Fulvestrant plus alpelisib: In a randomized phase III trial of patients ovarian ablation/suppression with HR-positive, HER2- negative (n=572) with advanced HR-positive breast cancer and confirmed Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-61 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha was 4.5 months (95% CI, 3.7–8.7) with tamoxifen alone versus 8.5 months (PIK3CA) status, all of whom had received a prior AI either for local or (95% CI, 6.01–13.9) with everolimus and tamoxifen.545 advanced disease. Patients were enrolled into either PIK3CA mutant (n=341) cohort or the PIK3CA non-mutant cohort and each cohort was A phase III trial in postmenopausal patients with advanced, HR-positive randomized to receive fulvestrant plus the phosphoinositide 3-kinase breast cancer with no prior endocrine therapy for advanced disease, (PI3K) inhibitor, alpelisib versus fulvestrant plus placebo. Patients with randomized subjects to letrozole with or without the mTOR inhibitor PIK3CA mutation, receiving alpelisib showed improved PFS compared to temsirolimus has been reported.546 In this study, PFS was not different fulvestrant alone. At a median follow-up of 20 months PFS was 11.0 between the treatment arms (HR, 0.89; 95% CI, 0.75–1.05; log-rank P = months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib group .18). compared with 5.7 months (95% CI, 3.7 to 7.4) in the group that received The results of this trial differ from that of the BOLERO-2 trial (described fulvestrant alone (HR for progression or death, 0.65; 95% CI, 0.50 to 0.85; below). The reasons for the differences in the outcomes of these two P < .001); in the cohort without PIK3CA-mutated tumors, the HR was 0.85 randomized phase III studies546,547 is uncertain, but may be related to the (95% CI, 0.58 to 1.25). In the overall population, the most frequently issues of patient selection and extent of prior endocrine therapy. reported grade 3 or 4 adverse events seen with alpelisib and fulvestrant versus fulvestrant alone were hyperglycemia (36.6% vs.0.7%); rash (9.9% A phase III study (BOLERO-2) randomized postmenopausal patients with vs. 0.3%) and diarrhea (grade 3) ( 6.7% vs. 0.3%); no diarrhea or rash of HR-positive advanced breast cancer that had disease progression or grade 4 was reported.544 recurrance during treatment with a nonsteroidal aromatase inhibitor to exemestane with or without the mTOR inhibitor everolimus.548 Final results Everolimus plus endocrine therapy: Resistance to endocrine therapy in reported after median 18-month follow-up show that median PFS (by patients with HR-positive disease is frequent. One mechanism of central review) remained significantly longer with everolimus plus resistance to endocrine therapy is activation of the mammalian target of exemestane versus placebo plus exemestane at 11.0 versus 4.1 months, rapamycin (mTOR) signal transduction pathway. respectively; (HR, 0.38; 95% CI, 0.31–0.48; P < .0001).547 The adverse A randomized phase II study estimated the efficacy of tamoxifen alone events (all grades) that occurred more frequently in those receiving versus tamoxifen combined with everolimus, an oral inhibitor of mTOR, in everolimus included stomatitis, infections, rash, pneumonitis, and patients with HR-positive, HER2-negative metastatic breast cancer hyperglycemia.547,548 Analysis of safety and efficacy in the elderly patients previously treated with an aromatase inhibitor.545 After a median follow-up enrolled in this trial showed that elderly patients treated with an of 13 months, an intent-to-treat analysis showed that the clinical benefit everolimus-containing regimen had similar incidences of these adverse was 42.1% (95% CI, 29.1–55.9) with tamoxifen alone and 61.1% (95% CI, events, but the younger patients had more on-treatment deaths.549 Based 46.9–74.1) with tamoxifen plus everolimus. An improvement in median on the evidence from the BOLERO-2 trial, the NCCN Panel has included time to progression was seen when everolimus was combined with everolimus plus exemestane as an option for patients who fulfill the entry tamoxifen compared with tamoxifen alone. Median time to progression criteria for BOLERO-2. Tamoxifen or fulvestrant in combination with everolimus have also been included as options. The NCCN panel also Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-62 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer notes that if there is disease progression while on an Megestrol acetate,527,553-555 estradiol556 androgens such as everolimus-containing regimen, there are no data to support an additional fluoxymesterone, and single agent abemaciclib have been listed as line of therapy with another everolimus regimen. options useful in certain circumstances. Aromatase inhibitors: Aromatase Inhibitors as monotherapy are options as The phase II MONARCH 1 trial, evaluated the activity of abemaciclib as a subsequent-line therapy. The three AIs (anastrozole, letrozole, and single agent in patients (n =132) with refractory HR-positive, exemestane) have shown similar efficacy in the second-line HER2-negative metastatic breast cancer who had disease progression setting.529,550,551 AI monotherapy maybe be useful in patients desiring while on endocrine therapy and already received multiple systemic single-agent treatment, if they have not received an AI as first-line therapies (average of three prior systemic regimens).557 Ninety percent of treatment or in patients who may not be suitable for combination therapy. patients had visceral disease and 50.8% had more than three sites of Patients who have received a prior nonsteroidal AI may benefit from a metastases.557 Single-agent abemaciclib induced partial response in 26 steroidal AI as subsequent -line of therapy or vice-versa. (19.7%) and demonstrated an ORR of 19.7% (95% CI: 13.3–27.5).557 Median PFS was 6 months (95% CI: 4.2–7.5). At the final analysis, at 18 Selective estrogen receptors modulator: An analysis of two randomized months, median OS was 22.3 months (95% CI: 17.7–not reached).557 studies of first-line treatment with anastrozole followed by second-line Diarrhea was the most frequent adverse event reported in 90.2% patients. tamoxifen and vice versa showed that tamoxifen is effective as Other common adverse events were fatigue (65.2%), nausea (64.4%) and second-line option.552 decreased appetite (45.5%). Grade 3 and 4 neutropenia occurred in 26.9% of patients.557 The NCCN panel has included single agent NCCN recommendations for second-line: For postmenopausal patients abemaciclib as an option for those with disease progression on prior with HR-positive, HER2-negative recurrent/stage IV breast cancer, the endocrine therapy and prior chemotherapy in the metastatic setting. preferred options available include fulvestrant with a CDK 4/6 inhibitor (palbociclib, ribociclib, abemaciclib) (category1), or for those with tumor Systemic Therapy for Stage IV or Recurrent HR-Negative, HER2-Positive PIK3CA mutations, fulvestrant with alpelisib, everolimus with either an AI, Breast Cancer tamoxifen or fulvestrant; monotherapy with fulvestrant, non-steroidal or For patients with HER2-positive, HR-negative recurrent/stage IV breast steroidal AI, or SERM. Estrogen receptor 1 (ESR1) activating mutations cancer, the treatment approach is HER2-targeted therapy in combination are frequently detected in patients with prior exposure to AIs. Tumors with with systemic chemotherapy. The NCCN panel notes that an these mutations are generally resistant to both AIs and tamoxifen. Certain FDA-approved biosimilar is an appropriate substitute for trastuzumab. tumors with these mutations retain sensitivity to fulvestrant. All may benefit Also, trastuzumab and hyaluronidase-oysk injection for subcutaneous use by adding one of the following to fulvestrant - a CDK 4/6-inhibitor, or an may be substituted for trastuzumab. This subcutaneous option has mTOR-inhibitor, or alpelisib, if the tumor has PIK3CA mutation. different dosage and administration instructions compared to intravenous trastuzumab. Doses and schedules of representative regimens for use in Regimens Useful in Certain Circumstances for Therapy for HR- Positive, HER2-positive metastatic breast cancer are also included in NCCN HER2-Negative Breast Cancer Guidelines. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-63 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Patients with disease progression while being treated with HER2-targeted the two treatment groups.560 In the PERUSE study, patients (n=1436) with therapy should be offered additional line of treatment with a advanced HER2-positive breast cancer and no prior systemic therapy HER2-targeted therapy since it is beneficial to continue suppression of the (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel HER2 pathway. The choice of the HER2-targeted therapy will depend on with trastuzumab and pertuzumab until disease progression or previously administered therapy, relapse-free interval, and patients’ unacceptable toxicity. The preliminary results after 52 months median preference and access. follow-up, show that median PFS was comparable between docetaxel, paclitaxel and nab-paclitaxel (median PFS reported was19.6, 23.0 and The optimal sequence of available HER2-targeted therapies and the 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively).561 optimal duration of HER2-targeted therapy for recurrent/stage IV is Compared with docetaxel-containing therapy, paclitaxel-containing therapy currently unknown. The NCCN panel recommends continuing was associated with more neuropathy (31% vs. 16%), but less febrile HER2-targted therapy until progression/unacceptable toxicity. neutropenia (1% vs. 11%) and mucositis (14% vs. 25%). Phase II trials have also found activity and tolerability for pertuzumab, Preferred Regimens for Stage IV/Recurrent HER2-Positive Breast Cancer pertuzumab with trastuzumab, and for other regimens combining A randomized, double-blind, phase III study (CLEOPATRA) compared the pertuzumab and trastuzumab together with other active cytotoxic agents efficacy and safety of pertuzumab in combination with trastuzumab and (i.e., paclitaxel, vinorelbine).562,563,564 Phase III trials of pertuzumab plus docetaxel versus trastuzumab and docetaxel as first-line treatment for 808 chemotherapy without trastuzumab have not been reported. patients (n=808) with HER2-positive metastatic breast cancer.558 This trial included patients (about 10%) who had previously received trastuzumab in The NCCN Panel recommends pertuzumab plus trastuzumab in the adjuvant or neoadjuvant setting. At a median follow-up of 19 months, combination with a taxane as a preferred option for first-line treatment of the addition of pertuzumab to docetaxel plus trastuzumab resulted in patients with HER2-positive metastatic breast cancer. Pertuzumab plus improvement in PFS compared with placebo (median, 18.5 versus 12.4 trastuzumab in combination with docetaxel is an NCCN category 1 and in months; hazard ratio [HR] 0.62, 95% CI 0.51-0.75, P < .001).558 At a combination with paclitaxel is an NCCN category 2A recommendation. median follow-up of 30 months the results showed a statistically significant improvement in OS in favor of the pertuzumab-containing regimen, with a Other Regimens for Regimens for Stage IV/Recurrent HER2-Positive 34% reduction in the risk of death (HR, 0.66; 95% CI, 0.52–0.84; P = Breast Cancer .0008).431 The most common adverse reactions reported in the pertuzumab group compared to the control group were diarrhea (67% vs. Ado-trastuzumab emtansine (T-DM1): T-DM1 is an antibody-drug 46%), rash(34% vs. 24%), mucosal inflammation (27% vs. 20%), febrile conjugate that stably links the HER2-targeting property of trastuzumab to neutropenia (14% vs. 8%), and dry skin(10% vs. 4%). Peripheral edema the cytotoxic activity of the microtubule-inhibitory agent DM1 (derivative of and constipation were greater in the control group.558 Cardiac adverse maytansine). events or left ventricular systolic dysfunction were reported slightly more In a phase III trial (MARIANNE), 1,095 patients with locally advanced or frequently in the control group.559 Health-related QOL was not different in metastatic breast cancer were randomized to first-line treatment with Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-64 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer T-DM1 with or without pertuzumab or trastuzumab plus a taxane. The dysfunction in patients treated with the combination of trastuzumab and primary endpoints were safety and PFS assessed by independent review. doxorubicin/cyclophosphamide chemotherapy in the metastatic setting is The PFS for T-DM1 with pertuzumab was found non-inferior to too high for use of this combination outside the confines of a prospective trastuzumab and a taxane (15.2 and 13.7 months respectively; HR, 0.87; clinical trial.566,571,572 97.5% CI, 0.69–1.08; P = .14).565 The PFS for T-DM1 alone was non-inferior to trastuzumab plus a taxane (14.1 and 13.7, respectively; In those with disease progression on first-line trastuzumab-containing HR, 0.91; 97.5% CI, 0.73–1.13; P = .31).565 The incidence of Grade 3–5 regimens, the NCCN Panel recommends continuation of HER2 blockade. adverse events was 54.1%, 45.4%, and 46.2% in the trastuzumab plus a This recommendation also applies to patients who are diagnosed with taxane arm, T-DM1 arm, and T-DM1 plus pertuzumab arm, respectively. HER2-positive metastatic disease after prior exposure to trastuzumab in Health-related QOL was maintained for a longer duration with a median of the adjuvant setting. Several trials have demonstrated benefit of 7.7 months for T-DM1 (HR, 0.70; 95% CI, 0.57–0.86) and a median of 9 continuation of trastuzumab therapy following disease progression on a months for T-DM1 plus pertuzumab (HR, 0.68; 95% CI, 0.55–0.84) trastuzumab-containing regimen.573-575 However, the optimal duration of compared with a median of 3.9 months for trastuzumab and a taxane.565 trastuzumab in patients with long-term control of disease is unknown. Based on the MARIANNE trial data demonstrating T-DM1 and T-DM1 with Pertuzumab is active in patients beyond the first-line setting. The results of pertuzumab being non-inferior, with better QOL compared with a multicenter, open-label, single-arm, phase II study (n = 66) show that the trastuzumab plus taxane and possibly better-tolerated for some patients, combination of pertuzumab and trastuzumab is active and well tolerated in 565 the NCCN Panel included T-DM1 as an option for treatment of patients patients with HER2-positive metastatic breast cancer that has progressed with HER2-positive metastatic breast cancer. Pertuzumab, trastuzumab, on prior trastuzumab therapy.576 The trial reported an objective response and a taxane, however, remains the preferred first-line regimen for rate of 24.2% (16 patients out of 66). The median PFS time observed with HER2-positive metastatic disease based on data demonstrating improved pertuzumab and trastuzumab combination was 15.5 months (range, 0.9– OS compared to trastuzumab and a taxane. TDM-1 as first-line therapy 17.0 months; 80% CI, 18-31 months.576 The reported median duration of should be considered only in those not suitable for the preferred treatment. response with the combination was 5.8 months (range, 2.9–15.3 months).576 First-line trastuzumab in combination with selected chemotherapy566 are additional options for HER2-positive metastatic breast cancer patients. To determine whether the clinical benefit seen in the study was from Randomized trials demonstrate benefit from adding trastuzumab to other pertuzumab alone or was a result of the combined effect of pertuzumab agents including paclitaxel with or without carboplatin,566-569 docetaxel,567 and trastuzumab, a cohort of patients (n = 29) whose disease progressed and vinorelbine,567 for patients with HER2-positive metastatic disease. In during prior trastuzumab-based therapy received pertuzumab addition, the combination of trastuzumab and capecitabine has also shown monotherapy until progressive disease or unacceptable toxicity. Of these, efficacy as a first-line trastuzumab-containing regimen in this setting.570,571 patients with disease progression (n = 17) continued to receive The NCCN panel believes the 27% frequency of significant cardiac pertuzumab with the addition of trastuzumab. In the 29 patients who received pertuzumab monotherapy, the objective response rate and Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-65 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer clinical benefit rate reported were 3.4% and 10.3%, respectively, whereas A phase II single-arm study evaluated fam-trastuzumab deruxtecan-nxki, a in the patients who received dual blockade after disease progression while HER2 antibody conjugated with a topoisomerase I inhibitor, in adults on pertuzumab, the objective response rate and clinical benefit rate were (n=184) with pathologically documented HER2-positive metastatic breast 17.6% and 41.2%, respectively.577 cancer who had received multiple previous treatments including treatment with T-DM1.579 After a median duration of follow-up of 11.1 months (range According to the NCCN Panel, for patients with disease progression after 0.7- to 19.9), the median response duration with fam-trastuzumab treatment with trastuzumab-based therapy without pertuzumab, a line of deruxtecan-nxki was 14.8 months (95% CI, 13.8 to 16.9), and the median therapy containing both trastuzumab plus pertuzumab with or without a PFS was 16.4 months (95% CI, 12.7 to not reached).579 Most commonly cytotoxic agent (such as vinorelbine or taxane) may be reported adverse events (grade 3 or higher) were a decreased neutrophil considered. Further research is needed to determine the ideal sequencing count (20.7%), anemia (in 8.7%), nausea (in 7.6%), and fatigue (6%).579 strategy for HER2-targeted therapy. Interstitial lung disease (ILD) was reported in 13.6% of the patients (grade 1 or 2 - 10.9%; grade 3 or 4 - 0.5%; and grade 5 - 2.2%). Based on this T-DM1 also has also shown activity in the second-line setting. A study and the approval from the U.S. FDA, the NCCN panel has included randomized, international, multicenter, open-label, phase III study this as an option for HER-2 positive metastatic disease noting that it is (EMILIA) evaluated the safety and efficacy of T-DM1 compared with indicated in patients after two or more lines of prior HER2-targeted therapy lapatinib plus capecitabine for HER2-positive patients with locally regimens in the metastatic setting and contraindicated for those with a advanced breast cancer or metastatic breast cancer previously treated history of or active ILD. with trastuzumab and a taxane.578 The primary endpoints of this study were PFS, OS, and safety. T-DM1 demonstrated a statistically significant Lapatinib in combination with capecitabine or trastuzumab are options for improvement in both primary endpoints of PFS and OS. PFS (assessed by patients with HER2-positive disease following disease progression on a independent review) was significantly improved with T-DM1 with median trastuzumab-containing regimen. PFS of 9.6 months vs. 6.4 months with lapatinib plus capecitabine; HR for progression or death from any cause was 0.65 (95% CI, 0.55–0.77; P < A phase III study compared lapatinib plus capecitabine with capecitabine .001). At the first interim analysis, T-DM1 also demonstrated significant alone in patients with advanced or metastatic breast cancer refractory to improvement in OS. The stratified HR for death from any cause with trastuzumab in the metastatic setting and with prior treatment with an T-DM1 versus lapatinib plus capecitabine was 0.62 (95% CI, 0.48–0.81; P anthracycline and a taxane in either the metastatic or adjuvant setting.580 = .0005).578 Rates of grade 3 or 4 adverse events were higher with Time to progression was increased in the group receiving combination lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The therapy when compared with the group receiving capecitabine incidences of thrombocytopenia and increased serum aminotransferase monotherapy (8.4 months vs. 4.4 months; HR, 0.49; 95% CI, 0.34–0.71; P levels were higher with T-DM1 (frequency >25%), whereas the incidences < .001). The patients who had disease progression on monotherapy were of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were allowed to cross over to the combination arm. This resulted in insufficient higher with lapatinib plus capecitabine.578 power to detect significant differences in OS; an exploratory analysis Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-66 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer demonstrated a trend toward a survival advantage with lapatinib plus lapatinib plus capecitabine until disease progression.585 All enrolled capecitabine.581 The analysis reported a median OS of 75.0 weeks for the patients received a least two lines of prior HER2-targeted treatment in the combination arm and 64.7 weeks for the monotherapy arm (HR, 0.87; 95% metastatic setting. Approximately 30% had received ≥3 prior treatment CI, 0.71–1.08; P = .210).581 lines. About a third of all patients had received prior treatment with trastuzumab, pertuzumab and T-DM1. Results from a phase III trial in which patients with heavily pretreated metastatic breast cancer and disease progression on trastuzumab therapy The ORR (32.8 % vs. 26.7%; P = .1201), the clinical benefit rate (44.5% randomly assigned to trastuzumab plus lapatinib or lapatinib monotherapy vs 35.6%; P = .0328), and median duration of response (8.5 vs 5.6 showed that PFS was increased from 8.1 weeks to 12 weeks (P = .008) months) all favored the neratinib arm. Fewer patients required intervention with the combination.582 The OS analysis data showed that lapatinib plus for CNS metastases with neratinib. The risk of progression was reduced trastuzumab improved median survival by 4.5 months, with median OS of by 24% in the neratinib group (HR 0.76; 95% CI 0.63–0.93; P = .0059). 14 months for the combination therapy and 9.5 months for lapatinib alone There was a non-significant trend towards improved survival. The OS (HR, 0.74; 95% CI, 0.57–0.97; P = .026). 583 This improvement in OS rates at 6 and 12 months were 90.2% vs 87.5% with neratinib + analysis included patients who were initially assigned to monotherapy and capecitabine compared with 72.5% vs 66.7% for lapatinib in crossed over to receive combination therapy at the time of progression.583 combination with capecitabine (HR = 0.88; 95% CI 0.72–1.07; P= Based on the absence of data, the panel does not recommend the .2086). Diarrhea was the most frequent side effect in the NALA trial in addition of chemotherapy to the trastuzumab and lapatinib combination. both arms, but a higher rate was observed in patients in the neratinib group (any grade diarrhea 83% vs. 66%; grade 3/4 diarrhea 24% vs. In a phase II trial of patients (n=49) with progressive, HER2-positive 13%). disease and brain metastases (92% received CNS surgery and/or radiotherapy),584 were treated with capecitabine plus neratinib, Based on the results of the NALA trial and the recent FDA approval, a second-generation (irreversible) pan-HER TKI inhibitor of the tyrosine NCCN has included neratinib plus capecitabine as a category 2A option in kinase domains of EGFR, HER2 and HER4. The patients were separated this setting. based on prior lapatinib treatment. The combination therapy resulted in a CNS objective response rate of 49% (95% CI, 32% to 66%), among Systemic Therapy for Recurrent or Stage IV HR- Positive, HER2-Positive Breast Cancer lapatinib-naïve patients, and 33% (95% CI, 10% to 65%) among those with prior lapatinib treatment.584 Median PFS and OS among lapatinib-naïve Patients with Stage IV or recurrent disease characterized by tumors that patients was 5.5 and 13.3 months, and 3.1 and 15.1 months among those are HR-positive, HER2-positive tumors have the option of receiving with prior lapatinib treatment. Grade 3 diarrhea occurred in 29% of HER2-directed therapy as a component of their treatment plan. Options patients.584 include, treatment with a HER2-targeted therapy plus chemotherapy or endocrine therapy alone or in combination with HER2-targeted therapy. A prospective randomized phase III trial (NALA) randomized patients (n = Endocrine therapy alone or in combination with HER2- targeted therapy is 621) with HER2-positive to neratinib in combination with capecitabine or a less toxic approach compared with HER2-targeted therapy combined Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-67 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer with chemotherapy. Premenopausal patients treated with HER2-targeted In the randomized phase II study (PERTAIN), postmenopausal patients therapy and endocrine therapy should receive ovarian suppression or (n=258) were randomly assigned to either first-line pertuzumab plus ablation. trastuzumab and an AI (anastrozole or letrozole) or trastuzumab plus an AI. There was an improvement in PFS with the three-drug combination Adding trastuzumab or lapatinib to an AI has demonstrated a PFS (18.9 versus 15.8 months; HR 0.65, 95% CI 0.48-0.89).589 Grade 3 or advantage compared with AI alone in post-menopausal patients with stage higher adverse events observed were higher trastuzumab and pertuzumab IV or recurrent HR-positive, HER2-positive tumors. versus pertuzumab alone (50% vs. 39%). Of note, about half of patients received induction therapy with a taxane for 18 to 24 weeks prior to the In the TAnDEM study, postmenopausal patients (n =207) with metastatic initiation of endocrine therapy. Based on the results of the PERTAIN HR-positive and HER2-positive tumors were randomized to receive trial,589 the NCCN panel notes that if treatment was initiated with anastrozole alone or anastrozole plus trastuzumab.586 Compared with chemotherapy and trastuzumab plus pertuzumab, and the chemotherapy single-agent anastrozole, an improvement in PFS was seen with was stopped, endocrine therapy may be added to the trastuzumab plus combination therapy (4.8 vs. 2.4 months; HR 0.63, 95% CI 0.47-0.84, P = pertuzumab. .0016). The combination was associated with a higher incidence of toxicities (all grades) fatigue (21% vs. 9%), diarrhea (20% vs. 8%), In the ALTERNATIVE trial, postmenopausal patients (n=355) with vomiting (21% vs. 4%), and pyrexia (18% vs. 7%); serious (grade 3/4) HER2-positive, HR-positive metastatic breast cancer were randomized to toxicities were rare in both treatment arms. receive lapatinib plus trastuzumab plus an AI, lapatinib plus an AI, or trastuzumab plus AI without chemotherapy.590 All patients in the trial The phase III eLEcTRA trial studied the efficacy and safety of trastuzumab received prior trastuzumab and prior endocrine therapy, either in the plus letrozole in patients (n=93) with HER2-positive and HR-positive adjuvant or metastatic disease setting. AI in combination with lapatinib metastatic breast cancer. Median time to progression was 3.3 months with plus trastuzumab demonstrated significant increase in PFS compared with letrozole and 14.1 months with trastuzumab plus letrozole. The results are trastuzumab without lapatinib (11 vs. 5.7 months; HR 0.62, 95% CI consistent with the TAnDEM trial, however, due to smaller numbers of 0.45-0.88, P = .0064).590 Most common adverse events with the patients enrolled in this trial, this was not statistically significant (HR, 0.67; 95% CI, 0.35 to 1.29; P = .23).587 combination compared with trastuzumab or lapatinib monotherapy were diarrhea (69%, 9%, 51%), rash (36%, 2%, 28%), nausea (22%, In a phase III study of postmenopausal patients (n=219) with HER2– 9%, 22%), and paronychia (30%, 0, 15%). positive and HR–positive disease, first-line treatment with lapatinib plus letrozole reduced the risk of disease progression compared to treatment The NCCN Panel has also included other combinations of available with letrozole alone (median PFS, 8.2 months v 3.0 months; HR, 0.71, endocrine therapies such as fulvestrant or tamoxifen with trastuzumab as 95% CI, 0.53 to 0.96; P = .019).588 The combination of letrozole plus options for HR-positive and HER2-positive metastatic disease. These trastuzumab was associated with a higher rate of grade 3 or grade 4 options would be mostly considered after completion of chemotherapy toxicities, including diarrhea (10% vs. 1%) and rash (1% vs. 0%).588 plus HER2-therapy or in a few patients with indolent or asymptomatic Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-68 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer disease based on the need for continuing HER2-targeted therapy for of single agent chemotherapy (n=144).595 The median PFS among disease control. The selection of appropriate endocrine therapy would patients in the talazoparib group was longer than the control group (8.6 depend on agents the patient has already received. months [95% CI, 7.2 to 9.3] vs. 5.6 months [95% CI, 4.2 to 6.7]; HR for disease progression or death, 0.54; 95% CI, 0.41 to 0.71; P <.001).595 Systemic Therapy for Recurrent or Stage IV Disease with germline BRCA1/2 mutations Based on the results of the above phase III trials, the two FDA approved About 5% of all patients with breast cancer carry the germline breast PARP inhibitors- olaparib and talazoparib are included as a category 1, cancer susceptibility gene (BRCA) mutations and rates of these mutations preferred options for those with germline BRCA1/2 mutations. The NCCN are higher rates among those with HER2-negative disease. 591,592 Panel recommends assessing for germline BRCA1/2 mutations in all patients with recurrent or metastatic breast cancer to identify candidates PARP inhibitors: The phase III OlympiAD trial randomized patients (n= for PARP inhibitor therapy. While olaparib and talazoparib are FDA 302) with metastatic breast cancer harboring the germline BRCA indicated in HER2-negative disease, the NCCN Panel supports use in any mutations to the PARP inhibitor, olaparib (n=205) or physicians choice breast cancer subtype associated with germline BRCA1/2 mutations. (n=97) of non-platinum chemotherapy (capecitabine, eribulin or vinorelbine).593 An improvement in PFS was seen in those receiving Platinums: The phase III, TNT trial compared docetaxel with carboplatin in olaparib relative to those receiving chemotherapy [7.0 vs. 4.2 months; HR: the first-line setting in patients (n=376) with triple negative breast cancer. 0.58; 95% CI: 0.43–0.80; P< .001].593 The study, included all In the unselected population, carboplatin was not more active than subtypes- those with HR-positive, HER2-negative and positive disease, docetaxel (ORR, 31.4% vs. 34.0%; P = .66). 596 Patients with a germline and triple negative. The PFS improvements noted with olaparib were BRCA1/2 mutation had a significantly better response to carboplatin than noted in all subtypes and greatest in the triple-negative docetaxel (ORR, 68.0% vs. 33.3%, absolute difference 34.7%, P =.03). 596 population. Subsequent follow-up did not show a statistically significant PFS was also improved with carboplatin treatment in patients with difference in OS between treatment arms and the study was also not a germline BRCA1/2 mutation (median PFS 6.8 months vs. 4.4 months), powered to evaluate OS. The median OS with olaparib compared with no difference was found in OS. However, patients with somatic BRCA 1/2 treatment of physician’s choice was 19.3 months versus 17.1 months, mutation in the tumor DNA did not appear to have the same advantage. respectively (HR 0.90, 95% CI 0.66-1.23; P = .513).594 The QOL was significantly better in the olaparib arm. It is interesting to note that patients For those with triple negative recurrent/stage IV breast cancer and who had not received prior chemotherapy in the metastatic setting germline BRCA1/2 mutations, the NCCN Panel has included platinum achieved a 7.9-month longer median OS with olaparib compared with agents (cisplatin and carboplatin) as preferred treatment options. It is treatment of physician’s choice.594 unknown how PARP-inhibitors compare with platinums in this setting. The phase III EMBRACA trial patients with advanced breast cancer harboring the germline BRCA mutations and no prior exposure to a PARP inhibitor, were randomized to talazoparib (n=287) or to physicians choice Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-69 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Systemic Therapy for PD-L1–Positive, Triple Negative, Recurrent or Stage tumors.599 Atezolizumab plus albumin-bound paclitaxel is included as a IV Disease preferred option for those with advanced triple negative breast cancer with In a randomized trial (IMpassion 130), patients (n= 902) with triple PD-L1 expression in ≥1% tumor-infiltrating immune cells. negative breast cancer who had not received treatment in the metastatic setting were randomized to the programmed cell death ligand 1 (PD-L1) Systemic Chemotherapy for Recurrent or Stage IV Disease inhibitor, atezolizumab plus albumin-bound paclitaxel or placebo plus Patients with HR-negative tumors not localized to the bone or soft tissue albumin-bound paclitaxel.597 only, or that are associated with symptomatic visceral metastasis irrespective of HR- or HER-status, or that have HR-positive tumors that All patients enrolled in the trial had to have completed previous are refractory to endocrine therapy should receive systemic chemotherapy (preoperative or adjuvant) at least 12 months before chemotherapy. randomization and not received any chemotherapy in the metastatic setting. At a median follow-up of 12.9 months, there was statistically A variety of chemotherapy regimens are felt to be appropriate, as outlined significant difference in PFS in those receiving atezolizumab plus in the treatment algorithm. Combination chemotherapy generally provides albumin-bound paclitaxel than in the placebo plus albumin-bound higher rates of objective response and longer time to progression, in paclitaxel (7.2 vs. 5.5 months; HR for progression or death 0.80, 95% CI comparison to single-agent chemotherapy. Combination chemotherapy is, 0.69-0.92), and a nonsignificant trend towards improved OS (21.3 vs. 17.6 however, associated with an increase in toxicity and is of little survival months; HR for death 0.84, 95% CI 0.69-1.02).597 However, in a planned benefit.600-604 Furthermore, administering single agents sequentially subset analysis of patients with PD-L1-expressing tumors, treatment with decreases the likelihood that dose reductions will be needed. Thus, the atezolizumab plus albumin-bound paclitaxel showed statistically significant NCCN Panel finds no compelling evidence that combination improvement in PFS (7.5 vs. 5 months; HR 0.62, 95% CI 0.49-0.78), and chemotherapy is superior to sequential single agents. Therefore, OS (25 vs. 15.5 months; HR 0.62, 95% CI 0.45-0.86).597 Grade 3 or higher sequential monotherapy is the preferred and combination therapy is useful adverse events occurred in 48.7% receiving atezolizumab plus in patients with rapid clinical progression or need for rapid symptom and/or albumin-bound paclitaxel versus 42.2% receiving placebo plus disease control. albumin-bound paclitaxel. Grade 3 or 4 neuropathy was more frequently seen among those receiving atezolizumab (5.5% vs. 2.7%). There were 3 Usually the first-line regimens are given until progression or unacceptable treatment-related deaths among the patients who received atezolizumab, toxicity. Considering what is unacceptable toxicity and considering no consistent with other studies of checkpoint inhibitors. Adverse events led further cytotoxic therapy should be decided together with the patient. to treatment discontinuation in 16% in the atezolizumab arm versus 8% in Adverse effects may require dose reduction and cessation of the control arm.597 PD-L1-positive expression in tumor-infiltrating immune chemotherapy prior to disease progression. cells of 1% or more has been associated with a better outcome with PD-L1 The NCCN panel recommends considering scalp cooling to reduce inhibitor treatment.598 A subsequent 18-month follow-up analysis incidence of chemotherapy-induced alopecia for patients receiving confirmed PFS and OS benefits among those with PD-L1-expressing chemotherapy. The data on efficacy of scalp cooling is mainly from the Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-70 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer adjuvant setting and also show that results may be less effective with The NCCN Panel has classified the chemotherapy agents into three anthracycline-containing regimens.605-609 categories- preferred, other recommended and useful in certain circumstances. The treatment decision should be individualized and A metanalyses showed favorable impact on OS by prolonging treatment considering previous therapies, pre-existing comorbidities, nature of the until disease progression.610 In this analysis, data from four studies disease, toxicity profiles, patient preferences and in some cases access to involving 666 patients, indicated that median OS was increased by 23% agents. (95% confidence interval [CI] 9–38%, P = .01) in patients receiving longer durations of chemotherapy versus a limited number of cycles.610 In a Among preferred single agents, the NCCN Panel has included taxanes systematic review, longer durations of chemotherapy demonstrated a (paclitaxel), anthracyclines (doxorubicin and liposomal doxorubicin), marginal increase in OS (HR, 0.91, 95% CI 0.84–0.99) and a significant anti-metabolites (capecitabine and gemcitabine), microtubule inhibitors improvement in PFS (HR 0.66, 95% CI 0.6–0.72), compared with shorter (eribulin and vinorelbine), platinum agents for patients with triple negative durations.604 tumors and germline BRCA 1/2 mutations. A more recent study of patients (n=420) with HER2-negative, advanced Paclitaxel can be administered weekly (80 mg/m2)612 or every three weeks breast cancer showed that intermittent first-line treatment with paclitaxel (175 mg/m2).613 A meta-analysis of randomized controlled trials that plus bevacizumab was not inferior to continuous treatment. The median compared weekly and every three weeks taxanes regimens in advanced overall PFS for intermittent versus continuous was 7.4 months and 9.7 breast cancer showed that compared with every three-week treatment, months respectively (HR of 1.17 (95% CI 0.88–1.57).). Median OS was weekly administration of paclitaxel resulted in an improvement in OS (HR 17.5 months versus 20.9 months for intermittent versus continuous 0.78, 95% CI 0.67-0.89).614 treatment, with a HR of 1.38 (95% CI 1.00-1.91).611 Doxorubicin (60 to 75 mg/m2) every three weeks, or 20 mg/m2 weekly has Determining the duration of chemotherapy in an individual patient typically shown an ORR between 30 to 47%.615-618 Liposomal doxorubicin (50 depends on the efficacy and tolerability and shared decision-making mg/m2 every 4 weeks) has been shown to have efficacy similar to between the treating physician and patient. doxorubicin (60 mg/m2 every 3 weeks).619 It has also been shown to have efficacy in the second-line setting for patients with metastatic breast Most patients will be candidates for multiple lines of systemic therapies for cancer.619 Compared with doxorubicin, the liposomal doxorubicin has a palliation. At each reassessment clinicians should assess value of ongoing less frequent dosing schedule and decreased risk of cardiotoxicity 7% vs. treatment, the risks and benefits of an additional line of systemic therapy, 26%, HR 3.16; 95% CI 1.58-6.31), decreased rate of nausea (37 % vs. patient performance status, and patient preferences through a shared 53%) and vomiting (19% vs. 31%), lower rates of alopecia (20% vs. 66%), decision-making process. and neutropenia (4% vs. 10%).619 However, compared with doxorubicin it was associated with a higher rate of palmar-plantar erythrodysesthesia Preferred Chemotherapy Regimens for Stage IV or Recurrent Metastatic (48% vs. 2%), stomatitis (22% vs. 15%), and mucositis (23% vs 13%).619 Disease Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-71 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer The benefit of capecitabine as a treatment option for patients with Among other recommended single agents, the NCCN Panel has included metastatic breast cancer has been demonstrated in multiple phase II trials. taxanes (docetaxel,628 albumin-bound paclitaxel629-631), anthracyclines Results of one study of patients (n=126) treated with capecitabine showed (epirubicin) 632), and ixabepilone.633-635 as other recommended regimens. ORR of 28%, median TTP of 4.9 months and median OS of15.2 months (95% CI: 13.5-19.6 months). 620 In another study, patients (n=95) were Ixabepilone as monotherapy has been evaluated in several phase II trials randomized to capecitabine or cyclophosphamide, methotreaxate and of patients with metastatic breast cancer: in a first-line setting in patients fluorouracil (CMF). 621 Treatment with single agent capecitabine resulted in previously treated with anthracycline chemotherapy 633; in patients with a higher ORR compared with CMF (30% vs. 16%). The median TTP and taxane-resistant metastatic breast cancer634; and in patients with OS were similar in both groups.621 advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine.635 In the phase II trials, objective response rate, median Eribulin is a non-taxane microtubule inhibitor used for the treatment of duration of response, and median OS duration were 41.5% (95% CI, patients with metastatic breast cancer who have previously received at 29.4%–54.4%), 8.2 months (95% CI, 5.7–10.2 months), and 22.0 months least two chemotherapeutic regimens for the treatment of metastatic (95% CI, 15.6–27.0 months) in the first-line setting;633 12% (95% CI, disease. Prior therapy should have included an anthracycline and a taxane 4.7%– 26.5%), 10.4 months, and 7.9 months for the taxane-resistant in either the adjuvant or metastatic setting. In a phase III trial, patients patients;634 and 11.5% (95% CI, 6.3%–18.9%), 5.7 months, and 8.6 (n=762) with metastatic breast cancer were randomized 2:1 to eribulin or months for the patients previously treated with an anthracycline, a taxane, treatment of physicians’ choice. The OS was improved in patients and capecitabine.635 In the study by Perez et al,635 grade 3/4 assigned to eribulin (median 13.1 months, 95% CI 11.8-14.3) compared treatment-related toxicities included peripheral sensory neuropathy (14%) with those receiving other treatments (10.6 months, 9.3-12.5;), a 19% and neutropenia (54%). statistically significant risk reduction (HR 0·81, 95% CI 0.66-0.99; P=.041).622 The NCCN Panel had included combination chemotherapy regimens as useful in certain circumstances. The combination regimen options include A phase III trial compared eribulin with capecitabine in patients with doxorubicin/cyclophosphamide (AC);636,637 epirubicin/cyclophosphamide metastatic breast cancer and showed that both treatments were similar (EC)638; docetaxel and capecitabine;602 gemcitabine and paclitaxel with respect to OS and PFS.623 The median PFS times for eribulin and (GT);639; cyclophosphamide/methotrexate/fluorouracil (CMF);640 capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, gemcitabine/ carboplatin;641-643 carboplatin with paclitaxel or 0.93 to 1.25; P= .30) and the OS with eribulin versus capecitabine was albumin-bound paclitaxel;644-646 and paclitaxel/bevacizumab.647-649 15.9 months versus 14.5 months; HR 0.88, 95% CI 0.77-1.00). 623 For the doublet regimens that are included, randomized phase III trials In addition to the above, gemcitabine624 and vinorelbine are both active as have shown that the ORR with first-line AC treatment ranges from 47% to a single agents even in heavily pretreated patients with metastatic breast 54%) and OS is around 20 months.636,637 For first-line EC, a phase III trial cancer.625-627 reported the ORR of 55%, PFS 7.1 months, and OS of 14 months.638 For first-line capecitabine/docetaxel, a phase III trial reported an ORR of 53% Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-72 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer and time-to-progression of 11 months.650 In the second-line setting, paclitaxel/ gemcitabine (16.8 vs. 12.1 months; HR, 0.73 [95% CI, 0.47– another phase III trial compared the efficacy and tolerability of 1.13]; P = .16) or gemcitabine/carboplatin (16.8 vs. 12.6 months; HR, 0.80 capecitabine/docetaxel therapy in anthracycline-pretreated patients and [95% CI, 0.52–1.22]; P = .29). The ORR was 73%, 39%, and 44%, showed significantly superior efficacy in time to disease progression (HR, respectively.644 0.652; 95% CI, 0.545 to 0.780; P =.0001; median, 6.1 vs. 4.2 months), OS (HR, 0.775; 95% CI, 0.634 to 0.947; P =.0126; median, 14.5 vs. 11.5 A series of trials have sought to define the role for bevacizumab in the months), and ORR (42% v 30%, P =.006) compared with single agent treatment of metastatic breast cancer. The E2100 trial randomized 722 docetaxel.602 patients with recurrent or metastatic breast cancer to first-line chemotherapy with paclitaxel with or without bevacizumab.647 This trial Combination chemotherapy regimens containing a platinum agent or a documented superior PFS (11.8 months vs. 5.9 months; HR 0.60; P taxane have been shown to be efficacious in patients with metastatic triple <.001) favoring bevacizumab plus paclitaxel compared with paclitaxel negative breast cancer. A randomized phase II study compared the alone. A similar trial enrolled 736 patients who were randomized to addition of iniparib to gemcitabine/carboplatin versus treatment with docetaxel and bevacizumab or docetaxel and placebo.651 gemcitabine/carboplatin in patients with triple negative breast cancer who This trial also documented increased PFS in the arm containing had received no more than two prior chemotherapies. ORR was similar in bevacizumab (10.1 months vs. 8.2 months with docetaxel alone; HR 0.77; both groups - 30.2% (95% CI, 24.6 to 35.8) with P = .006). An additional trial, RIBBON-1, combined bevacizumab with gemcitabine/carboplatin.641 and the median OS was 11.1 months with capecitabine, with a taxane (docetaxel, nab-paclitaxel), with anthracyclines gemcitabine/carboplatin [HR of 0.88 (95% CI, 0.69 to 1.12)].641 (FEC, CAF, AC, or EC), or with the same chemotherapy alone. Results of this trial show a statistically significant increase in PFS with bevacizumab Several phase II studies have evaluated the efficacy of and capecitabine (8.6 months vs. 5.7 months; HR, 0.69; P < .001) and paclitaxel/carboplatin as first-line for patients with metastatic breast cancer taxane- or anthracycline- (9.2 months vs. 8.0 months; HR, 0.64; P < .001) and found the combination to be an effective therapeutic option in this containing arms.648,649 In a subset analysis of the phase III CALGB 40502 setting.645,646 The randomized the trial, tnAcity, evaluated the efficacy and trial, patients (n = 201) with metastatic triple negative breast cancer, safety of first-line albumin-bound paclitaxel plus first-line albumin-bound paclitaxel in combination with bevacizumab carboplatin, albumin-bound paclitaxel plus gemcitabine, and gemcitabine resulted in a median PFS of 7.4 months.652 plus carboplatin in patients with metastatic triple negative breast cancer.644 The results of this trial reported that median PFS was significantly longer The NCCN panel notes that albumin-bound paclitaxel may be substituted with albumin-bound paclitaxel plus carboplatin versus albumin-bound for paclitaxel or docetaxel due to medical necessity (i.e., hypersensitivity paclitaxel/ gemcitabine (8.3 vs. 5.5 months; HR, 0.59 [95% CI, 0.38– reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly 0.92]; P = .02) or gemcitabine/carboplatin (8.3 vs. 6.0 months; HR, 0.58 dose of nab-paclitaxel should not exceed 125 mg/m2. [95% CI, 0.37–0.90]; P = 0.02). The median OS was also longer with albumin-bound paclitaxel plus carboplatin versus albumin-bound The data from the above-mentioned randomized trials, document that the addition of bevacizumab to first- or second-line chemotherapy agents Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-73 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer modestly improves time to progression and response rates. The mismatch repair deficient (dMMR) solid tumors that have progressed time-to-progression impact may vary among cytotoxic agents and appears following prior treatment and who have no satisfactory alternative greatest with bevacizumab in combination with weekly paclitaxel. None of treatment options.659-661 Pembrolizumab has demonstrated anti-tumor these studies demonstrates an increase in OS or QOL when analyzed activity in heavily pre-treated patients with metastatic breast cancer and alone or in a meta-analyses of the trials.653 Therefore, the NCCN Panel high tumor mutation burden (greater than or equal to 9 has included bevacizumab in combination with paclitaxel as an option mutations/megabase) determined by commercially available tests.662 If useful in only select circumstances. patient with recurrent/stage IV breast cancer presents has a tumor with MSI-H/MMR mutation, whose disease has progressed following prior The only triplet regimen listed as an option in the metastatic setting is treatments and no satisfactory alternative treatment options, treatment CMF. This regimen was compared in the first-line setting with capecitabine pembrolizumab is an option. monotherapy, and results show similar ORR and PFS.640 However, CMF resulted in a shorter OS (median, 22 versus 18 months; HR 0.72, 95% CI Monitoring Metastatic Disease 0.55-0.94) compared to capecitabine. Monitoring the treatment of metastatic breast cancer involves a wide array of assessments and the need for the clinician to integrate several different Additional Targeted Therapies for Stage IV disease Useful in Certain Circumstances forms of information to decide on the effectiveness of treatment and the Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are seen acceptability of toxicity. The information includes those from direct in of a few rare types of cancer, such as secretory carcinoma of observations of the patient, including patient-reported symptoms, the breast or salivary gland and infantile fibrosarcoma and also performance status, change in weight, and physical examination; infrequently in some common cancers, such as melanoma, glioma and laboratory tests such as alkaline phosphatase, liver function, blood counts, carcinomas of the thyroid, lung and colon.654 NTRK fusions are identified and calcium; radiographic imaging; functional imaging; and, where by fluorescence in situ hybridization (FISH), Next Generation Sequencing appropriate, tumor biomarkers. The results of these evaluations generally (NGS) or polymerase chain reaction (PCR). Larotrectinib655-657 and are classified as response, continued response to treatment, stable entrectinib657,658 are two NTRK-inhibitors that are U.S FDA approved for disease, uncertainty regarding disease status, or progression of disease. the treatment of solid tumors that have an NTRK gene fusion without a The clinician typically must assess and balance multiple different forms of known acquired resistance mutation and have no satisfactory alternative information to decide, along with the patient, whether disease is being treatments or that have progressed following treatment. If patient with controlled and the toxicity of treatment is acceptable. Sometimes individual recurrent/stage IV breast presents with a tumor with an NTRK fusion, pieces of information can be conflicting with regards to disease response, treatment with a NTRK-inhibitor is an option if no satisfactory alternative and clinical judgement along with patient input is critical. treatments exists or that have disease progression following treatment. The NCCN Panel recommends using widely accepted criteria for reporting Pembrolizumab is U.S FDA approved for the treatment of patients with response, stability, and progression of disease such as the RECIST unresectable or metastatic, microsatellite instability-high (MSI-H) or criteria663 and the WHO criteria.664 The Panel also recommends using the Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-74 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer same method of response assessment over time. For example, an abnormality initially found on diagnostic CT scan of the chest should be monitored with repeat diagnostic CT scans of the chest. The optimal frequency of testing is uncertain, and is primarily based on the monitoring strategies utilized in breast cancer clinical trials. The page titled Principles of Monitoring Metastatic Disease in the algorithm provides a table outlining general recommendations for the frequency and type of monitoring as a baseline before initiation of new therapy, for monitoring the effectiveness of cytotoxic chemotherapy and endocrine therapy, and as an assessment when there is evidence of disease progression. The panel has indicated in a footnote that the frequency of monitoring can be reduced in patients who have long-term stable disease. These are guidelines and should be modified for the individual patient using clinical judgment, especially for those with stable or responding disease for long periods of time. The clinical use of Circulating Tumor Cells (CTC) or circulating DNA (ctDNA) in metastatic breast cancer is not yet included in the NCCN Guidelines for Breast Cancer for disease assessment and monitoring. Patients with persistently increased CTC after 3 weeks of first-line chemotherapy have a poor PFS and OS.665 In spite of its prognostic ability, CTC count has failed to show a predictive value. A prospective, randomized, phase 3 trial (SWOG S0500) evaluated the clinical utility of serial enumeration of CTC in patients with metastatic breast cancer. 665 According to the study results, switching to an alternative cytotoxic therapy after 3 weeks of first-line chemotherapy in patients with persistently increased CTC did not affect either PFS or OS.665 Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-75 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Special Situations the NAC followed by whole breast radiation therapy.671-675 The risk of Paget’s Disease ipsilateral breast recurrence after breast-conserving NAC resection and radiation therapy with or without an associated cancer is similar to that Paget’s disease of the breast is a rare manifestation of breast cancer with breast-conserving surgery and radiation therapy with the typical characterized by neoplastic cells in the epidermis of the NAC.666 It most invasive or in situ cancer. commonly presents with eczema of the areola, bleeding, ulceration, and itching of the nipple. The diagnosis is often delayed because of the rare For Paget’s disease without an associated cancer (ie, no palpable mass or nature of the condition and confusion with other dermatologic conditions. imaging abnormality), it is recommended that breast-conserving surgery There is an associated cancer elsewhere in the breast in up to about 80% consist of removal of the entire NAC with a negative margin of underlying to 90% of cases.667-669 The associated cancers are not necessarily located breast tissue. In cases with an associated cancer elsewhere in the breast, adjacent to the NAC and may be either DCIS or invasive cancer. the surgery includes removal of the NAC with a negative margin and removal of the peripheral cancer using standard breast-conserving Patients with clinical signs that raise suspicion for Paget’s disease require technique to achieve a negative margin. It is not necessary to remove the a complete history and physical examination and diagnostic breast NAC and the peripheral cancer in continuity in a single surgical specimen imaging. Any breast lesion identified by imaging or examination should be or through a single incision. Mastectomy also remains an appropriate evaluated according to the NCCN Guidelines for Breast Screening and treatment option. Diagnosis. The skin of the NAC should undergo surgical biopsy, including the full thickness of the epidermis including at least a portion of any ALN staging is not necessary when breast-conserving therapy is used to clinically involved NAC. When biopsy of the NAC is positive for Paget’s treat Paget’s disease with underlying DCIS without evidence of invasive disease, breast MRI is recommended to define the extent of disease and cancer following clinical examination, imaging evaluation, and identify additional disease.669,670 full-thickness skin biopsy of the involved NAC. In the presence of an underlying invasive breast cancer treated with breast-conserving surgery, There are no category 1 data that specifically address local management axillary surgery should be performed according to the Surgical Axillary of Paget’s disease. Systemic therapy is based on the stage and biological Staging outlined in the NCCN Guidelines. In cases treated by total characteristics of any underlying cancer, and is supported by the evidence mastectomy, axillary staging is recommended for patients with invasive cited in the relevant stage-specific breast cancer treatment guidelines. disease and should also be considered for patients with underlying DCIS Management of Paget’s disease has traditionally been total mastectomy without evidence of invasive disease. This is because the final pathology with axillary dissection. Total mastectomy remains a reasonable option for may reveal an invasive cancer in the mastectomy specimen and the patients regardless of the absence or presence of an associated breast mastectomy precludes subsequent sentinel node biopsy. Two cancer.668 Data demonstrate that satisfactory local control may be retrospective studies have provided evidence for a high degree of achieved with breast-conserving surgery including the excision with accuracy in the identification of the sentinel node(s) in patients with negative margins of any underlying breast cancer along with resection of Paget’s disease.676,677 Patients treated with breast conservation should Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-76 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer receive whole breast radiation. Extended-field radiation to regional lymph nodes should be used in cases of an associated invasive breast cancer with involved lymph nodes as for any breast cancer as described in the initial sections of the NCCN Guidelines. A radiation boost should be considered for the site of the resected NAC and any associated resected cancer site, if applicable. Patients with an associated invasive cancer have substantial risk of developing metastases. Adjuvant systemic therapy should be administered according to the stage of the cancer. Patients with Paget’s disease treated with breast conservation and without an associated cancer or those with associated ER-positive DCIS should consider tamoxifen for risk reduction. Those with an associated invasive cancer should receive adjuvant systemic therapy based on the stage and HR status. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-77 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Phyllodes Tumors of the Breast recurrence, resection of the recurrence with wide, tumor-free surgical (also known as phyllodes tumors, cystosarcoma phyllodes) margins should be performed. Some panel members recommend local Phyllodes tumors of the breast are rare tumors comprised of both stromal radiation therapy of the remaining breast or chest wall following resection and epithelial elements.678 Phyllodes tumors exist in benign, borderline, of a local recurrence, but this recommendation is controversial (category and malignant subtypes, although there is not uniform agreement on the 2B).684 criteria for assigning subtype or for predicting biological behavior.679 The subtype of phyllodes tumor appears less important for risk of recurrence While the epithelial component of most phyllodes tumors contains ER than does the margin of tumor-free resection achieved by surgical (58%) and/or PR (75%),685 endocrine therapy has no proven role in the treatment. Diagnosis of phyllodes tumors prior to excisional treatment of phyllodes tumors. Similarly, there is no evidence that adjuvant biopsy/lumpectomy is uncommon. Phyllodes tumors occur in an older age cytotoxic chemotherapy provides benefit in reduction of recurrences or distribution than fibroadenoma, a younger age distribution than the death. In the rare patient who experiences a systemic recurrence (usually invasive ductal and lobular cancers, and with a mean age of 40.680 in the lung), treatment should be as recommended in the NCCN Phyllodes tumors often enlarge rapidly and are usually painless. Phyllodes Guidelines for Soft Tissue Sarcoma. tumors often appear on ultrasound and mammography as fibroadenomas, and FNA cytology and even core needle biopsy are inadequate to reliably distinguish phyllodes tumors from fibroadenoma.680 Thus, in the setting of a large or rapidly enlarging clinical fibroadenoma, excisional biopsy should be considered to pathologically exclude a phyllodes tumor. Patients with Li-Fraumeni syndrome (germline TP53 mutation, see NCCN Guidelines for Genetic/Familial High Risk Assessment) have an increased risk for phyllodes tumors.681 Local recurrences of phyllodes tumors are the most common site of recurrence. Most distant recurrences occur in the lung, and may be solid nodules or thin-walled cavities. Treatment of phyllodes tumors (which includes benign, borderline, and malignant subtypes) is with local surgical excision with tumor-free margins of 1 cm or greater. Lumpectomy or partial mastectomy is the preferred surgical therapy. Total mastectomy is necessary only if negative margins cannot be obtained by lumpectomy or partial mastectomy.682 Since phyllodes tumors rarely metastasize to the ALNs, surgical axillary staging or ALN dissection is not necessary unless the lymph nodes are pathologic on clinical examination.683 In those patients who experience a local Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-78 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Breast Cancer During Pregnancy the treatment plan and influence the patient’s decision regarding Breast cancer occurring concurrently with pregnancy is an infrequent maintenance of the pregnancy. Assessment of the pregnancy should clinical event. In a California registry study, there were 1.3 breast cancers include a maternal fetal medicine consultation and review of antecedent diagnosed per 10,000 live births.686 Unfortunately, breast cancer during maternal risks such as hypertension, diabetes, and complications with pregnancy is most often ALN-positive and with larger primary tumor size. prior pregnancies. Documentation of fetal growth and development and Histologically the tumors are poorly differentiated, are more frequently fetal age by means of ultrasonographic assessment is appropriate. ER/PR-negative, and approximately 30% are HER2-positive.687,688 The Estimation of the date of the delivery will help with systemic chemotherapy diagnosis is often delayed because neither the patient nor the physician planning. In addition, maternal fetal medicine consultation should include suspects malignancy. counseling regarding maintaining or terminating pregnancy. Counseling of the pregnant patient with breast cancer should include a review of the Evaluation of the pregnant patient with suspected breast cancer should treatment options, which include mastectomy or breast-conserving surgery include a physical examination with particular attention to the breast and as well as the use of systemic therapy. The most common surgical regional lymph nodes. Mammogram of the breast with shielding can be procedure has been modified radical mastectomy. However, done safely and the accuracy is reported to be greater than 80%.689 breast-conserving surgery is possible if radiation therapy can be delayed Ultrasound of the breast and regional lymph nodes can be used to assess to the postpartum period,690 and breast-conserving therapy during the extent of disease and also to guide biopsy. Ultrasound has been pregnancy does not appear to have a negative impact on survival.690,691 reported to be abnormal in up to 100% of breast cancers occurring during When surgery is performed at 25 weeks of gestation or later, obstetrical pregnancy.689 Biopsies for cytologic evaluation of a suspicious breast and prenatal specialists must be onsite and immediately available in the mass may be done with FNA of the breast and suspicious lymph nodes. event of precipitous delivery of a viable fetus. However, the preferred technique is core needle biopsy. This provides tissue for histologic confirmation of invasive disease as well as adequate Although there are a limited number of isolated case reports and small tissue for HR and HER2 analyses. retrospective studies evaluating use of SLN biopsy in pregnant patients,692,693 the sensitivity and specificity of the procedure has not been Staging assessment of the pregnant patient with breast cancer may be established in this setting. Thus, there are insufficient data on which to guided by clinical disease stage. The staging studies should be tailored to base recommendations for its use in pregnant patients. Decisions related minimize fetal exposure to radiation. For clinically node-negative T1-T2 to use of SLN biopsy in pregnancy should be individualized. A review of tumors, a chest x-ray (with shielding), liver function and renal function the relative and absolute contraindications to sentinel node biopsy assessment, and a CBC with differential are appropriate. In patients who concluded that sentinel node biopsy should not be offered to pregnant have clinically node-positive or T3 breast lesions, in addition to the patients under 30 weeks gestation.694 There are limited data with only aforementioned, an ultrasound of the liver and consideration of a case reports and estimations of fetal radiation dose regarding use of screening MRI of the thoracic and lumbar spine without contrast may be radioactive tracer (eg, technetium 99m sulfur colloid).695-697 Isosulfan blue employed. The documentation of the presence of metastases may alter Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-79 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer or methylene blue dye for sentinel node biopsy procedures is discouraged There are limited data on the use of taxanes during pregnancy.703-706 If during pregnancy. used, the NCCN Panel recommends weekly administration of paclitaxel after the first trimester if clinically indicated by disease status. There are The indications for systemic chemotherapy are the same in the pregnant only case reports of trastuzumab use during pregnancy.707-714 The majority patient as in the non-pregnant breast cancer patient, although of these case reports indicated oligo- or anhydramnios with administration chemotherapy should not be administered at any point during the first of trastuzumab; fetal renal failure occurred in one case. If trastuzumab is trimester of pregnancy. The largest experience in pregnancy has been otherwise indicated, it should be administered in the postpartum period; with anthracycline and alkylating agent chemotherapy.698,699 Collected data the panel recommends against its use during pregnancy. of chemotherapy exposure in utero indicate that the first trimester has the greatest risk of fetal malformation.700,701 Fetal malformation risks in the A single case report of first trimester exposure to lapatinib during second and third trimester are approximately 1.3%, not different than that treatment for breast cancer reported an uncomplicated delivery of a of fetuses not exposed to chemotherapy during pregnancy. If systemic healthy female neonate.715 therapy is initiated, fetal monitoring prior to each chemotherapy cycle is appropriate. Chemotherapy during pregnancy should not be given after Endocrine therapy and radiation therapy are contraindicated during week 35 of pregnancy or within 3 weeks of planned delivery in order to pregnancy. Endocrine therapy and radiation therapy, if indicated, should avoid the potential for hematologic complications during delivery. Data thus not be initiated until the postpartum period. from a single-institution prospective study indicate that FAC chemotherapy Communication between the oncologist and maternal fetal medicine (5-FU 500 mg/m2 IV days 1 and 4, doxorubicin 50 mg/m2 by IV infusion specialist is essential at every visit and for every treatment decision point over 72 hours, and cyclophosphamide 500 mg/m2 IV day 1) may be given for the patient. with relative safety during the second and third trimesters of pregnancy.699 As reported by Gwyn et al, the median gestational age at delivery was 38 weeks, more than 50% of the patients had a vaginal delivery, and there were no fetal deaths.687 An update of this experience reported on 57 patients treated with FAC in the adjuvant or neoadjuvant setting. There were 57 live births. A survey of parents/guardians reported on the health of 40 children. There was one child with Down syndrome and two with congenital abnormalities (club foot, congenital bilateral ureteral reflux). The children are reported to be healthy and progressing well in school.699,702 Ondansetron, lorazepam, and dexamethasone can be used as part of the pre-chemotherapy antiemetic regimen. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-80 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Inflammatory Breast Cancer disease entity and to optimize treatment.728,729 Nevertheless, current Inflammatory breast cancer (IBC) is a rare, aggressive form of breast evidence provides justification for a separate guideline for the workup and cancer estimated to account for 1% to 6% of breast cancer cases in the treatment of patients diagnosed with IBC. United States.716,717 IBC is a clinical diagnosis that requires erythema and StageT4d, N0- N3, M0 dermal edema (peau d’orange) of a third or more of the skin of the breast. Workup IBC is usually HR-negative and is more frequently HER2-positive than the Patients with a clinical/pathologic diagnosis of IBC without distant usual ductal breast cancers. Studies on gene expression profiling of IBC metastasis (stage T4d, N0-N3, M0) should undergo a thorough staging have demonstrated that all the subtypes of IBC exist, but basal and HER2 evaluation by a multidisciplinary team. overexpressed are more frequent.718-721 According to the 7th edition of the Recommendations for workup include a complete history and physical AJCC Cancer Staging Manual, IBC is classified as stage IIIB, stage IIIC, examination involving a CBC and platelet count. or stage IV breast cancer, depending on the degree of nodal involvement and whether distant metastases are present. The primary tumor of IBC is A pathology review and pre-chemotherapy determinations of tumor classified as T4d by definition, even when no mass is specifically apparent HR- and HER2- status should be performed. HER2 has a predictive role in in the breast. On radiographic imaging, findings of skin thickening and, in determining which patients with IBC will benefit from HER2-targeted some cases, an underlying mass are observed. Despite use of the term therapy. The NCCN Panel endorses the CAP protocol for pathology “inflammatory,” the characteristic clinical features of IBC are due to reporting (www.cap.org) and endorses the ASCO CAP recommendations blockage of dermal lymphatics by tumor emboli. Although a biopsy is for quality control performance of HER2 testing and interpretation of IHC required to evaluate for the presence of cancer in breast tissue and the and ISH results.730 dermal lymphatics, a diagnosis of IBC is based on clinical findings, and dermal lymphatic involvement is neither required, nor sufficient by itself, to Imaging studies help facilitate image-guided biopsy, delineate locoregional assign a diagnosis of IBC.722,723 The differential diagnosis includes cellulitis disease, and identify distant metastases. Evaluation of all patients of the breast and mastitis. suspected with IBC must include diagnostic bilateral mammogram, with the addition of ultrasound as necessary. A breast MRI scan is optional. In the past, IBC has often been placed under the general heading of locally advanced breast cancer. There is a growing body of evidence that Evaluations for the presence of distant metastasis in the asymptomatic IBC patients, when compared with noninflammatory forms of locally patient include LFTs, bone scan or sodium fluoride PET/CT (category 2B), advanced breast cancer, are more likely to have a less favorable and diagnostic CT imaging of the chest, abdomen, and pelvis (category prognosis724-726 and to be younger at the time of disease presentation.727 2B; category 2A for diagnostic CT imaging of the chest when pulmonary symptoms are present). The NCCN Panel acknowledges that studies focusing on genetic characterization of IBC are needed to more clearly define IBC as a Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-81 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer FDG PET/CT may be most helpful in situations where standard imaging approach.733 Results from a large retrospective study of patients with IBC results are equivocal or suspicious. However, there is limited evidence performed over a 20-year period at The University of Texas M.D. suggesting that PET/CT may be a useful adjunct to standard imaging of Anderson Cancer Center demonstrated that initial treatment with IBC due to the increased risk of regional lymph node involvement and doxorubicin-based chemotherapy followed by local therapy (ie, radiation distant spread of disease in this group of patients.109,110,731,732 therapy or mastectomy, or both) and additional postoperative Nevertheless, equivocal or suspicious sites identified by FDG PET/CT chemotherapy resulted in a 15-year DFS rate of 28%.734 scanning or other imaging methods should be biopsied for confirmation of stage IV disease whenever possible. FDG PET/CT is a category 2B A retrospective study demonstrated that the addition of a taxane to an recommendation. The consensus of the panel is that FDG PET/CT can be anthracycline-based regimen improved PFS and OS in patients with performed at the same time as diagnostic CT. If FDG PET and diagnostic ER-negative IBC.735 A systematic review found evidence for an CT are performed and both clearly indicate bone metastases, bone scan association between the intensity of preoperative therapy and the or sodium fluoride PET/CT may not be needed. likelihood of a pCR.736 A study of IBC patients, with cytologically confirmed ALN metastases, treated with anthracycline-based chemotherapy with or Genetic counseling is recommended if the patient is considered to be at without a taxane indicated that more patients receiving the high risk for hereditary breast cancer as defined by the NCCN Guidelines anthracycline-taxane combination achieved a pCR compared with those for Genetic/Familial High-Risk Assessment: Breast and Ovarian. who received only anthracycline-based therapy. In addition, patients who had a pCR in the ALNs had superior OS and DFS compared with those Treatment with residual axillary disease.737 The treatment of patients with IBC should involve a combined modality approach716 comprising preoperative systemic therapy followed by surgery The NCCN Panel recommends preoperative systemic therapy with an (mastectomy) and radiotherapy. anthracycline-based regimen with or without taxanes for the initial treatment of patients with IBC. The panel also recommends completing Preoperative Chemotherapy the planned chemotherapy prior to mastectomy. If the chemotherapy was There are no large randomized trials evaluating the optimal systemic not completed preoperatively, it should be completed postoperatively. treatment of IBC, since it is a rare disease. The systemic therapy recommendations are based on data from retrospective analyses, small Targeted Therapy prospective studies, and data from non-IBC, locally advanced breast All patients with HR-positive IBC are recommended to receive endocrine cancer. therapy sequentially after completing the planned preoperative systemic therapy. The benefit of preoperative systemic therapy followed by mastectomy over preoperative systemic therapy alone in patients with IBC was shown in a HER2-positive IBC is associated with a poor prognosis.720,738 For patients retrospective analysis in which lower local recurrence rates and longer with HER2-positive disease, the addition of trastuzumab to primary disease-specific survival were reported for the combined modality systemic chemotherapy is associated with better response rates.739-743 A Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-82 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer prospective study that randomized patients with locally advanced breast Mastectomy with level I/II ALN dissection is the recommended surgical cancers, including those with IBC, to neoadjuvant anthracycline-based procedure recommended by the NCCN Panel for patients who respond chemotherapy with or without trastuzumab for 1 year demonstrated that to neoadjuvant chemotherapy. The NCCN Panel has listed delayed the addition of trastuzumab significantly improved the response rate and breast reconstruction as an option that can be recommended to patients event-free survival.739 The NCCN Panel recommends inclusion of with IBC who have undergone a modified radical mastectomy. trastuzumab in the chemotherapy regimen and is recommended for Reconstruction of the breasts soon after mastectomy may compromise patients with HER2-positive disease. There are no available data to the post-mastectomy radiation therapy outcomes.747 indicate the optimal duration of trastuzumab, specifically among patients with IBC. However, based on the available data,739 the panel recommends For patients with IBC who do not respond to preoperative systemic continuing trastuzumab therapy for up to 1 year. therapy, mastectomy is not generally recommended. Additional systemic chemotherapy and/or preoperative radiation should be considered for Results of small phase II trials indicate that other HER2-targeting agents these patients. Patients with tumors responding to this secondary such as lapatinib and pertuzumab have a clinical benefit in IBC.260,744 The therapy should undergo mastectomy and subsequent treatment as results of the NEOSPHERE trial that included patients with IBC showed described above. increased pCR with the pertuzumab-containing regimens. Therefore, the Radiation NCCN Panel has included in a footnote that a pertuzumab-containing regimen may be administered preoperatively in patients with After mastectomy, radiation therapy is recommended after the HER2-positive IBC.260 completion of the planned chemotherapy. Determination of response to neoadjuvant chemotherapy in IBC should The probability of locoregional lymph node involvement is high for include a combination of physical examination and radiologic patients with IBC. To reduce the risk of local recurrence, the panel assessment. recommends radiation therapy to the chest wall and the supraclavicular region. If the internal mammary lymph node(s) is clinically or Surgery pathologically involved, radiation therapy should include the internal Patients with a clinical/pathologic diagnosis of IBC should always be mammary nodes. If the internal mammary nodes are not clinically or treated with chemotherapy before surgery. It has been known for many pathologically involved, then including the internal mammary nodes in years that surgical treatment as primary treatment of patients with IBC is the radiation therapy field is at the discretion of the treating radiation associated with poor outcomes.745 SLN dissection is not a reliable oncologist (category 3). For HER2-positive disease, trastuzumab may be method of assessing ALNs among patients with IBC.746 Use of administered concomitantly with radiation therapy. breast-conserving surgery in patients with IBC has been associated with poor cosmesis, and limited data suggest that rates of local recurrence may be higher when compared with mastectomy. Breast-conserving therapy is not recommended for patients with IBC. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-83 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Stage IV or Recurrent IBC patients.749 In addition, of the 7 patients with a negative MRI who Patients with stage IV or recurrent IBC should be treated according to subsequently underwent ALN dissection and radiation therapy to the the guidelines for recurrence/stage IV breast cancer (See NCCN whole breast, no evidence of local recurrence was evident at a median Guidelines for Breast Cancer). follow-up of 19 months. Axillary Breast Cancer The NCCN Guidelines for Occult Primary Cancer provide guidance on Occult breast cancer presenting with axillary metastases is an unusual the diagnosis and initial workup of patients with a suspicious axillary presentation that can be a diagnostic and therapeutic challenge. mass without any signs of a primary tumor. A small subset of these Evidence to support recommendations on the management of patients patients may have a primary cancer in the axillary tail of the breast. presenting with axillary breast cancer comes from a limited number of Adenocarcinoma with positive axillary nodes and mediastinal nodes in a retrospective studies involving small numbers of patients748-750(see also woman is highly suggestive of a breast primary. Adenocarcinoma in the references therein). Although treatment of patients with axillary supraclavicular nodes, chest, peritoneum, retroperitoneum, liver, bone, metastases from an unknown primary tumor has typically involved or brain could also indicate primary breast cancer in patients. The mastectomy and axillary nodal dissection, some of these patients have guidelines suggest the use of a mammogram and breast ultrasound for also been successfully treated with axillary nodal dissection followed by such patients. radiation therapy.749,750 Testing for immunohistochemical markers including ER/PR and HER2 is Patients with a suspected occult primary breast cancer will typically recommended. Elevated ER/PR levels provide strong evidence for a present to the oncologist after undergoing an initial biopsy: core needle breast cancer diagnosis.752 MRI of the breast should be considered for a biopsy (preferred), and/or FNA. Accurate pathologic assessment of the patient with histopathologic evidence of breast cancer when biopsied material is most important. Therefore, the pathologist must be mammography and ultrasound are not adequate to assess the extent of consulted to determine whether the available biopsy material is the disease. MRI may be especially helpful in patients with dense breast adequate, or if additional biopsy material is necessary (eg, core needle, tissue, positive axillary nodes, and suspected occult primary breast incisional, or excisional biopsy) to provide an accurate and complete tumor or to evaluate the chest wall.753 Breast MRI has been shown to be diagnosis. useful in identifying the primary site in patients with occult primary breast cancer and may also facilitate breast conservation in selected patients by Workup for Possible Primary Breast Cancer allowing for lumpectomy instead of mastectomy.749,754 In one report, the MRI of the breast can facilitate the identification of occult breast cancer, primary site was identified using MRI in about half of the patients and can help select those patients most likely to benefit from presenting with axillary metastases, irrespective of the breast density.755 mastectomy.751 For example, in a study of 40 patients with biopsy-proven breast cancer in the axilla, and a negative or indeterminate The NCCN Guidelines for Occult Primary Cancer also provide mammogram, MRI identified the primary breast lesion in 70% of the recommendations for additional workup, including chest and abdominal CT to evaluate for evidence of distant metastases for patients diagnosed Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-84 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer with adenocarcinoma (or carcinoma not otherwise specified) of the axillary nodes without evidence of a primary breast lesion. In particular, breast MRI and ultrasound are recommended. Axillary ultrasound should also be performed. Treatment for Possible Primary Breast Cancer Patients with MRI-positive breast disease should undergo evaluation with ultrasound or MRI-guided biopsy and receive treatment according to the clinical stage of the breast cancer. Treatment recommendations for those with MRI-negative disease are based on nodal status. For patients with T0, N1, M0 disease, options include mastectomy plus axillary nodal dissection or axillary nodal dissection plus whole breast irradiation with or without nodal irradiation. Systemic chemotherapy, endocrine therapy, or trastuzumab is given according to the recommendations for stage II or III disease. Neoadjuvant chemotherapy, trastuzumab, and endocrine therapy should be considered for patients with T0, N2-N3, M0 disease followed by axillary nodal dissection and mastectomy as for patients with locally advanced disease. Summary The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. In many situations, the patient and physician have the responsibility to jointly explore and select the most appropriate option from among the available alternatives. With few exceptions, the evaluation, treatment, and follow-up recommendations in these guidelines are based on the results of past and present clinical trials. However, there is not a single clinical situation in which the treatment of breast cancer has been optimized with respect to either maximizing cure or minimizing toxicity and disfigurement. Therefore, patient/physician participation in prospective clinical trials allows patients to not only receive state-of-the-art cancer treatment but also to contribute to improving the treatment outcomes. Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-85 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer Trial. Journal of Clinical Oncology 2021;39:2367-2374. Available at: References https://ascopubs.org/doi/abs/10.1200/JCO.20.02824. 1. 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Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer 2006;24:3381-3387. Available at: 23. McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective http://www.ncbi.nlm.nih.gov/pubmed/16801628. randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol 2015;33:709-715. Available 17. Emdin SO, Granstrand B, Ringberg A, et al. SweDCIS: Radiotherapy at: https://www.ncbi.nlm.nih.gov/pubmed/25605856. after sector resection for ductal carcinoma in situ of the breast. Results of a randomised trial in a population offered mammography screening. 24. Holmberg L, Garmo H, Granstrand B, et al. Absolute risk reductions Acta Oncol 2006;45:536-543. Available at: for local recurrence after postoperative radiotherapy after sector http://www.ncbi.nlm.nih.gov/pubmed/16864166. resection for ductal carcinoma in situ of the breast. J Clin Oncol 2008;26:1247-1252. Available at: 18. Fisher B, Dignam J, Wolmark N, et al. Lumpectomy and radiation http://www.ncbi.nlm.nih.gov/pubmed/18250350. therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 25. Goodwin A, Parker S, Ghersi D, Wilcken N. Post-operative 1998;16:441-452. Available at: radiotherapy for ductal carcinoma in situ of the breast--a systematic http://www.ncbi.nlm.nih.gov/pubmed/9469327. review of the randomised trials. Breast 2009;18:143-149. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19447038. 19. Houghton J, George WD, Cuzick J, et al. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of 26. Narod SA, Iqbal J, Giannakeas V, et al. Breast Cancer Mortality After the breast in the UK, Australia, and New Zealand: randomised controlled a Diagnosis of Ductal Carcinoma In Situ. JAMA Oncol 2015;1:888-896. trial. Lancet 2003;362:95-9102. Available at: Available at: https://www.ncbi.nlm.nih.gov/pubmed/26291673. http://www.ncbi.nlm.nih.gov/pubmed/12867108. 27. Sagara Y, Freedman RA, Vaz-Luis I, et al. Patient Prognostic Score 20. Julien JP, Bijker N, Fentiman IS, et al. Radiotherapy in breast- and Associations With Survival Improvement Offered by Radiotherapy conserving treatment for ductal carcinoma in situ: first results of the After Breast-Conserving Surgery for Ductal Carcinoma In Situ: A EORTC randomised phase III trial 10853. EORTC Breast Cancer Population-Based Longitudinal Cohort Study. J Clin Oncol 2016;34:1190- Cooperative Group and EORTC Radiotherapy Group. Lancet 1196. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26834064. 2000;355:528-533. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10683002. 28. Giannakeas V, Sopik V, Narod SA. Association of Radiotherapy With Survival in Women Treated for Ductal Carcinoma In Situ With 21. Cuzick J, Sestak I, Pinder SE, et al. Effect of tamoxifen and Lumpectomy or Mastectomy. JAMA Netw Open 2018;1:e181100. radiotherapy in women with locally excised ductal carcinoma in situ: Available at: https://www.ncbi.nlm.nih.gov/pubmed/30646103. long-term results from the UK/ANZ DCIS trial. Lancet Oncol 2011;12:21- 29. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21145284. 29. Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy 22. Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes of of early breast cancer: 10-year results of the randomized boost versus invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP no boost EORTC 22881-10882 trial. J Clin Oncol 2007;25:3259-3265. B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst Available at: http://www.ncbi.nlm.nih.gov/pubmed/17577015. 2011;103:478-488. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21398619. 30. Bartelink H, Maingon P, Poortmans P, et al. Whole-breast irradiation with or without a boost for patients treated with breast-conserving Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-87 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer surgery for early breast cancer: 20-year follow-up of a randomised phase World J Surg Oncol 2008;6:61-61. Available at: 3 trial. Lancet Oncol 2015;16:47-56. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18564426. https://www.ncbi.nlm.nih.gov/pubmed/25500422. 38. Silverstein MJ, Lagios MD, Craig PH, et al. A prognostic index for 31. Romestaing P, Lehingue Y, Carrie C, et al. Role of a 10-Gy boost in ductal carcinoma in situ of the breast. Cancer 1996;77:2267-2274. the conservative treatment of early breast cancer: results of a Available at: http://www.ncbi.nlm.nih.gov/pubmed/8635094. randomized clinical trial in Lyon, France. J Clin Oncol 1997;15:963-968. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9060534. 39. Silverstein MJ, Lagios MD, Groshen S, et al. The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J 32. Polgar C, Fodor J, Orosz Z, et al. Electron and high-dose-rate Med 1999;340:1455-1461. Available at: brachytherapy boost in the conservative treatment of stage I-II breast http://www.ncbi.nlm.nih.gov/pubmed/10320383. cancer first results of the randomized Budapest boost trial. Strahlenther Onkol 2002;178:615-623. Available at: 40. Hughes LL, Wang M, Page DL, et al. Local excision alone without https://www.ncbi.nlm.nih.gov/pubmed/12426672. irradiation for ductal carcinoma in situ of the breast: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2009;27:5319-5324. 33. Moran MS, Zhao Y, Ma S, et al. Association of Radiotherapy Boost Available at: http://www.ncbi.nlm.nih.gov/pubmed/19826126. for Ductal Carcinoma In Situ With Local Control After Whole-Breast Radiotherapy. JAMA Oncol 2017. Available at: 41. McCormick B, Winter KA, Woodward W, et al. Randomized Phase III https://www.ncbi.nlm.nih.gov/pubmed/28358936. Trial Evaluating Radiation Following Surgical Excision for Good-Risk Ductal Carcinoma In Situ: Long-Term Report From NRG 34. King MT, Link EK, Whelan TJ, et al. Quality of life after breast- Oncology/RTOG 9804. J Clin Oncol 2021;39:3574-3582. Available at: conserving therapy and adjuvant radiotherapy for non-low-risk ductal https://www.ncbi.nlm.nih.gov/pubmed/34406870. carcinoma in situ (BIG 3-07/TROG 07.01): 2-year results of a randomised, controlled, phase 3 trial. Lancet Oncol 2020;21:685-698. 42. Vicini FA, Cecchini RS, White JR, et al. Long-term primary results of Available at: https://www.ncbi.nlm.nih.gov/pubmed/32203696. accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial. 35. Chua BH, Link E, Kunkler I, et al. Abstract GS2-04: A randomized Lancet 2019;394:2155-2164. Available at: phase III study of radiation doses and fractionation schedules in non-low https://www.ncbi.nlm.nih.gov/pubmed/31813636. risk ductal carcinoma in situ (DCIS) of the breast (BIG 3-07/TROG 07.01). Cancer Research 2021;81:GS2-04-GS02-04. Available at: 43. Whelan TJ, Julian JA, Berrang TS, et al. External beam accelerated https://doi.org/10.1158/1538-7445.SABCS20-GS2-04. partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node- 36. Di Saverio S, Catena F, Santini D, et al. 259 Patients with DCIS of negative breast cancer (RAPID): a randomised controlled trial. Lancet the breast applying USC/Van Nuys prognostic index: a retrospective 2019;394:2165-2172. Available at: review with long term follow up. Breast Cancer Res Treat 2008;109:405- https://www.ncbi.nlm.nih.gov/pubmed/31813635. 416. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17687650. 44. Livi L, Meattini I, Marrazzo L, et al. Accelerated partial breast 37. Gilleard O, Goodman A, Cooper M, et al. The significance of the Van irradiation using intensity-modulated radiotherapy versus whole breast Nuys prognostic index in the management of ductal carcinoma in situ. irradiation: 5-year survival analysis of a phase 3 randomised controlled Version 5.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-88 Printed by Nick Tsoulos on 1/3/2024 3:28:56 AM. For personal use only. Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer trial. Eur J Cancer 2015;51:451-463. Available at: 51. Edge SB, Sheldon DG. Counterpoint: sentinel lymph node biopsy is https://www.ncbi.nlm.nih.gov/pubmed/25605582. not indicated for ductal carcinoma in situ. J Natl Compr Canc Netw 2003;1:207-212. Available at: 45. Strnad V, Ott OJ, Hildebrandt G, et al. 5-year results of accelerated http://www.ncbi.nlm.nih.gov/pubmed/19768879. partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast- 52. Lyman GH, Giuliano AE, Somerfield MR, et al. American Society of conserving surgery for low-risk invasive and in-situ carcinoma of the Clinical Oncology guideline recommendations for sentinel lymph node female breast: a randomised, phase 3, non-inferiority trial. Lancet biopsy in early-stage breast cancer. J Clin Oncol 2005;23:7703-7720. 2016;387:229-238. Available at: Available at: http://www.ncbi.nlm.nih.gov/pubmed/16157938. https://www.ncbi.nlm.nih.gov/pubmed/26494415. 53. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ 46. Morrow M, Van Zee KJ, Solin LJ, et al. Society of Surgical Oncology- of the breast: a systematic review of incidence, treatment, and outcomes. 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Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer adolescent and young adult oncology patients' medical records. J Oncol 2010;28:4683-4686. Available at: Pract 2015;11:137-144. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20876425. http://www.ncbi.nlm.nih.gov/pubmed/25549654. 98. Peate M, Meiser B, Friedlander M, et al. It's now or never: fertility- 90. Yee S, Abrol K, McDonald M, et al. Addressing oncofertility needs: related knowledge, decision-making preferences, and treatment views of female cancer patients in fertility preservation. J Psychosoc intentions in young women with breast cancer--an Australian fertility Oncol 2012;30:331-346. Available at: decision aid collaborative group study. J Clin Oncol 2011;29:1670-1677. http://www.ncbi.nlm.nih.gov/pubmed/22571247. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21444865. 91. Yeomanson DJ, Morgan S, Pacey AA. Discussing fertility 99. 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Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer 354. Davies C, Pan H, Godwin J, et al. ATLAS - 10 v 5 years of adjuvant breast cancer. J Natl Cancer Inst 2007;99:167-170. Available at: tamoxifen (TAM) in ER+ disease: Effects on outcome in the first and in http://www.ncbi.nlm.nih.gov/pubmed/17228000. the second decade after diagnosis. Cancer Research 2012;72:S1-2. Available at: 362. Schroth W, Goetz MP, Hamann U, et al. Association between http://cancerres.aacrjournals.org/cgi/content/meeting_abstract/72/24_Me CYP2D6 polymorphisms and outcomes among women with early stage etingAbstracts/S1-2. breast cancer treated with tamoxifen. JAMA 2009;302:1429-1436. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19809024. 355. Jakesz R, Greil R, Gnant M, et al. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from 363. Leyland-Jones B, Regan M, Bouzyk M, et al. 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Not approved for distribution. Copyright © 2024 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN Guidelines Version 5.2023 Breast Cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 2013;14:741-748. trastuzumab alone (T), their sequence (T->L), or their combination (T+L) Available at: http://www.ncbi.nlm.nih.gov/pubmed/23764181. in the adjuvant treatment of HER2-positive early breast cancer (EBC). ASCO Meeting Abstracts 2014;32:LBA4. Available at: 421. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus http://meeting.ascopubs.org/cgi/content/abstract/32/18_suppl/LBA4. 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013;382:1021-1028. 428. Curigliano G, Viale G, Bagnardi V, et al. Clinical relevance of HER2 Available at: http://www.ncbi.nlm.nih.gov/pubmed/23871490. overexpression/amplification in patients with small tumor size and node- negative breast cancer. 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