Breast CancerSe dae) 8 3 GUIDELINES COMMITTEE Chair: Giuseppe Curigliano; Deputy Chair: Emanuela Romano; Steering Committee Members: Christian Buske, Paolo G. Casal, Nathan Chemy, Nicoletta Colombo, Sike Gilessen, Karin Jordan, Sibylle Loibl, Jean-Pascal Machiels, Matihias Preusser, Cristiana Sessa, Ross Soo, Silvia Stacchiott Amat Vogel; Subject Ealtors: Paolo Ascierto, redo Berut, Andrew Davies, Michel Ducreux, Caraline Even, Karim Fizaz, Francesca Gay, Nicolas Girard, Nadia Harbeck, Mats Jerkerman, Karin Jordan, Angela Lamarca, James Larkin, Jonathan Lederman, ‘Natasha Leighl, Erika Martineli, Olivier Michielin, Ana Oaknin, Shani Paluch-Shimon, Thomas Powles, Martin eck, Carla Ripamonti, Daniele Santini, Florian Scotté, Eizabeth Smyth, Sivia Stacchiott, Michael Weller International Coordinator of Guidelines Adaptation in Asia Pacific: fakayuki Yoshino; Staff: Claire Bramley, Catherine Evans, Svetlana Jeedic, Lone Kristoffersen, Jennifer Lamarre, Richard Lutz, Keith McGregor, loanna ‘Nai, Teodora Pavlova, George Pentharoudakis, Francesco Rho, Fraser Simpson. Medical writing support Kstorfin Medical Communications (KMG) La. ESMO CLINICAL PRACTICE GUIDELINES Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up Cardoso F. Kyriakides , Ohno S, Penault-Llorea F, Poartinans Rubio IT, Zackrisson $ and Senkuss E, on bekalf of the ESMO Guidelines Committee ‘Ann Oncol 2019;30(8):1194-220 https://mwwrannalsofoncology.org/artice/$0023-7534(19)31287-6/tulkext ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer Gennari, André F; Barrios CH, Cortés J, de Azambuja E, DeMichele A, Dent R, Fenlon D, Gligorov J, Hurvitz SA, imS-A Krug D, Kunz WG, Loi S, Perault-Llorca F; Ricke J, Rabson M, Rugo HS, Saura C, Schmid P Singer CF, Spanic |, Tolaney SM, Turner NC, Curigliano 6, Loibl S, Paluch-Shimon S and Harbeck N, on behalf of the ESMO Guidelines Committee Ann Oncol 2021;32{12):1475-95 hitips:/émww.annalsofoncology.org/artice/S0923-7534(21)04498- 7/ultoxt htips:/Anwwesmo.or/ving-guidelines/esmo-metastatic-breast-cancer-lving-quidelines Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes: ESMO Clinical Practice Guideline ‘Sessa C, Balmafia J, Baber Sl, Cardoso MJ, Colombo N, Curigliano 6, Domchek SM, Evans DG, Fischerova D, Harbeck N, Kuhl C, Lemley B, Levy-Lakad E, Lambertini M, Ledermana JA, Loibt S, Philips &-A and Palucl- Shimon S, on behalf of the ESMO Guidelines Committee Full citafion not available at time of printing For publication details, see: hitps/Awvarr esmo.org/guidelines/quidelines-by-topic/hereditary-syndromesSE Sete ey ESMO POCKET GUIDELINES PROVIDE YOU WITH A CONCISE SUMMARY OF THE FUNDAMENTAL RECOMMENDATIONS MADE IN THE PARENT GUIDELINES IN AN EASILY ACCESSIBLE FORMAT. This quick reference booklet provides you with the most important content of the ESMO Clinical Practice Guidelines (CPGs) on the management of breast cancer (including early breast cancer, metastatic breast cancer and hereditary breast cancer syndromes). Key content includes diagnostic criteria, staging of disease, treatment plans and follow-up. The ESMO CPGs on breast cancer are intended to provide you with a set of recommendations for the best standards of care for breast cancer, using evidence-based medicine. Implementation of ESMO CPGs facilitates knowledge uptake and helps you to deliver an appropriate quality of focused care to your patients. The approval and licensed indication of drugs mentioned in this pocket guideline may vary in different countries. Please consult your local prescribing information. This booklet can be used as a quick reference guide to access key content on evidence-based management of breast cancer. Please visit http://www.esmo.org or http://oncologypro.esmo.org to view the full guidelines.gE ese 7-22 EARLY BREAST CANCER SCREENING/DIAGNOSIS/PATHOLOGY/MOLECULAR BIOLOG STAGING AND RISK ASSESSMENT. TREATMENT . Local treatment (Neo)adjuvant systemic treatment. PERSONALISED MEDICINE... FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP. 23-41 METASTATIC BREAST CANCER DIAGNOSIS........ a STAGING AND RISK ASSESSMENT. TREATMENT...... Luminal breast cance! HER2-positive breast cancer. TNBC.... Hereditary breast cance: Site-specific management New drugs....... PERSONALISED MEDICINE LONG-TERM IMPLICATIONS AND SURVIVORSHIP Patient perspective... 42-51 HEREDITARY BREAST CANCER SYNDROMES INCIDENCE AND EPIDEMIOLOGY... POST-TEST COUNSELLING AND FOLLOW-UP OF INDIVIDUALS WITH HEREDITARY BREAST AND OVARIAN CANCER SYNDROME (HBO! Genetic counsellinE OF CONTENTS (CONT'D) Follow-up.... BREAST CANCER RISK MANAGEMEN Screening for women with high-risk pathogenic variants Lifestyle factors and breast cancer risk Risk-reducing medication ............ Risk-reducing surgery Approach to male carriers of high-risk pathogenic variants Screening for additional malignancies... COUNSELLING, RISK-REDUCTION AND SCREENING N THE PRESENCE OF OTHER MODERATE-HIGH RISK PATHOGENIC VARIANTS..... REPRODUCTIVE AND ENDOCRINOLOGICAL ISSUES IN INDMI DUALS WITH HBOC Contraception... Fertility... Management of me: nopausal ‘symptom UNIQUE PSYCHOLOGICAL ISSUES FOR INDIVIDUALS WITH HBO‘ PERSONALISED MEDICINE AND FUTURE DIRECTIONS... 52-53 GLOSSARYNaS ee sy ‘SCREENING/DIAGNOSIS/PATHOLOGY/MOLECULAR BIOLOGY ® Regular (annual or every 2 years) mammography is recommended in women aged 50-69 years and may also be reasonable for women aged 40-49 and 70-74 years, although there is less evidence of benefit ‘¢ In women with a strong familial history of breast cancer (BC), with or without proven BARCA mutations, annual magnetic resonance imaging (MRI) and annual mammography (concomitant or alternating) are recommended + Diagnosis is based on clinical examination in combination with imaging and confirmed by pathological assessment, as shown in the table below DIAGNOSTIC WORK-UP FOR EARLY BC Assessment of general health status Assessment of primary tumour Assessment of regional lymph nodes Assessment of metastatic disease History Menopausal status Physical examination cac Liver, renal and cardiac function tests (in patients planned for anthracycline and/or trastuzumab treatment), ALP and calcium Physical examination Mammography Breast US Breast MRI in selected cases Gore biopsy with pathology determination of histology, grade, ER, PgR, HER2 and Ki67 Physical examination us US. guided biopsy if suspicious Physical examination Other tests are not routinely recommended, unless high tumour burden, aggressive biology or when symptoms suggestive of metastases are present ‘ALR. alkaline phosphatase; BC, breast cancer; CBC, complete blood count; ER, oestrogen receptor, HER2, human epidermal growth, factor receptor 2: MR, magnetic resonance imaging; PgR, progesterone receptor; US, ultrasound ® Bilateral mammogram and ultrasound (US) of breasts and axillae are recommended in all cases, with additional MRI in case of uncertainty or in special clinical situations© Pathological evaluation includes primary tumour histology and axillary node cytology/ histology (if involvement is suspected) * Pathological diagnosis should be made according to the World Health Organization (WHO) classification and the eighth edition of the American Joint Committee on Cancer (AJCC) tumour-node—metastasis (TNM) staging system, and the report should include histological type, grade, immunohistochemistry (IHC) evaluation of oestrogen receptor (ER), progesterone receptor (PgR) (for invasive cancer), human epidermal growth factor receptor 2 (HER2) (for invasive cancer) and a proliferation marker (e.g. Ki67 for invasive cancer) © Tumours should be grouped into surrogate intrinsic subtypes, defined by routine histology and IHC data, as shown in the table below SURROGATE DEFINITIONS OF INTRINSIC SUBTYPES OF BC Ua Sees aS PEM eRe SU Ta Sa) Tt] “Luminal A-like” ER+ HER2— Lumina A urinal vier we PgR hight Low-rik molecular signature (jf available) “Lumina Bike HER2)" ER+ HER2— either Ki67 high ar PgR ow High-risk molecular signature (available) Luminal & *Luminal B-lke (HER2-+)" ER+ HER2+ any Ki67 any PgR *HER2+ (non-luminal” HER2 HERDS ER and PgR absent “Thiple-negatve"* “Basal-ike" ER and Pa absent* HER2+“Ki-B7 ecorse should be interpreted in light of local laboratory weluse:Aa an example, fs lsborstory hes s madian Ki-S7 acore in recepior-positive dissase of 208s, values of = 30% could be considered clearly high; those of = 10% clear low ‘Suggested cut-off value is 20%; quality ezourance programme are sesential for laboratoriea reparting thaea reaulta *Thars ig en ~80% overiag bstwesn “tiple-negetivs” and intrinsic “besal” sulatyps, but “triple-negative” lao includss coms special histelogicel types euch ex earcinama with rien lympheeyte stroma (fermer mecullsry), eeerstory eareinams, low-geeds motaplastio carcinoma and adenoid cyatie carcinoma EG, braset cancer; ER, pestrogen receptor, HERZ, human epidermal growth factor receptor 2; PoR, progesterone receptor ‘Adapted trom the 2013 St Gallen Consenaus Gonfsrsnce recommendations. Goldhirsch A at al. Ann Oncol 2013:24(8)-2206-23 © Tumour-infiltrating lymphocyte scoring may add information on a patient's prognosis but should not be used to guide treatment decisions or to escalate/de-escalate treatment Genetic counselling and testing for germline BRCA? and BRCA2 mutations should be offered to patients with BC in high-risk groups ‘STAGING AND RISK ASSESSMENT * Disease stage should be assessed according to the AJCC TNM staging system ‘¢ Minimum blood work-up (a complete blood count, liver and renal function tests, alkaline phosphatase and calcium levels) is recommended before surgery and systemic (neo)adjuvant therapy * Chest, abdomen and bone imaging is recommended for higher-risk patients (high tumour burden, aggressive biology or clinical signs, symptoms or laboratory values suggesting the presence of metastases) © ['°F]2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)-computed tomography (CT) scanning may be useful for high-risk patients and when conventional methods are inconclusive Postoperative pathological assessment of surgical specimens should be made according to the pathological TNM system Validated gene expression profiles may complement pathology assessment and help in adjuvant chemotherapy (ChT) decision-making TREATMENT ‘ Treatment options for early BC (EBC) are shown in the figure on the next pageaigeai\dde (S09 Jaye Aojepue) eiqeaydde HJeradoysog | saad} BANBIECO}SO4 ayqeardde j! Adeveuy ZHSH-Nue F YO aalevadaysog uoyjonjsuosel ¥ AWwojoe\seyy esuadsal A1ojoe|siyesun) asuodsal Auojae|sies ava Ade16y} uowonpu! oiwelshg Alans jeundo 40 Ajjiqiseay JO ssejpueBar eyyixe anyisod Ulm J0/DUe WO 2 < suNoWN) +2H5H JO JEN Sad Mouayd anissalibe 40 uondeoxe ey) yjion aigyssod Jou UoeAJasuoD Isealg 10 UO JBAJ2SU09 YSBaNK JO} YSIA ON 4a Sed Ajouayd aalssauBBe yo uondeoxe ey) Yl .2iq)seay Auséuns [ewido Jo/pue wo 2 = Jnowny BulBejsumop seye aiqiseay A\yenuajod uolersasuoo 3882/9 PUE UO|JeNs sud Jse219 JO) Ys|m DUE 9]q/9e9) you Avabuns jewiyida 10 wo @ 2 mm for in situ disease is preferred Mastectomy Breast reconstruction should be available for all women requiring mastectomy [mmediate reconstruction is suitable for the vast majority of cases except inflammatory cancer The optimal reconstruction technique for each patient should be discussed individually taking into account anatomic, treatment- and patient-related factors and preferencesAdvances in axillary management © Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in early, clinically node-negative BC © Further axillary surgery following a positive SLNB is not required for low axillary disease burden [micrometastases or one to two sentinel lymph nodes containing metastases treated with postoperative tangential breast radiotherapy (RT)] ¢ Axillary BT is a valid alternative in patients with a positive SLNB, irrespective of the type of breast surgery Surgery for in sifu malignancy (intraepithelial neoplasia) © BCS followed by whole-breast RT or total mastectomy are acceptable treatment options for ductal carcinoma in situ (DCIS) # In BCS, a2 mm margin is adequate for DCIS treated with whole-breast AT * Routine SLNB is not recommended for DCIS, except in patients with large and/or high-grade tumours, especially when mastectomy is required Management of occult breast cancer © The preferred locoregional management of occult BC is axillary lymph node dissection (ALND) and whole-breast RT Risk-reducing mastectomy Risk-reducing surgery (with prophylactic bilateral mastectomy and reconstruction) may be offered to women at a very high risk, such as BRCA7 or BRCA2 mutation carriers or those who have had previous chest RT at a young age © Presurgery genetic assessment and psychological counselling are mandatory and intense surveillance should also be discussed © Non-high-risk patients opting for bilateral mastectomy rather than BCS should be counselled that survival outcomes with BCS may be better (and are certainly not worse) than those with mastectomy Surgery after primary systemic therapy © Surgery following primary systemic therapy (PST) should be carried out according to general rules for EBC and considering the baseline tumour characteristics as well as the post-treatment outcomes * If BCS is anticipated, the tumour site should be marked and pre- and post-treatment breast MRI should be carried out In clinically negative axilla, post-PST SLNB is preferred to pre-PST SLNBSLNB may be carried out in selected cases of baseline axillary involvement converting to negative, and if negative, further axillary surgery may be avoided * Identification of tumour deposits in post-PST SLNB prompts ALND Radiotherapy + In terms of doses and fractionation, moderate hypofractionation schedules (15-16 fractions of < 3 Gy/fraction) are recommended for routine postoperative RT of BC * After BCS, postoperative whole-breast RT is strongly recommended, with boost RT to reduce the risk of in-breast relapse in patients at higher risk of local recurrence © Accelerated partial-breast RT is an acceptable treatment option in patients with a low risk for local recurrence Post-mastectomy RT (PMRT) is recommended for high-risk patients, including those with involved resection margins, > 3 involved axillary lymph nodes and T3-T4 tumours; it should also be considered in patients with 1-3 positive axillary lymph nodes Regional comprehensive nodal RT is recommended for patients with involved lymph nodes, although after ALND, routine axillary irradiation should not be applied to the operated part of the axilla * After immediate breast reconstruction, postoperative RAT can be administered, if ‘ated, and a multidisciplinary and interactive patient-involving approach is required ividualise the best combination of the sequence and type of breast reconstruction and RT In intraepithelial neoplasia (DCIS), whole-breast RT is recommended for most women undergoing BCS, although omission of RT is an option for patients with low-risk disease and tumour bed boost can be considered for patients at higher risk for local failure ‘¢ PMAT is not recommended for DCIS t (Neo)adjuvant systemic treatment ‘# The choice of therapies should be based on an individual's risk of relapse, the predicted sensitivity to treatment, the benefit and toxicities of treatment, and the patient's biological age, general health status, comorbidities and preferences, as shown in the tables and figure on the next pagesSYSTEMIC TREATMENT RECOMMENDATIONS FOR EBC SUBTYPES suere | Pie aaa ag Consider ChT if high tumour burden Lumina A-like ET alone forthe maoriy of cases ch nodes, = 13) Luminal B-like CHT followed by ET for the majority (HERZ) of cases {f contraindications for the use of Luminal B-like ChT + anti-HER? therapy followed by = ChT, one may consider ET + anti-HER2 (HER2+) ET for all patients therapy, although no randomised data exist HER2+ aoa CHT + anfi-HER2 therapy Triple-negative (ductal) CHT For special histological types, the: 2013 St Gallen Consensus Conference recommendations [Goldhirsch A etal. Ann Oncol 2013;24(9):2206-23] propose ET for endoorine-responsive histalogies (cribriform, tubular and mucinous), CAT for high-risk endocrine-nonresponsive histologies (medullary, metaplastic) and ne systemic therapy for low-risk endocrine-nonresponsive histologies (adenoid cystic and apocrine} CT, chemotherapy; EBC, early breast cancer; ET, endocrine therapy: HER2, human epidermal growth factor receptor 2 SUMMARY OF BIOMARKERS USED IN TREATMENT DECISION-MAKING mn ewe ee Essential to the characterisation of the IHC luminal-ike group IHC ER Poor prognostic marker if negative Positive it = 1% Predictive marker for ET Mandatory fr ET prescription if negative tumour classified as IHC luminal IHC Balke PaR Positive if > 1% ‘Strong poor prognostic marker if negative Predictive marker for ET IHC Positive if > 10% complete caterer Essential to the characterisation of: ISH © HER2-enriched (ER-) Single probe + Luminal B-like, HER2+ HER? Positive if HER2 > 6 copies Prognostic marker Dual probe Predictive marker for anti-HER? treatment Positive if HER2/CEP17 ratio > 2 and HER2 > 4 copies Or HER2/CEP17 ratio < 2 and HER2 2 6 copies Mandatory for anti-HER2 therapy regardless of treatment lineKi67 Intinsic subtypes First-generation signatures (MammaPrint®, Oncotype DX*) Second-goneration signatures (Prosigna®, Endopredict®) IHC: No final consensus on cut-off but values < 10% are considered low and > 30% are considered high* Gene expression profile, N-Counter™ technology Gene expression profile, RT-PCR N-Counter™ technology, RT-PCR: Absence of international consensus for sooring and threshold Prognostic value in ER+-, HER2— tumours (primary tumours and post-neoadjuvant residual tumour) Absence of prognestic value in HER2+ of triple-negative tumours Predictive of response to neoadjuvant ET? Predictive of response to neoadjuvant ChT if elevated, ChT is offen prescribed in ER+, HER2 tumours Part ofthe IHC definition of luminal-tke tumours © KiG7 low, luminal A-tike © Ki67 high, luminal Bike Prognostic Precictive: Different responses to neoadjuvant ChT and anti-HER2 therapy according to the subtype For ER+, HER2— tumours Prognostic (Neojadjuvant ChT is indicated i high risk or high score Can be carried outin biopsy or surgical specimen For ER+, HER2— tumours, include T size and Nisiatus in their final score Prognostic (Neojadjuvant CHT is indicated i high risk or high score Can be carried out.in biopsy or surgical specimen “According tothe Inteenstonal Ki67 Working Group Guidslines, Dowestt M etal. J Naif Gancer Inet 2011;103(27)-1656-64 1A dooraese in KiG7 axpreasion during naoadjuvant ET is highly pradictive of ragponse (Gh, chemotherapy; ER, osetrogsn recaptor; ET, endocrine therapy: HER2. human epidermal growth factor raospter 2; IMG, immunohistechanvtry ISH in stu hybridisation: N, neds: PER, progesterone recepter, RT-PCR, reveras tanecrpton polymarses chain reaction; 7, tumoursous} sea a ye UMC ORL, “umdogas avo mse. 'y fy ‘asnefiou-apau' gn 'Z.snideoa) sm>ey Lp.40,8 euLepACe UeLINY ‘43H AcevaLA aUoMpUE|3 “yd AOI UofIAg sO ‘ya | JeoUeD ISeAN Ke'Oga ‘eALAOLLALO 4D, Ppavopjsuos oy ues oUE KCeONY ZU H- LEAL LP JO} ORL LL SWHALE yA ACY KOK my WED souauijeut jusyed Jeypur Wspure ANCL Yau psssese KpeArLLOUSB ung eee. ut scare By UE Up Jo ode] BPH) Powe ap sed etal ope 18: oy ‘eUOU aie K.xyaroe ‘auLsoede Jono POLAR oo, qeuurery od eq eunrerysey 4 LU IIHR ON ELL YaL-ihG Ss gdh ssED poraqias poucdose oyqissce Ky My uspng asessip 13+ ..Adzauy UBIY UjIM sese0 1uo ‘esNCROU cuaH e+ uo LU. 40 wo 2UaH We wwennldD uo}jeuasqg +N T I Si0}92} YSU 184)0 OU ‘ON aan'S8dA) g reujwiny || q leulwny | vy aun) | jeoiBoj0%s|4 lejong t t * AdALONSHd SISNIMLNI CNY NOISSZUdXa YaMUVIN AG JIIOHD LNAWIVSHL SIWALSAS LNVANray(oaN) 6* Adjuvant systemic treatment should preferably start within 3-6 weeks after surgery and neoadjuvant systemic therapy should start as soon as diagnosis and staging are completed (ideally within 2-4 weeks) All luminal-like cancers should be treated with endocrine therapy (ET) Most luminal A-like tumours do not require ChT, except those with high disease burden ® ChT use in luminal B-like HER2-negative patients depends on individual risk of recurrence, presumed responsiveness to ET and patient preference * In cases of uncertainty, adjuvant ChT can be guided by expression of urokinase plasminogen activator-plasminogen activator inhibitor 1 (uPA-PAH) or gene expression assays Luminal B-like HER2-positive tumours should be treated with ChT, ET and anti-HER2 therapy, although selected low-risk patients (Tiab NO) may receive the combination of anti-HER2 therapy and/or ET alone Patients with triple-negative BC (TNBC) should receive ChT, with the possible exception of low-risk ‘special histological subtypes’ such as secretory or adenoid cystic carcinomas or very early (T1a NO) tumours + HER2-positive cancers should be treated with ChT plus anti-HER? therapy, with the possible exception of selected cases with very low-risk, such as T1a NO tumours * ChT should not be used concomitantly with ET, except for gonadotropin-releasing hormone analogues used for ovarian protection Anti-HER2 therapy may routinely be combined with non-anthracycline-based ChT, ET and RT © RT may be delivered safely during anti-HER2 therapy, ET and non-anthracycline, non-taxane-based ChT ‘© When used together, ChT should usually precede RT ET Premenopausal patients For premenopausal women, tamoxifen for 5-10 years is a standard of care Patients becoming postmenopausal during the first 5 years of tamoxifen can be switched to letrozole, depending on the predicted risk of late recurrence In patients requiring ChT who recover menses, the addition of ovarian function suppression (OFS) to ET should be strongly considered Replacing tamoxifen with an aromatase inhibitor (Al) can be considered in high-risk patients © If an Alis used, it mandates effective OFS, with regular biochemical control of oestrogen levels.* In patients < 35 years not requiring ChT, a combination of OFS with the most effective ET is suggested ® OFS during ChT should not be the sole fertility preservation method used in case of desired pregnancy Postmenopausal patients. © For postmenopausal women, Als (both non-steroidal and steroidal) and tamoxifen are standard treatments Als can be used upfront (non-steroidal Al and exemestane), after 2-3 years of tamoxifen (non-steroidal Al and exemestane) or as extended adjuvant therapy after 5 years of tamoxifen (letrozole and anastrozole) ® Extended adjuvant ET should be discussed with all patients except those with a very low risk of relapse, although the optimal duration and regimen are unknown © There is only a minimal benefit for the use of Als for more than 5 years. ¢ Patients undergoing OFS or receiving Als should be advised to have adequate calcium and vitamin D3 intake and should undergo a periodic dual energy X-ray absorption scan for assessment of bone mineral density cht ® ChT should be administered for 12-24 weeks (4-8 cycles) # A sequential anthracycline—taxane-based regimen is the standard treatment regimen for the majority of patients, although 4 cycles of anthracycline- or taxane-based ChT or cyclophosphamide—methotrexate—5-fluorouracil (5-FU) may be used in selected lower-risk patients * Non-anthracycline-based regimens may be used in patients at risk of cardiac complications @ Anthracycline-based regimens should not include 5-FU (epirubicin—cyclophosphamide or doxorubicin—-cyclophasphamide are standard) ¢ Platinum compounds should not be used routinely in the adjuvant setting * Granulocyte colony-stimulating factor-supported dose-dense schedules should be considered, particularly in highly proliferative tumours Anti-HER2 therapy ¢ The treatment of HER2-positive BC is shown in the figure on the next pageMANAGEMENT OF HER2-POSITIVE BC HER2+ BC Preoperative ChT—trastuzumab + pertuzumab Initially Ns or ERR Vv. Complete 1 year of dual ‘Complete 1 year of trastuzumnab blockade or Complete 1 year of trastuzumab BG, reat cancer; 6, chemotherapy; ER, osstragen receptor; HERZ, human epidermal grawth factor recaptor 2; N, nods BGR, pathological complsts rsenonee; T-DM1, ado-trestuzumat emiansine (Neo)adjuvant trastuzumab should be given to all HER2-positive EBC patients without contraindications for its use, with the possible exception of selected very low-risk cases, such as T1a NO tumours * HER2-targeted therapy may also be considered in cases where a HER2 test result is deemed to be equivocal, even after reflex testing with an alternative assay One year of (neo)adjuvant trastuzumab is the standard for most HER2-positive patients, but a 6-month course can be considered for highly selected, low-risk patients receiving anthracycline—taxane-based ChT + Trastuzumab must not be given concomitantly with anthracycline-based ChT but it can be safely combined with non-anthracycline-based ChT (i.e. taxanes), concomitant use being more effective than sequential treatment Regular cardiac monitoring before starting and during trastuzumab treatment is mandatory* One-year of treatment with combined trastuzumab—pertuzumab, starting before or after surgery, can be considered in high-risk patients (node-positive or ER-negative) In cases of residual invasive disease after completion of combined neoadjuvant ChT and anti-HER2 therapy, adjuvant trastuzumab should be replaced by adjuvant ado-trastuzumab emtansine ¢ Extended anti-HER?2 therapy with neratinib may be considered in selected high-risk patients not previously treated with dual blockade and with appropriate diarrhoea prophylaxis and management PST (neoadjuvant) © PST is recommended to reduce the extent of surgery in locally advanced and large operable cancers, particularly when mastectomy is required due to tumour size, and should also be considered in all patients with tumours > 2 cm for which ChT is deemed necessary (particularly with TNBC and HER2-positive subtypes) Drugs and drug regimens for preoperative and postoperative settings should be selected according to the same rules; sequential anthracyclines and taxanes are recommended for most patients * The addition of a platinum compound may be considered in NBC and/or in patients with deleterious BRCA1/2 mutations ® Where PST is used, all ChT should be delivered preoperatively # In high-risk TNBC not achieving pathological complete response after standard neoadjuvant ChT, the postoperative addition of 6-8 cycles of capecitabine may be considered In postmenopausal patients with ER-positive, HER2-negative tumours requiring PST and without a clear indication for ChT, preoperative ET (4-8 months or until maximum response) should be considered and continued postoperatively Bisphosphonates for EBC Bisphosphonates for EBC are recommended in women with low-oestrogen status, especially if at high risk of relapse, and in patients with treatment-related bone loss Other clinical scenarios * The treatment of elderly early BC patients should be preceded by a geriatric assessment and then adapted to biological (not chronological) age © Patients suitable for standard ChT should receive a standard multidrug regimen, with consideration being given to less aggressive regimens for frail patientsIn male BC patients, tamoxifen is the standard adjuvant ET, although a combination of an Al plus a luteinising hormone-releasing hormone agonist may be considered in patients with contraindications to tamoxifen, but its higher toxicity must be discussed with the patient fo avoid compliance issues # Male BC patients should not receive an Al alone as adjuvant ET © ChT and anti-HER2 therapy indications and regimen recommendations are the same for males and females In DCIS, systemic adjuvant therapy with both tamoxifen and Als may be used after conservative local treatment (to prevent local recurrence and to decrease the risk of development of a second primary BC) Following mastectomy for DCIS, tamoxifen or Al might be considered to decrease the risk of contralateral BC in patients at a high risk of new breast tumours PERSONALISED MEDICINE @ ER, PgR and HER2 status should quide all systemic treatment decisions © Surrogate intrinsic tumour phenotypes, based on expression of ER, PgR, HER2 and Ki67, should be used to define BC subpopulations Expression of uPA-PAIH or multigene panels, such as MammaPrint®, Oncotype DX®, EndoPredict®, Prosigna® or Breast Cancer Index™, may be used in conjunction with all clinicopathological factors to guide challenging systemic treatment decisions, such as in cases of luminal B-like (HER2-negative) and node-negative or nodes 1-3-positive BC FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP Regular follow-up visits are recommended every 3-4 months in the first 2 years (every 6 months for low-risk and DCIS patients), every 6-8 months from years 3-5 and annually thereafter. The interval between visits should be adapted to the risk of relapse and the patients’ needs Annual bilateral (after breast-conserving therapy) and/or a contralateral mammography (after mastectomy), with US and breast MRI when needed, is recommended In asymptomatic patients, other laboratory or imaging tests are not recommended * Regular bone density evaluation is recommended for patients on Als or undergoing OFS * Patients should be encouraged to adopt a healthy lifestyle, including diet modification and exercise ® Hormone replacement therapy should usually not be used a* Patients should have unlimited access to specialised rehabilitation facilities and services ® Long-term survivorship problems, including psychological needs and issues related to work, family and sexuality, should be addressedMETASTATIC BREAST CANCER DIAGNOSIS ® The recommended diagnostic work-up for metastatic breast cancer (MBC) is shown in the figure below DIAGNOSTIC WORK-UP AND STAGING OF MBC Fe eae La Biopsy of metastatic lesion to confirm diagnosis Reassess biomarkers ER, PgR, HER2* Patients with Patients with TINEC tumours: ‘Al patients ER+, HER2— tumours PO-LI by IHC, gBAGAM (PALB2 assessment optional) PIK3CA mutation status, g8RCAm (PALB2 assessment optional) Assessments only where corresponding therapies are available: MSI, TMB, NTRK | a + t Optional assessments with potential to guide treatment: ESA (in ER+, HER2— tumours if further ‘Al-based therapy is considered), somatic BRCA mutations, HER-low status by IHC Staging: History and physical examination, haematology, biochemistry, tumour markers, CT of the chest and abdomen and bone scintigraphy (or PET-C7), brain imaging (symplomatic patients or according to subtype ifthe presence of CNS metastases wil alter the choice of therapy) “Hf there ars important diffrence in ER, PgR and HER2 atatue between the primary tumour and recurrence, patients ahould be maneged according to receptor atetua of the recurrent disease biopsy Al, sromataes inhibitor; CNS, cantral nervous aystom: CT, computed tomography; ER, osstragan receptor, ESAT, osstrogsn receptor 1; g8RCAm, germline BRCAT/2 mutation; HER2, human egidermal growth factor receptar 2; IMC, immunchiatechemiatry: ‘MBC, metastatic breaat canoer, MSI, microastellta instability; NTRK, nourotrophie tyrosine reoeptor kinaea; FPALEZ, partner ‘and locslieer of BAGAZ; PD-L1, programmed daeth-ligend 1; PET, positron emission tomography; PgR, progesterone recs ‘PIK3A, phosphatidylinosite-4,5-biephosphate 2-kinase catalytic subunit alpha; TMB, tamour mutation burden; TNEG, trl negative braast cancer %* Patients with newly diagnosed or recurrent MBC should have a biopsy to confirm the histology and assess oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) status © Biopsies of bone metastases should be avoided due to the technical limitations of biomarker detection in decalcified tissue © If there are important differences in ER, PgR and HER? status between the primary tumour and recurrence, it is not known which biological features should drive treatment decision making © The biological features of the disease at baseline, degree of biomarker heterogeneity, type of treatment received that could potentially induce a selection of clones resistant to a specific targeted therapy and the burden of disease should all be considered © Tumour heterogeneity should be considered for each new line of treatment; are-biopsy may be appropriate in cases of mixed response * Other therapeutically-relevant biomarkers that should be assessed include: © Germline BRCA7/2 mutation (gBRCAm) status in HER2-negative MBC © Programmed death-ligand 1 (PD-L1) status in triple-negative breast cancer (TNBC) © Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in ER/PgR-positive, HER2-negative MBC * Genomic profiling and further diagnostic tests (e.g. on tumour tissue or circulating tumour DNA) should only be carried out if the result will change the treatment approach or if the patient can access an appropriate clinical trial ¢ The following should be evaluated when corresponding therapies are available: © Microsatellite instability (MSI) © Tumour mutation burden © Neurotrophic tyrosine receptor kinase (NTAK) fusionSTAGING AND RISK ASSESSMENT Imaging work-up for staging should include computed tomography (CT) of the chest/ abdomen and bone scintigraphy © ['#F]2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)-CT may be used as an alternative to CT and bone scans The imaging modality chosen at baseline should also be used for disease monitoring to ensure comparability ‘ There is no evidence that any staging or monitoring approach provides an overall survival (OS) benefit over any other * The interval between imaging and the start of treatment should be < 4 weeks Evaluation of response should be every 2-4 months, depending on disease dynamics, location, extent of metastasis and type of treatment © Disease monitoring intervals should not be shortened as this does not provide an 0S. benefit, but may cause emotional and financial harm © Less frequent monitoring is acceptable, particularly for indolent disease © If disease progression is suspected, additional tests should be carried out in a timely manner, irrespective of the planned intervals Repeat bone scans are a mainstay of evaluation for bone-only/predominant metastases © |mage interpretation may be confounded by a possible flare during the first few months of treatment © PET-CT might provide earlier guidance in monitoring bone-only or bone-predominant metastases, but prospective trials are needed to study the impact on treatment decisions and OS * Magnetic resonance imaging (MRI) is recommended for suspected cord compression # Brain imaging should not be routinely carried out in all asymptomatic patients at initial MBC diagnosis or during disease monitoring © Patients with asymptomatic HER2-positive disease or TNBC have higher rates of brain metastases (BMs) at initial MBC diagnosis, which may warrant subtype- oriented brain imaging if detection of central nervous system (CNS) metastases will affect the choice of systemic therapy © Symptomatic patients should always undergo brain imaging, preferably with MRITREATMENT ¢ Systemic therapy is the standard of care in MBC but may be supplemented with locoregional treatments (LRATs) according to the disease status of the individual patient © A multidisciplinary team is a prerequisite for optimal management ® Treatment decisions should be made irrespective of patient age, but comorbidities, patient characteristics and patient preferences need to be considered * Rechallenge with drugs previously used in the early breast cancer (BC) setting is a reasonable option, provided that the disease-free interval (DFI) is > 12 months after the last drug administration and that no toxicities remain * Patients with MBC should be encouraged to consider participation in clinical trials early in their disease course Luminal breast cancer * Management options for ER-positive, HER2-negative MBC are shown in the figure on the next page © Premenopausal women may be treated in the same way as postmenopausal women, providing they undergo ovarian function suppression (OFS) or ovarian ablation © If a rapid response is required, bilateral oophorectomy may be preferable over gonadotropin-releasing hormone agonists © Primary endocrine resistance is defined as: © Relapse during the first 2 years of adjuvant endocrine therapy (ET) ® Progressive disease (PD) within the first 6 months of first-line ET for MBC * Secondary (acquired) resistance is defined as: © Relapse during adjuvant ET but after the first 2 years © Relapse within 12 months of completing adjuvant ET © PD 6 months after initiating ET for MBC First-line treatment * A cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor combined with ET is the standard of care first-line therapy for patients with ER-positive, HER2-negative MBC © Aromatase inhibitor (Al-CDK4/6 inhibitor is recommended for patients who did not relapse on an Al or within 12 months of stopping adjuvant Al ® Fulvestrant-CDK4/6 inhibitor is recommended for patients who relapsed on adjuvant Al therapy or within 12 months of stopping adjuvant Al ¢ ET alone in the first-line setting should be reserved for patients with comorbidities or a performance status that precludes the use of CDK4/6 inhibitor combinationsUw Zaeyeeons yay yy ‘PAD “OHM HUY esEpEUILE py eIGIALL STPHCCW a JURA PL Joye S\yOWN Z| <8 EU) ICURIMLE SP HO-WRNESA|TY IW IUEA MAE Ho PL ANE S\PUAL Z|. > COX OAs oe unused ue 149 WON ALR H Paeya |wsnedouauvaid = quored oy) 1 $40, -sajd 2184) peyebie} = 13 jo Sau) jesenes 1eye Ce 20,QIMU| ie ’ ' sw ol EA}SON Ny jadje-yUeNSaN. WeETee vee 1 * Sh wy.01843 10 ou jf s0HqIUU) GPOD +) /POHG AUN Use8 }| _AUEISAINAKE-SNW UeA JUBNSaH 4 anya, ueB.0 uau)MiLy) une UeB10 JO 8. ON Bunse uone;nw oneuiog, eae AOWQIMU| QéPHOD-13 dc Ree Ro ‘OG SALLVOAN-2H3H ‘FALLISOd-Y JO LNAWSOVNVW caSecond-line treatment © The optimal sequence of endocrine-based therapy after progression on CDK4/6. inhibitors is uncertain © Treatment choice depends on prior therapy, duration of response to prior ET, disease burden, patient preference and treatment availability ¢ In patients who required first-line chemotherapy (ChT) due to imminent organ failure, or who did not have access to a CDK4/6 inhibitor in the first-line setting, ET-CDK4/6 inhibitor is acceptable as subsequent therapy © Determination of somatic PIK3CA and oestrogen receptor 1 (ESA7) mutations, as well as germline BRCA1/2 and partner and localiser of BRCA2 (PALB2) mutations, is recommended in patients who relapse after ET-CDK4/6 inhibitor © The choice of second-line therapy (ChT versus endocrine-based therapy) should be based on disease aggressiveness, extent and organ function, and should consider the associated toxicity profiles * Fulvestrant-alpelisib is an option for patients with PIK3C4-mutant tumours, prior exposure to an Al (+ CDK4/6 inhibitor) and appropriate glycated haemoglobin levels © Hyperglycaemia can occur with alpelisib so collaboration with a diabetes specialist is recommended ¢ Everolimus—exemestane is a second-line treatment option © Capecitabine is a good alternative in patients unlikely to tolerate everolimus—exemestane © Tamoxifen or fulvestrant can also be combined with everolimus © Stomatitis prophylaxis must be used during everolimus treatment * A poly (ADP-ribose) polymerase (PARP) inhibitor (olaparib or talazoparib) should be considered for patients with germline pathogenic BRCA7/2 mutations and is an option for patients with somatic pathogenic (or likely pathogenic) BRCA 7/2 or germline PALB2 mutations ¢ At least two lines of endocrine-based therapy are preferred before moving to ChT ¢ In patients with imminent organ failure, ChT is preferred Beyond second line * Treatment decisions should consider sensitivity to previous treatments, time to progression, g8ACAm status, tumour biolagy and mechanisms of resistance that may have arisen during previous treatments ¢ For endocrine-sensitive tumours, continuation of ET with agents not previously received in the metastatic setting may be an option © For endocrine-resistant tumours where targeted agents have already been used or ruled out due to lack of therapeutically-relevant molecular alterations, ChT should be considered* Sequential single-agent ChT is generally preferred over combination strategies © Single-agent ChT options include anthracyclines, taxanes, capecitabine, eri vinorelbine and platinums © The optimal ChT sequence in MBC has not been established © When a rapid response is needed due to imminent organ failure, combination ChT is preferred lin, Rechallenge with anthracyclines or taxanes is feasible in patients with a DFI = 12 months © Liposomal anthracyclines or protein-bound paclitaxel may be considered for the rechallenge, if available © Anthracycline lifetime cumulative dose limits must be considered; cardiac monitoring is mandatory ® Bevacizumab (if available) plus taxane or capecitabine is a first-line ChT option ‘¢ If capecitabine is used, patients should undergo germline variant testing for lack of the enzyme, dihydropyrimidine dehydrogenase, before treatment starts # ChT should generally be continued until PD or intolerable toxicity, except for anthracyclines where the cumulative dose limit must be considered HER2-positive breast cancer First-line treatment * First- and second-line management options for HER2-positive MBC are shown in the figure on the next page ® The gold-standard first-line treatment for HER2-positive MBC is trastuzumab— pertuzumab—docetaxel, regardless of hormone receptor (HR) status © Docetaxel should be given for at least 6 cycles, if tolerated, followed by maintenance trastuzumab—pertuzumab until PD © An alternative taxane (e.g. paclitaxel or nab-paclitaxel) may be used ET may be added to trastuzumab-pertuzumab maintenance therapy for HER2-positive, HR-positive tumours © OFS should be added for pre- and perimenopausal women In patients with HER2-positive, HR-positive disease who are not suitable for first-line ChT, ET (e.g. an Al) with HER2-targeted therapy (e.g. trastuzumab, trastuzumab— pertuzumab, trastuzumab—lapatinib or lapatinib), may be recommended ® Single-agent ET without HER2-targeted therapy is not routinely recommended unless comorbidities (e.g. cardiac disease) preclude the safe use of HER2-directed therapies: