AGO Algorithms for the Treatment of Breast Cancer: Update 2021

Abstract

Therapy options shown in the algorithms are based on the current AGO recommendations, but cannot represent all evidence-based treatment options, since prior therapies, performance status, comorbidities, patient preference, etc. must be taken into account for the actual treatment choice. In individual cases, other evidence-based treatment options may also be appropriate and justified. Regardless of approval status, the algorithms only take into account drugs that were available in Germany at the time the algorithm was last updated. Here we present the 2021 update of AGO treatment algorithms for early and metastatic breast cancer, which are intended to intensify structured treatment decision by providing reproducible and evidence-based treatment paths and may be helpful for a broad treatment landscape.

Zusammenfassung

Die in den Algorithmen aufgezeigten Behandlungsoptionen basieren zwar auf den aktuellen AGO-Empfehlungen, können aber nicht alle evidenzbasierten Behandlungsoptionen darstellen, da frühere Therapien, der Patientinnenstatus, Begleiterkrankungen, Patientinnenpräferenzen usw. bei der tatsächlichen Therapiewahl mitberücksichtigt werden müssen. Andere evidenzbasierte Behandlungsoptionen können in Einzelfällen auch angemessen und gerechtfertigt sein. Ungeachtet ihres Zulassungsstatus werden nur die Medikamente in den Algorithmen aufgenommen, die zum Zeitpunkt des letzten Algorithmus-Updates in Deutschland zugelassen waren. Die Aktualisierung der AGO-Behandlungsalgorithmen für die Therapie von frühen und metastasierten Brustkrebserkrankungen von 2021 wird hier vorgestellt. Diese Aktualisierung soll strukturierte Behandlungsentscheidungen durch die Darlegung reproduzierbarer, evidenzbasierter Therapiepfade verstärken und kann für eine breit angelegte Behandlungslandschaft nützlich sein.

Key words

therapy algorithms - evidence-based treatment - breast cancer guidelines

Schlüsselwörter

Behandlungsalgorithmen - evidenzbasierte Therapie - Brustkrebs-Leitlinien

Introduction

The Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) provides annual recommendations on prevention, diagnosis and treatment of early and metastatic breast cancer [1], [2]. The Committee is a multidisciplinary team of national experts.

Since 2020, this group also publishes algorithms to better illustrate the overall therapeutic concept. These algorithms are based on the current AGO recommendations, but obviously cannot represent all evidence-based treatment options, since prior therapies, performance status, comorbidities, patient preference, etc. must be considered for the actual treatment choice. The recommendations are evidence-based but also reflect expert opinion, reflected by different grades of recommendation ([Table 1]). In individual cases, other evidence-based treatment options (not listed here) may also be appropriate and justified. In some situations, e.g. positive Phase III data or U. S. Food and Drug Administration (FDA) approval, the algorithms also take into account drugs that are not approved in Germany at the time the algorithm was last updated. The general structure of the formatting is illustrated in [Fig. 1].

Table 1 Grades of recommendation.

++	This investigation or therapeutic intervention is highly beneficial for patients, can be recommended without restrictions and should be performed.
+	This investigation or therapeutic intervention is of limited benefit for patients and can be performed.
+/−	This investigation or therapeutic intervention has not shown benefit for patients and may be performed only in individual cases. According to current knowledge a general recommendation cannot be given.
–	This investigation or therapeutic intervention can be of disadvantage for patients and might not be performed.
− −	This investigation or therapeutic intervention is of clear disadvantage for patients and should be avoided or omitted in any case.

Fig. 1 Format legend for the AGO agorithms.

Algorithm (Neo)adjuvant Therapy of HER2-positive Breast Cancer ([Fig. 2])

Fig. 2 Algorithm (Neo)adjuvant Therapy of HER2-positive Breast Cancer. ¹ Gianni L et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13: 25 – 32. ² Tolaney SM et al. Seven-Year Follow-Up Analysis of Adjuvant Paclitaxel and Trastuzumab Trial for Node-Negative, Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. J Clin Oncol 2019; 37: 1868 – 1875. ³ Perez EA et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 2014; 32: 3744 – 3752. ⁴ Cameron D et al., Herceptin Adjuvant (HERA) Trial Study Team. 11 yearsʼ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 2017; 389: 1195 – 1205. ⁵ Martin M et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2017; 18: 1688 – 1700. ⁶ von Minckwitz G et al., APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med 2017; 377: 122 – 131. ⁷ Piccart M et al. Interim overall survival analysis of APHINITY (BIG 4 – 11): A randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer. SABCS 2019; Abstr. GS01-04. ⁸ Gianni L et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 2014; 15: 640. ⁹ von Minckwitz G et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 2019; 380: 617 – 628. ¹⁰ Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Waldron-Lynch M, Eng-Wong J, Kirk S, Cortés J. Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: Evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer. Eur J Cancer 2018; 89: 27 – 35.

Patients with HER2-positive cT1 cN0 breast cancer should undergo upfront surgery in order to confirm the low-risk situation (pT1 pN0), histologically. In this case, systemic treatment can be deescalated to 12 × paclitaxel qw and trastuzumab monotherapy completed for one year. In case of pT2 pN0 a taxane based polychemotherapy plus trastuzumab monotherapy is recommended which might be followed in case of a HR+ tumor by neratinib monotherapy for up to 1 year. For patients with confirmed positive lymph nodes (pN+) HER2 targeted therapy should be escalated to trastuzumab and pertuzumab for up to one year.

Patients with HER2-positive breast cancer ≥ 2 cm and/or clinically positive lymph nodes should be treated with a taxane based polychemotherapy and dual antibody blockade in the neoadjuvant setting. Based on therapy response (pCR/non pCR) different postneoadjuvant therapy options should be offered after surgery. In initially node positive patients (cN+) with pCR trastuzumab and pertuzumab should be completed for one year. In patients with a pCR and low risk of recurrence (cN0) a deescalation to trastuzumab monotherapy is recommended. Patients with non pCR should be treated with 14 cycles T-DM1 q3w as postneoadjuvant therapy.

Algorithm Adjuvant Endocrine Therapy in Premenopausal Patients ([Fig. 3])

Fig. 3 Algorithm Adjuvant Endocrine Therapy in Premenopausal Patients. ¹ Early Breast Cancer Trialistsʼ Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011; 378: 771 – 784. ² Davies C, Pan H, Godwin J et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013; 381: 805 – 806. ³ Goss PE, Ingle JN, Martino S et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005; 97: 1262 – 1271. ⁴ Francis PA, Regan MM, Fleming GF et al. The SOFT Investigators and the International Breast Cancer Study Group. Adjuvant Ovarian Suppression in Premenopausal Breast Cancer. N Engl J Med 2015; 372: 436 – 446. ⁵ Pagani O, Regan MM, Walley BA et al. TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 2014; 371: 107 – 118.

Although recruitment was more than 10 years ago SOFT and TEXT trials are the main evidence for the treatment recommendations for premenopausal patients. However, it must be noticed that therapy practice and indication for chemotherapy have changed since the recruitment and generalization of data for the current patient population might be limited. Therefore, the recommendations and the algorithms were simplified. Patients with a low risk of recurrence may receive just tamoxifen, patients with a higher risk of recurrence should be treated with ovarian function suppression (OFS) in addition to tamoxifen, and patients with a higher risk of recurrence can be considered for an aromatase inhibitor and OFS (for 5 years). Patients do not need to be treated with chemotherapy prior to receiving an OFS. In the above-mentioned trials, chemotherapy can be considered as a surrogate marker for high-risk. In case a patient has a high risk of recurrence and does not for whatever reason receive (neo)adjuvant chemotherapy, the use of an AI an OFS is still indicated. In general, in HR+/HER2− breast cancer, age is an independent risk factor. Patients being amenorrheic after chemotherapy can start with Tamoxifen. OFS can be added later when the menstruation/premenopausal status has been regained. An AI should only be added when the ovarian function is sufficiently and reliably suppressed. Tamoxifen can be extended for up to 10 years. An extended adjuvant therapy with 5 years of tamoxifen should also be offered to those patients with ovarian suppression and tamoxifen or AI for their initial treatment. If the patient is confirmed as being postmenopausal within the first 5 years, endocrine therapy can be continued after 5 years of tamoxifen with 2.5 – 5 years or letrozole.

Algorithm Adjuvant Endocrine Therapy in Postmenopausal Patients ([Fig. 4])

Fig. 4 Algorithm Adjuvant Endocrine Therapy in Postmenopausal Patients. ¹ Early Breast Cancer Trialistsʼ Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011; 378: 771 – 784. ² Davies C, Pan H, Godwin J et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013; 381: 805 – 806. ³ Early Breast Cancer Trialistsʼ Collaborative Group (EBCTCG): Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 2015; 386: 1341 – 1352. ⁴ Gray R (EBCTCG) et al. Extended aromatase inhibitor treatment following 5 or more years of endocrine therapy: a metaanalysis of 22 192 women in 11 randomised trials. SABCS 2018; GS3-03.

In postmenopausal women there has been an extensive discussion about the use of tamoxifen in comparison with an AI or sequential use of tamoxifen and an AI. Two metaanalyses have been published during the last years and both suggest that AIs should be preferred to tamoxifen. In the Early Breast Cancer Trialistsʼ Collaborative Group meta-analysis, either upfront AI or sequential treatment with tamoxifen followed by an AI or vice versa was superior regarding mortality in postmenopausal patients. In summary, depending on the individual risk profile an AI should be part of the endocrine treatment in the first 5 years for at least 2 – 3 years. In patients with low risk of recurrence, tamoxifen therapy upfront is still an option. After 5 years of tamoxifen, extended therapy with 5 years of tamoxifen is an option in patients with higher risk of recurrence – but switching to an AI for 2 – 5 years should be preferred. If patients received an AI (upfront or switch), patients at higher risk should be offered 2 – 5 additional years of AI. It is important to take into consideration the risk benefit and the tolerability of the endocrine therapy. Treatment can be adapted to individual needs. This is preferred to stopping prematurely.

Algorithm HR-positive/HER2-negative Metastatic Breast Cancer: Strategies ([Fig. 5])

Fig. 5 Algorithm HR-positive/HER2-negative Metastatic Breast Cancer: Strategies. ¹ Qi WX, Tang LN, He AN et al. Comparison between doublet agents versus single agent in metastatic breast cancer patients previously treated with an anthracycline and a taxane: A meta-analysis of four phase III trials. Breast 2013; 22: 314 – 319. ² Belfiglio M, Fanizza C, Tinari N et al., Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO). Meta-analysis of phase III trials of docetaxel alone or in combination with chemotherapy in metastatic breast cancer. J Cancer Res Clin Oncol 2012; 138: 221 – 229. ³ Pallis AG, Boukovinas I, Ardavanis A et al. A multicenter randomized phase III trial of vinorelbine/gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxane-pretreated women with metastatic breast cancer. Ann Oncol 2012; 23: 1164 – 1169. ⁴ Dear RF, McGeechan K, Jenkins MC et al. Combination versus sequential single agent chemotherapy for metastatic breast cancer. Cochrane Database Syst Rev 2013; (12): CD008792. doi:10.1002/14651858.CD008792.pub2. ⁵ Petrelli F, Ghidini A, Pedersini R et al. Comparative efficacy of palbociclib, ribociclib and abemaciclib for ER+ metastatic breast cancer: an adjusted indirect analysis of randomized controlled trials. Breast Cancer Res Treat 2019; 174: 597 – 604. doi:810.1007/s10549-019-05133-y. PMID: 30659432. ⁶ Rossi V, Berchialla P, Giannarelli D et al. Should All Patients With HR-Positive HER2-Negative Metastatic Breast Cancer Receive CDK 4/6 Inhibitor As First-Line Based Therapy? A Network Meta-Analysis of Data from the PALOMA 2, MONALEESA 2, MONALEESA 7, MONARCH 3, FALCON, SWOG and FACT Trials. Cancers (Basel) 2019; 11; pii: E1661. doi:10.3390/cancers11111661. ⁷ Robson M et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017; 377: 523 – 533. ⁸ Robson ME, Tung N, Conte P et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physicianʼs choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol 2019; 30: 558 – 566. doi:10.1093/annonc/mdz012. PMID: 30689707. ⁹ Robson M, Ruddy KJ, Im SA et al. Patient-reported outcomes in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer receiving olaparib versus chemotherapy in the OlympiAD trial. Eur J Cancer 2019; 120: 20 – 30. doi:10.1016/j.ejca.2019.06.023. PMID: 31446213. ¹⁰ Litton J et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med 2018; 379: 753 – 763. doi:10.1056/NEJMoa180290510. ¹¹ Turner NC, Telli ML, Rugo HS et al., ABRAZO Study Group. A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO). Clin Cancer Res 2019; 25: 2717 – 2724. doi:10.1158/1078-0432.CCR-18-1891. PMID: 30563931. ¹² Ettl J, Quek RGW, Lee KH et al. Quality of life with talazoparib versus physicianʼs choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2 mutation: patient-reported outcomes from the EMBRACA phase III trial. Ann Oncol 2018; 29: 1939 – 1947. doi:10.1093/annonc/mdy257. PMID: 30124753. ¹³ Hurvitz SA, Gonçalves A, Rugo HS et al. Talazoparib in Patients with a Germline BRCA-Mutated Advanced Breast Cancer: Detailed Safety Analyses from the Phase III EMBRACA Trial. Oncologist 2020; 25: e439 – e450. doi:10.1634/theoncologist.2019-0493. PMID: 31767793. ¹⁴ Cardoso F, Senkus E, Costa A et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC4). Ann Oncol 2018; 29: 1634 – 1657. ¹⁵ Kornblum NS et al. PrECOG 0102: A randomized, double-blind, phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC) resistant to aromatase inhibitor (AI) therapy. SABCS 2016; #S1-02. ¹⁶ André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu YS, Inoue K, Takahashi M, Pápai Z, Longin AS, Mills D, Wilke C, Hirawat S, Juric D, SOLAR-1 Study Group. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med 2019; 380: 1929 – 1940.

Recent evidence from previous years has resulted in additional therapeutic options for treating the advanced or metastasic hormone receptor (HR-)positive and HER2-negative breast cancer. In order to reach the therapeutic goal of maintaining as high a quality of life as possible, today the endocrine-based therapy is considered to be the standard of care first-line treatment. Thus, CDK4/6 inhibitors (abemaciclib, palbociclib, ribociclib) are administered in first line together with an aromatase inhibitor or fulvestrant. Only if a very rapid remission is required due to severe symptoms or impending organ failure, cytostatic drugs, if necessary combined with bevacicumab, should be used as first-line therapy. Second-line therapy options depend on the aggressiveness of progressive disease and the patientʼs wish for therapy. In case of a germline mutation (gBRCA1/2mt), therapy with PARP inhibitors should be offered. In addition, depending on endocrine sensitivity and resistance further endocrine mono or combination therapies are available. Besides the combination with everolimus, in case of a somatic PIK3CA mutation the use of alpelisib is a valuable therapeutic option. In case of endocrine resistance cytostatic drugs should be offered as further-line therapy.

Algorithm HR-positive/HER2-negative Metastatic Breast Cancer: Endocrine-based First Line Treatment ([Fig. 6])

Fig. 6 Algorithm HR-positive/HER2-negative Metastatic Breast Cancer: Endocrine-based First Line Treatment. ¹ Turner N et al. Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer. N Engl J Med 2015; 373: 209 – 219. ² Loibl S et al. Palbociclib Combined with Fulvestrant in Premenopausal Women with Advanced Breast Cancer and Prior Progression on Endocrine Therapy: PALOMA-3 Results. Oncologist 2017; 22: 1028 – 1038. ³ Layman RM et al. Comparative effectiveness of palbociclib plus letrozole vs. letrozole for metastatic breast cancer in US-real world clinical practises. ESMO 2019; #329P. ⁴ Tripathy D et al. First-line ribociclib vs. placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from the randomized phase III MONALEESA-7 trial. SABCS2017; GS-26. ⁵ Im SA, Lu YS, Bardia A et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med 2019; 381: 307 – 316. doi:10.1056/NEJMoa1903765. PMID:31166679. ⁶ Sledge GW jr., Toi M, Neven P et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol 2019. doi:10.1001/jamaoncol.2019.4782 [Epub ahead of print]. PMID:31 563 959. ⁷ Klijn JG, Blamey RW, Boccardo F et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 2001; 19: 343 – 353. ⁸ Rugo HS et al. Endocrine Therapy for Hormone Receptor-Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline. J Clin Oncol 2016; 34: 3069 – 3103. ⁹ Forward DP, Cheung KL, Jackson L et al. Clinical and endocrine data for goserelin plus anastrozole as second-line endocrine therapy for premenopausal advanced breast cancer. Br J Cancer 2004; 90: 590 – 594. ¹⁰ Park IH, Ro J, Lee KS et al. Phase II parallel group study showing comparable efficacy between premenopausal metastatic breast cancer patients treated with letrozole plus goserelin and postmenopausal patients treated with letrozole alone as first-line hormone therapy. J Clin Oncol 2010; 28: 2705 – 2711. ¹¹ Carlson RW et al. Phase II trial of anastrozole plus goserelin in the treatment of hormone receptor-positive, metastatic carcinoma of the breast in premenopausal women. J Clin Oncol 2010; 28: 3917 – 3921. ¹² Bartsch R, Bago-Horvath Z et al. Ovarian function suppression and fulvestrant as endocrine therapy in premenopausal women with metastatic breast cancer. Eur J Cancer 2012; 48: 1932 – 1938. ¹³ Taylor CW, Green S, Dalton WS et al. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol 1998; 16: 994 – 999. ¹⁴ Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med 1998; 339: 1609 – 1618. ¹⁵ Crump M, Sawka CA, DeBoer G et al. An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer. Breast Cancer Res Treat 1997; 44: 201 – 210. ¹⁶ Finn RS et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 2016; 375: 1925 – 1936. ¹⁷ Finn RS et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015; 16: 25 – 35. ¹⁸ Im SA, Mukai H, Park IH et al. Palbociclib Plus Letrozole as First-Line Therapy in Postmenopausal Asian Women With Metastatic Breast Cancer: Results From the Phase III, Randomized PALOMA-2 Study. J Glob Oncol 2019; 5: 1 – 19. doi:10.1200/JGO.18.00173. PMID: 31125276. ¹⁹ Rugo HS, Finn RS, Diéras V et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat 2019; 174: 719 – 729. doi:10.1007/s10549-018-05125-4. PMID: 30632023. ²⁰ Hortobagyi GN et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med 2016; 375: 1738 – 1748. ²¹ Yardley DA, Hart L, Favret A et al. Efficacy and Safety of Ribociclib With Letrozole in US Patients Enrolled in the MONALEESA-2 Study. Clin Breast Cancer 2019; 19: 268 – 277.e1. doi:10.1016/j.clbc.2019.02.007. ²² Goetz MP et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol 2017; 35: 3638 – 3646. ²³ Johnston S, Martin M, Di Leo A et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 2019; 5: 5. doi:10.1038/s41523-018-0097-z. PMID: 30675515. ²⁴ Bonneterre J et al. Anastrozole versus Tamoxifen as First-Line Therapy for Advanced Breast Cancer in 668 Postmenopausal Women: Results of the Tamoxifen or Arimidex Randomized Group Efficacy and tolerability Study. J Clin Oncol 2000; 18: 3748 – 3757. ²⁵ Thürlimann B et al. Anastrozole (Arimidex) versus tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer: results of the double-blind cross-over SAKK trial 21/95 – a substudy of the TARGET (Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability) trial. Breast Cancer Res Treat 2004; 85: 247 – 254. ²⁶ Bonneterre J et al. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma Cancer 2001; 92: 2247 – 2258. ²⁷ Mouridsen H et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group Journal of Clinical Oncology. J Clin Oncol 2003; 21: 2101 – 2109. ²⁸ Paridaens R et al., European Organization for the Research and Treatment of Cancer (EORTC) – Investigational Drug Branch for Breast Cancer (IDBBC). Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Ann Oncol 2003; 14: 1391 – 1398. ²⁹ Gibson L, Lawrence D, Dawson C et al. Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane Database Syst Rev 2009; (4): CD003370. ³⁰ Fulvestrant 500 mg plus Palbociclib (vs. Fulvestrant alone). ³¹ Turner NC, Ro J, André F et al., PALOMA3 Study Group. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med 2015; 373: 209 – 219. ³² Turner NC et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med 2018; 379: 1926 – 1936. doi:10.1056/NEJMoa1810527. ³³ Slamon DJ, Neven P, Chia S et al. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol 2018; 36: 2465 – 2472. doi:10.1200/JCO.2018.78.9909. PMID: 29860922. ³⁴ Slamon DJ, Neven P, Chia S et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med 2020; 382: 514 – 524. doi:10.1056/NEJMoa1911149. ³⁵ Sledge GW jr. et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol 2017; 35: 2875 – 2884. ³⁶ Sledge GW jr., Toi M, Neven P et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol 2020; 6: 116 – 124. doi:10.1001/jamaoncol.2019.4782. PMID: 31563959. ³⁷ Ellis MJ et al. Fulvestrant 500 mg Versus Anastrozole 1 mg for the First-Line Treatment of Advanced Breast Cancer: Overall Survival Analysis From the Phase II FIRST Study. J Clin Oncol 2015; 33: 3781 – 3787. ³⁸ Robertson JF et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet 2016; 388: 2997 – 3005. ³⁹ Di Leo A et al. Final overall survival: fulvestrant 500 mg vs. 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst 2014; 106: djt337.

Data from PALOMA-, MONALEESA- and MONARCH-studies showed significant and clinically relevant improvements of progression-free survival in pre-, peri- and postmenopause if CDK4/6 inhibitors had been used. Currently, data referring to overall survival are only available for individual drug combinations in defined situations. If CDK4/6 inhibitors are not administered, the initial treatment strategy in premenopausal patients is to shutdown the ovarian function (e.g. with GnRH analogues) combined with tamoxifen. In case of tumor progression or if tamoxifen is contraindicated, a third-generation aromatase inhibitor plus a GnRH analogue can be administered. Fulvestrant plus GnRH analogue is a further option. In postmenopausal patients depending on the previous adjuvant therapy, aromatase inhibitors or tamoxifen can be administered. After a previous therapy with an aromatase inhibitor fulvestrant should be considered.

Algorithm HER2-positive Metastatic Breast Cancer: 1st–3rd line ([Fig. 7])

Fig. 7 Algorithm HER2-positive Metastatic Breast Cancer: 1st–3rd-line. ¹ Swain SM, Baselga J, Kim SB et al.; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015; 372: 724 – 734. ² Perez EA, López-Vega JM, Petit T et al. Safety and efficacy of vinorelbine in combination with pertuzumab and trastuzumab for first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer: VELVET Cohort 1 final results. Breast Cancer Res 2016; 18: 126. ³ Verma S, Miles D, Gianni L et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; 367: 1783 – 1791. ⁴ Krop IE, Lin NU, Blackwell K et al. Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA. Ann Oncol 2015; 26: 113 – 119. ⁵ Murthy RK, Loi S, Okines A et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med 2020; 382: 597 – 609. ⁶ Lin NU, Borges V, Anders C et al. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial. J Clin Oncol 2020; 38: 2610 – 2619. ⁷ Cameron D, Casey M, Press M et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008; 112: 533 – 543. ⁸ Geyer CE, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355: 2733 – 2743. ⁹ Saura C, Oliveira M, Feng Y-H et al. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial. J Clin Oncol 2020; 38: 3138 – 3149. ¹⁰ Modi S, Saura C, Yamashita T et al. Trastuzumab-Deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 2020. doi:10.1056/NEJMoa1914510. ¹¹ von Minckwitz G, Schwedler K, Schmidt M et al.; GBG 26/BIG 03 – 05 study group and participating investigators. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3 – 05 phase III study in HER2-positive breast cancer. Eur J Cancer 2011; 47: 2273 – 2281. ¹² Rimawi M, Ferrero J – M, de La Haba-Rodriguez J et al. First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor Receptor 2-Positive and Hormone Receptor-Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial. J Clin Oncol 2018; 36: 2826 – 2828. ¹³ Blackwell KL, Burstein HJ, Storniolo AM et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol 2012; 30: 2585 – 2592. ¹⁴ Blackwell KL, Burstein HJ, Storniolo AM et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 2010; 28: 1124 – 1130. ¹⁵ Giordano SH, Temin S, Kirshner JJ et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2014; 32: 2078 – 2099. ¹⁶ Kaufman B, Mackey JR, Clemens MR et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol 2009; 27: 5529 – 5537. ¹⁷ Huober J, Fasching PA, Barsoum M et al. Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer – results of the eLEcTRA trial. Breast 2012; 21: 27 – 33. ¹⁸ Johnston S, Pippen J jr., Pivot X et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 2009; 27: 5538 – 5546. ¹⁹ Burstein HJ, Cirrincione CT, Barry WT et al. Endocrine Therapy With or Without Inhibition of Epidermal Growth Factor Receptor and Human Epidermal Growth Factor Receptor 2: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Fulvestrant With or Without Lapatinib for Postmenopausal Women With Hormone Receptor-Positive Advanced Breast Cancer-CALGB 40 302 (Alliance). J Clin Oncol 2014; 32: 3959 – 3966. ²⁰ Rimawi M, Ferrero JM, de la Haba-Rodriguez J et al.; PERTAIN Study Group. First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor Receptor 2-Positive and Hormone Receptor-Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial. J Clin Oncol 2018; 36: 2826 – 2835. doi:10.1200/JCO.2017.76.7863. PMID:30106636.

In HER2-positive breast cancer with de novo metastases or a treatment-free interval (TFI) > 6 months, taxane-based chemotherapy plus dual antibody blockade with trastuzumab and pertuzumab is recommended as first-line combination. In patients not suitable for chemotherapy or according to patientʼs preference, combination of endocrine therapy and anti-HER2 therapy might be an option. In these patients as well as in secondary metastatic breast cancer with a TFI ≤ 6 months after (neo-)adjuvant anti-HER2 treatment with dual blockade, T-DM1 is the preferred second-line option. In case of progression after two prior lines of anti-HER2 therapy, including patients after (neo)adjuvant therapy with trastuzumab +/− pertuzumab followed by adjuvant T-DM1, tucatinib in combination with trastuzumab and capecitabine is a new anti-HER2 combination therapy that results in improved overall survival. There is a plethora of further anti-HER2 treatment options including trastuzumab deruxtecan and neratinib in combination with capecitabine representing new therapeutic options in heavily pretreated patients with HER2-positive advanced breast cancer.

Algorithm Triple-negative Metastatic Breast Cancer ([Fig. 8])

Fig. 8 Algorithm Triple-negative Metastatic Breast Cancer. ¹ Cardoso F, Senkus E, Costa A et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC4). Ann Oncol 2018; 29: 1634 – 1657. ² Condorelli R, Mosele F, Verret B et al. Genomic alterations breast cancer: level of evidence for actionability according to ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann Oncol 2019; 30: 365 – 373. ³ Hu XC, Zhang J, Xu BH et al. Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 2015; 16: 436 – 446. ⁴ Litton JK, Rugo HS, Ettl J et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med 2018; 379: 753 – 763. ⁵ Miles DW, Diéras V, Cortés J et al. First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients. Ann Oncol 2013; 24: 2773 – 2780. ⁶ Miller K, Wang M, Gralow J et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357: 2666 – 2676. ⁷ Miller KD, Chap LI, Holmes FA et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23: 792 – 799. ⁸ Robson M, Im S-A, Senkus E et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017; 377: 523 – 533. ⁹ Robson M, Tung N, Conte P et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physicianʼs choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol 2019; 30: 558 – 566. ¹⁰ Schmid P, Adams S, Rugo HS et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med 2018; 379: 2108 – 2121. ¹¹ 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. ¹² Tutt A, Tovey H, Cheang MCU et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med 2018; 24: 628 – 637. ¹³ Twelves C, Cortes J, Vahdat L et al. Efficacy of eribulin in women with metastatic breast cancer: a pooled analysis of two phase 3 studies [published correction appears in Breast Cancer Res Treat 2015; 149: 313. Breast Cancer Res Treat 2014; 148: 553 – 561. ¹⁴ Yardley DA, Coleman R, Conte P et al. nab-Paclitaxel plus carboplatin or gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative metastatic breast cancer: results from the tnAcity trial. Ann Oncol 2018; 29: 1763 – 1770. ¹⁵ Zielinski C, Láng I, Inbar M et al., TURANDOT investigators. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, noninferiority, phase 3 trial. Lancet Oncol 2016; 17: 1230 – 1239. ¹⁶ Bardia A, Hurvitz SA, Tolaney SM et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med 2021; 384: 1529 – 1541. ¹⁷ Bardia A, Mayer IA, Vahdat LT et al. Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. N Engl J Med 2019; 380: 741 – 751

In advanced or metastatic triple-negative breast cancer (TNBC) evaluation of PD-L1 status and germline BRCA mutation (gBRCAmt) is needed as a basis for standard-of-care therapy decision making because the optimal choice of therapies depends on these two biomarkers. In patients with PDL-1-negative/gBRCAwt, paclitaxel or capecitabine plus bevacizumab, cisplatin plus gemcitabine or carboplatin +/− nab-paclitaxel are recommended treatment options. In later lines, the antibody-drug-conjugate sacituzumab govitecan offers promising activity.

In patients with PDL-1-negative/gBRCAmt, PARP inhibitors should be considered after anthracycline and taxane pretreatment and chemotherapy +/− bevacizumab in chemotherapy-naïve patients. For those patients with PD-L1-positive/gBRCAwt metastatic breast cancer, the combination of nab-paclitaxel and the immune checkpoint-inhibitor (ICI) atezolizumab is recommended. In addition, a combination of the ICI pembrolizumab and first-line chemotherapy (i.e. paclitaxel or nab-paclitaxel or carboplatin plus gemcitabine) could be considered. Finally, in PDL-1-positive/gBRCA mutant patients, either nab-paclitaxel plus atezolizumab or PARP inhibitors are recommended. The choice of further therapies after tumor progression depends on PD-L1 and gBRCA status, clinical presentation, pretreatments and approval status.

Conclusion

The treatment options shown in these algorithms are based on the 2021 AGO recommendations, but cannot represent all evidence-based treatment options, since prior therapies, performance status, comorbidities, patient preference, etc. must be considered for the actual treatment choice. In individual cases, other evidence-based treatment options (not listed here) may also be appropriate and justified. However, theses treatment algorithms are intended to intensify structured treatment decision by providing reproducible and evidence-based treatment paths and may be helpful for a broad treatment landscape.

Conflict of Interest

Consultancy: Sanofi-Aventis, Novartis, Roche, Pfizer, Lilly, AstraZeneca, Chugai, GSK, Eisai, Cellgene, Johnson & Johnson, Seagen, MSD, PierreFabre, Amgen, Gilead, DaiichiSankyo. Research Funding: Sanofi-Aventis, Novartis, Roche, Pfizer, Lilly, AstraZeneca, Chugai, GSK, Eisai, Cellgene, Johnson & Johnson, Seagen, MSD, PierreFabre, Amgen, Gilead, DaiichiSankyo. Honoraria: Sanofi-Aventis, Novartis, Roche, Pfizer, Lilly, AstraZeneca, Chugai, GSK, Eisai, Cellgene, Johnson & Johnson, Seagen, MSD, PierreFabre, Amgen, Gilead, DaiichiSankyo.

^* Prof. Dr. W. Janni, Ulm | Prof. Dr. V. Müller, Hamburg | Prof. Dr. U.-S. Albert, Würzburg | PD Dr. M. Banys-Paluchowski, Hamburg | Dr. I. Bauerfeind, Landshut | Prof. Dr. J.-U. Blohmer, Berlin | Prof. Dr. W. Budach, Düsseldorf | Prof. Dr. P. Dall, Lüneburg | Prof. Dr. N. Ditsch, Augsburg | PD Dr. E. Fallenberg, München | Prof. Dr. P. Fasching, Erlangen | Prof. Dr. T. Fehm, Düsseldorf | Prof. Dr. M. Friedrich, Krefeld | Prof. Dr. B. Gerber, Rostock | PD Dr. O. Gluz, Mönchengladbach | Prof. Dr. N. Harbeck, München | Prof. Dr. J. Heil, Heidelberg | Prof. Dr. J. Huober, St. Gallen/Ulm | Prof. Dr. C. Jackisch, Offenbach | Prof. Dr. C. Kolberg-Liedtke, Berlin | Prof. Dr. H. Kreipe, Hannover | Dr. D. Krug, Kiel | Prof. Dr. T. Kühn, Esslingen | Prof. Dr. S. Kümmel, Essen | Prof. Dr. S. Loibl, Neu-Isenburg | Prof. Dr. D. Lüftner, Berlin | Prof. Dr. M. Lux, Paderborn | Prof. Dr. N. Maass, Kiel | Prof. Dr. C. Mundhenke, Bayreuth | Prof. Dr. U. Nitz, Mönchengladbach | Prof. Dr. T.-W. Park-Simon, Hannover | Prof. Dr. T. Reimer, Rostock | PD Dr. K. Rhiem, Köln | Prof. Dr. A. Rody, Lübeck | Prof. Dr. M. Schmidt, Mainz | Prof. Dr. A. Schneeweiss, Heidelberg | Prof. Dr. F. Schütz, Speyer | Prof. Dr. H.-P. Sinn, Heidelberg | Prof. Dr. C. Solbach, Frankfurt | Prof. Dr. E. Solomayer, Homburg | Prof. Dr. E. Stickeler, Aachen | Prof. Dr. M. Thill, Frankfurt/Main | Prof. Dr. C. Thomssen, Halle/Saale | Prof. Dr. M. Untch, Berlin | Prof. Dr. I. Witzel, Hamburg | Prof. Dr. A. Wöckel, Würzburg

• References

• 1 Thill M, Friedrich M, Kolberg-Liedtke C. et al. AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer (MBC): Update 2021. Breast Care 2021; DOI: 10.1159/00051620.
• 2 Ditsch N, Kolberg-Liedtke C, Friedrich M. et al. AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer (EBC): Update 2021. Breast Care 2021; DOI: 10.1159/00051619.

Publication History

Received: 17 May 2021

Accepted: 26 May 2021

Article published online:
06 October 2021