Update Mammakarzinom 2020 Teil 5 – Einführung von Substanzen aus der metastasierten Therapiesituation in die frühe Therapiesituation

Zusammenfassung

Bei neuen Therapieansätzen des Mammakarzinoms sind insbesondere bei Patientinnen mit HER2-positivem und HER2-negativem/hormonrezeptorpositivem (HR+) Mammakarzinom in den letzten Jahren deutliche Fortschritte gesehen worden. Bei HER2-positiven Tumoren müssen in dem Zusammenhang Pertuzumab, T‑DM1, Neratinib und bald auch Tucatinib und Trastuzumab-Deruxtecan (beide in Europa noch nicht zugelassen) genannt werden. Bei den Patientinnen mit HER2−/HR+-Mammakarzinom sind insbesondere die CDK4/6-Inhibitoren und der PIK3CA-Inhibitor Alpelisib zu nennen. Weitere, neue Therapien wie Akt-Kinase-Inhibitoren und orale SERDs (selective estrogen receptor down-regulators) werden bereits in laufenden klinischen Studien untersucht. Nicht nur bei den HER2-positiven Tumoren halten die Therapien Einzug in die kurative, (neo-) adjuvante Therapiesituation, sondern es wurde nun eine erste positive Studie mit Abemaciclib in der adjuvanten Situation vorgestellt. Bei Patientinnen mit einem triple-negativen Mammakarzinom ist nach vielen Jahren mit negativen Studienergebnissen mit dem Trop-2-Antikörper-Wirkstoff-Konjugat (antibody drug conjugate, ADC) Sacituzumab-Govitecan eine randomisierte Studie veröffentlicht worden, die einen deutlichen Therapiefortschritt bedeuten kann. Diese Übersichtsarbeit beschreibt die neuesten Entwicklungen beim Mammakarzinom nach dem ESMO-Kongress 2020.

Abstract

In recent years, significant progress has been made in new therapeutic approaches to breast cancer, particularly in patients with HER2-positive and HER2-negative/hormone receptor-positive (HR+) breast cancer. In the case of HER2-positive tumours, these approaches have included, in particular, treatment with pertuzumab, T‑DM1, neratinib and, soon, also tucatinib and trastuzumab deruxtecan (neither of which has yet been authorised in Europe). In patients with HER2−/HR+ breast cancer, CDK4/6 inhibitors and the PIK3CA inhibitor alpelisib are of particular importance. Further novel therapies, such as Akt kinase inhibitors and oral SERDs (selective estrogen receptor down regulators), are already being investigated in ongoing clinical trials. These therapeutic agents are not only being introduced into curative, (neo-)adjuvant therapeutic settings for HER2-positive tumours; a first favourable study on abemaciclib as an adjuvant therapy has now also been published. In patients with triple-negative breast cancer, after many years of negative study results with the Trop-2 antibody drug conjugate (ADC) sacituzumab govitecan, a randomised study has been published that may represent a significant therapeutic advance. This review describes the latest developments in breast cancer subsequent to the ESMO Congress 2020.

Schlüsselwörter

frühes Mammakarzinom - Therapie - Prognose - Immuntherapie - digitale Medizin

Key words

early breast cancer - therapy - prognosis - immune therapy - digital medicine

Publication History

Article published online:
30 September 2021

• Literatur

• 1 Schneeweiss A, Hartkopf AD, Müller V. et al. Update Breast Cancer 2020 Part 1 – Early Breast Cancer: Consolidation of Knowledge About Known Therapies. Geburtshilfe Frauenheilkd 2020; 80: 277-287
• 2 Lüftner D, Schneeweiss A, Hartkopf AD. et al. Update Breast Cancer 2020 Part 2 – Advanced Breast Cancer: New Treatments and Implementation of Therapies with Companion Diagnostics. Geburtshilfe Frauenheilkd 2020; 80: 391-398
• 3 Welslau M, Hartkopf AD, Müller V. et al. Update Breast Cancer 2019 Part 5 – Diagnostic and Therapeutic Challenges of New, Personalised Therapies in Patients with Advanced Breast Cancer. Geburtshilfe Frauenheilkd 2019; 79: 1090-1099
• 4 Schütz F, Fasching PA, Welslau M. et al. Update Breast Cancer 2019 Part 4 – Diagnostic and Therapeutic Challenges of New, Personalised Therapies for Patients with Early Breast Cancer. Geburtshilfe Frauenheilkd 2019; 79: 1079-1089
• 5 Kolberg HC, Schneeweiss A, Fehm TN. et al. Update Breast Cancer 2019 Part 3 – Current Developments in Early Breast Cancer: Review and Critical Assessment by an International Expert Panel. Geburtshilfe Frauenheilkd 2019; 79: 470-482
• 6 Janni W, Schneeweiss A, Müller V. et al. Update Breast Cancer 2019 Part 2 – Implementation of Novel Diagnostics and Therapeutics in Advanced Breast Cancer Patients in Clinical Practice. Geburtshilfe Frauenheilkd 2019; 79: 268-280
• 7 Hartkopf AD, Müller V, Wöckel A. et al. Update Breast Cancer 2019 Part 1 – Implementation of Study Results of Novel Study Designs in Clinical Practice in Patients with Early Breast Cancer. Geburtshilfe Frauenheilkd 2019; 79: 256-267
• 8 Hartkopf AD, Müller V, Wöckel A. et al. Translational Highlights in Breast and Ovarian Cancer 2019 – Immunotherapy, DNA Repair, PI3K Inhibition and CDK4/6 Therapy. Geburtshilfe Frauenheilkd 2019; 79: 1309-1319
• 9 Fasching PA, Schneeweiss A, Kolberg HC. et al. Translational highlights in breast cancer research and treatment: recent developments with clinical impact. Curr Opin Obstet Gynecol 2019; 31: 67-75
• 10 Schmid P, Cortés J, Dent R. et al. KEYNOTE‑522: Phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs. placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs. pbo as adjuvant treatment for early triple-negative breast cancer (TNBC). Ann Oncol 2019; 30 (Suppl. 05) v851-v934 DOI: 10.1093/annonc/mdz394.
• 11 Schmid P, Cortes J, Pusztai L. et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med 2020; 382: 810-821
• 12 Schmid P, Park YH, Ferreira M. et al. KEYNOTE‑522 study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early triple-negative breast cancer: pathologic complete response in key subgroups and by treatment exposure, residual cancer burden, and breast-conserving surgery. San Antonio Breast Cancer Symposium 2019; 2019: GS3-03
• 13 Harbeck N, Zhang H, Barrios CH. et al. IMpassion031: Results from a phase III study of neoadjuvant (neoadj) atezolizumab + chemotherapy in early triple-negative breast cancer (TNBC). Ann Oncol 2020; 31 (Suppl. 04) S1142-S1215 DOI: 10.1016/annonc/annonc325.
• 14 Baum M, Budzar AU, Cuzick J. et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359: 2131-2139
• 15 Cuzick J, Sestak I, Baum M. et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010; 11: 1135-1141
• 16 Janni W, Hepp P. Adjuvant aromatase inhibitor therapy: outcomes and safety. Cancer Treat Rev 2010; 36: 249-261
• 17 Early Breast Cancer Trialistsʼ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level metaanalysis of the randomised trials. Lancet 2015; 386: 1341-1352
• 18 clinicaltrials.gov. NCT03701334. A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2-Early Breast Cancer (NATALEE). NIH U.S. National Library of Medicine 2018. https://clinicaltrials.gov/ct2/show/NCT03701334 ; Stand 07.11.2020
• 19 Slamon DJ, Fasching PA, Patel R. et al. NATALEE: Phase III study of ribociclib (RIBO) + endocrine therapy (ET) as adjuvant treatment in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) early breast cancer (EBC). J Clin Oncol 2019; 37 (Suppl. 15) TPS597
• 20 clinicaltrials.gov. NCT03155997. Endocrine Therapy With or Without Abemaciclib (LY2835219) Following Surgery in Participants With Breast Cancer (monarchE). NIH U.S. National Library of Medicine 2017. https://clinicaltrials.gov/ct2/show/NCT03155997 ; Stand 17.11.2018
• 21 clinicaltrials.gov. NCT02513394. PALbociclib CoLlaborative Adjuvant Study: A Randomized Phase III Trial of Palbociclib With Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant Endocrine Therapy Alone for Hormone Receptor Positive (HR+)/Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Early Breast Cancer (PALLAS). NIH U. S. National Library of Medicine 2015. https://clinicaltrials.gov/ct2/show/NCT02513394 ; Stand 17.11.2018
• 22 clinicaltrials.gov. NCT01864746. A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery (PENELOPE‑B). NIH U.S. National Library of Medicine 2015. https://clinicaltrials.gov/ct2/show/NCT01864746 ; Stand 17.10.2020
• 23 Mayer EL, Gnant MI, DeMichele A. et al. PALLAS: A randomized phase III trial of adjuvant palbociclib with endocrine therapy versus endocrine therapy alone for HR+/HER2-early breast cancer. Ann Oncol 2020; 31 (Suppl. 04) S1142-S1215 DOI: 10.1016/annonc/annonc325.
• 24 Johnston SRD, Harbeck N, Hegg R. et al. Abemaciclib in high risk early breast cancer. Ann Oncol 2020; 31 (Suppl. 04) S1142-S1215 DOI: 10.1016/annonc/annonc325.
• 25 Johnston SRD, Harbeck N, Hegg R. et al. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2–, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol 2020; 38: 3987-3998 DOI: 10.1200/JCO.20.02514.
• 26 German Breast Group; Pfizer Inc. PENELOPE‑B Trial of IBRANCE^® (palbociclib) in Early Breast Cancer Did Not Meet Primary Endpoint. https://www.gbg.de/de/newsroom/meldungen/2020-10-penelopeB.php ; Stand 07.11.2020
• 27 Mittendorf EA, Jeruss JS, Tucker SL. et al. Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol 2011; 29: 1956-1962
• 28 Loibl S, Marmé F, Martin M. et al Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancerand with high relapse risk after neoadjuvant chemotherapy (NACT): First results from PENELOPE‑B. Cancer Res 2021; 81 (Suppl. 04) GS1-02 DOI: 10.1158/1538-7445. . SABCS20-GS1–02
• 29 clinicaltrials.gov. NCT03701334. A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2-Early Breast Cancer (NATALEE). NIH U.S. National Library of Medicine 2018. https://clinicaltrials.gov/ct2/history/NCT03701334?V_37=View#StudyPageTop ; Stand 17.11.2018
• 30 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
• 31 Schmid P, Rugo HS, Adams S. et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2020; 21: 44-59
• 32 Miles DW, Gligorov J, André F. et al. Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). Ann Oncol 2020; 31 (Suppl. 04) S1142-S1215 DOI: 10.1016/annonc/annonc325.
• 33 Bracci L, Schiavoni G, Sistigu A. et al. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ 2014; 21: 15-25
• 34 Rossi A, Lucarini V, Macchia I. et al. Tumor-Intrinsic or Drug-Induced Immunogenicity Dictates the Therapeutic Success of the PD1/PDL Axis Blockade. Cells 2020; 9: 940
• 35 Verma S, Miles D, Gianni L. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; 367: 1783-1791
• 36 von Minckwitz G, Huang CS, Mano MS. et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 2019; 380: 617-628
• 37 Modi S, Saura C, Yamashita T. et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med 2020; 382: 610-621
• 38 Vidula N, Yau C, Rugo HS. Trop2 gene expression (Trop2e) in primary breast cancer (BC): Correlations with clinical and tumor characteristics. J Clin Oncol 2017; 35 (15) 1075
• 39 Ambrogi F, Fornili M, Boracchi P. et al. Trop-2 is a determinant of breast cancer survival. PLoS One 2014; 9: e96993
• 40 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
• 41 André 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
• 42 André F, Ciruelos EM, Juric D. et al. Overall survival (os) results from SOLAR‑1, a phase III study of alpelisib (ALP) + fulvestrant (FUL) for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). Ann Oncol 2020; 31 (Suppl. 04) S1142-S1215 DOI: 10.1016/annonc/annonc325.
• 43 Müller V, Nabieva N, Häberle L. et al. Impact of disease progression on health-related quality of life in patients with metastatic breast cancer in the PRAEGNANT breast cancer registry. Breast 2018; 37: 154-160
• 44 Schneeweiss A, Ettl J, Lüftner D. et al. Initial experience with CDK4/6 inhibitor-based therapies compared to antihormone monotherapies in routine clinical use in patients with hormone receptor positive, HER2 negative breast cancer – Data from the PRAEGNANT research network for the first 2 years of drug availability in Germany. Breast 2020; 54: 88-95
• 45 Harbeck N, Iyer S, Turner N. et al. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA‑3 trial. Ann Oncol 2016; 27: 1047-1054
• 46 Rugo HS, Diéras V, Gelmon KA. et al. Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA‑2 trial. Ann Oncol 2018; 29: 888-894
• 47 Fasching PA, Beck JT, Chan A. et al. Ribociclib plus fulvestrant for advanced breast cancer: Health-related quality-of-life analyses from the MONALEESA‑3 study. Breast 2020; 54: 148-154
• 48 Harbeck N, Franke F, Villanueva-Vazquez R. et al. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol 2020; 12: 1758835920943065
• 49 Fasching PA, Bardia A, Nusch A. et al. Pooled analysis of patient (pt)-reported quality of life (QOL) in the MONALEESA (ML)-2, -3, and -7 trials of ribociclib (RIB) plus endocrine therapy (ET) to treat hormone receptor-positive, HER2-negative (HR+/HER2−) advanced breast cancer (ABC). Ann Oncol 2020; 31 (Suppl. 04) S348-S395 DOI: 10.1016/annonc/annonc268.
• 50 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
• 51 Mueller V, Paplomata E, Hamilton EP. et al. Impact of tucatinib on healthrelated quality of life (HRQoL) in patients with HER2+ metastatic breast cancer (MBC) with and without brain metastases (BM). Ann Oncol 2020; 31 (Suppl. 04) S348-S395 DOI: 10.1016/annonc/annonc268.
• 52 Tresp V, Overhage JM, Bundschus M. et al. Going Digital: A Survey on Digitalization and Large-Scale Data Analytics in Healthcare. Proc IEEE Inst Electr Electron Eng 2016; 104: 2180-2206
• 53 Perez MV, Mahaffey KW, Hedlin H. et al. Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. N Engl J Med 2019; 381: 1909-1917
• 54 Loibl S, Untch M, Burchardi N. et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann Oncol 2019; 30: 1279-1288
• 55 Cardoso F, Jia L, Hirshfield K. et al. KEYNOTE‑756: A randomized, doubleblind, phase III study of pembrolizumab or placebo with neoadjuvant chemotherapy and adjuvant endocrine therapy for high-risk, early-stage, ER+/HER2-breast cancer. Ann Oncol 2019; 30 (Suppl. 03) III38 DOI: 10.1093/annonc/mdz097.013.
• 56 Gianni L, Huang CS, Egle D. et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer. NeoTRIPaPDL1 Michelangelo randomized study. Cancer Res 2020; 80 (Suppl. 04) GS3-04
• 57 Geyer CE, Loibl S, Rastogi P. et al. NSABP B‑59/GBG 96-GeparDouze: A randomized double-blind phase III clinical trial of neoadjuvant chemotherapy (NAC) with atezolizumab or placebo in patients (pts) with triple-negative breast cancer (TNBC) followed by adjuvant atezolizumab or placebo. J Clin Oncol 2019; 37 (Suppl. 15) TPS605
• 58 Tolaney S, Jerusalem G, Salgado R. et al Abstract OT2-04-02: CheckMate 7A8: A phase 2 trial of nivolumab + abemaciclib or palbociclib + anastrozole in postmenopausal women with ER+, HER2−primary breast cancer. Cancer Res 2020; 80 (Suppl. 04) OT2-04-02
• 59 clinicaltrials.gov. NCT03595592. Atezolizumab, Pertuzumab and Trastuzumab With Chemotherapy as Neoadjuvant Treatment of HER2 Positive Early High-risk and Locally Advanced Breast Cancer (APTneo). NIH U.S. National Library of Medicine 2020. https://clinicaltrials.gov/ct2/show/NCT03595592 ; Stand 17.11.2020
• 60 Bardia A, Tolaney SM, Loirat D. et al. ASCENT: A randomized phase III study of sacituzumab govitecan (SG) vs. treatment of physicianʼs choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Ann Oncol 2020; 31 (Suppl. 04) S1142-S1215 DOI: 10.1016/annonc/annonc325.