Update Mammakarzinom 2021 Teil 4 – Prävention und frühe Krankheitsstadien

Christoph Thomssen; Tanja N. Fehm; Elmar Stickeler; Peter A. Fasching; Wolfgang Janni; Cornelia Kolberg-Liedtke; Hans-Christian Kolberg; Diana Lüftner; Volkmar Müller; Florian Schütz; Erik Belleville; Simon Bader; Michael Untch; Manfred Welslau; Marc Thill; Andreas D. Hartkopf; Hans Tesch; Nina Ditsch; Michael P. Lux; Achim Wöckel; Bahriye Aktas; Andreas Schneeweiss; Rachel Würstlein

doi:10.1055/a-1816-1625

Senologie - Zeitschrift für Mammadiagnostik und -therapie, Table of Contents

Senologie - Zeitschrift für Mammadiagnostik und -therapie 2022; 19(02): 175-184
DOI: 10.1055/a-1816-1625

Übersicht

Update Mammakarzinom 2021 Teil 4 – Prävention und frühe Krankheitsstadien

Update Breast Cancer 2021 Part 4 – Prevention and Early Stages

Christoph Thomssen

¹Department of Gynecology, Martin-Luther-University Halle-Wittenberg, Halle (Saale)

,

Tanja N. Fehm

²Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf

,

Elmar Stickeler

³Department of Gynecology and Obstetrics, RWTH University Hospital Aachen, Aachen

,

Peter A. Fasching

⁴Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen

,

Wolfgang Janni

⁵Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm

,

Cornelia Kolberg-Liedtke

⁶Department of Gynecology and Obstetrics, University Hospital Essen, Essen

⁷palleos healthcare, Wiesbaden

⁸Phaon Scientific, Wiesbaden

,

Hans-Christian Kolberg

⁹Department of Gynecology and Obstetrics, Marienhospital Bottrop, Bottrop

,

Diana Lüftner

¹⁰Charité University Hospital, Department of Hematology, Oncology and Tumour Immunology, University Medicine Berlin, Berlin

,

Volkmar Müller

¹¹Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg

,

Florian Schütz

¹²Gynäkologie und Geburtshilfe, Diakonissen-Stiftungs-Krankenhaus Speyer, Speyer

,

Erik Belleville

¹³ClinSol GmbH & Co. KG, Würzburg

,

Simon Bader

⁴Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen

,

Michael Untch

¹⁴Clinic for Gynecology and Obstetrics, Breast Cancer Center, Genecologic Oncology Center, Helios Klinikum Berlin Buch, Berlin

,

Manfred Welslau

¹⁵Onkologie Aschaffenburg, Aschaffenburg

,

Marc Thill

¹⁶Agaplesion Markus Krankenhaus, Department of Gynecology and Gynecological Oncology, Frankfurt am Main

,

Andreas D. Hartkopf

¹⁷Department of Obstetrics and Gynecology, University of Tübingen, Tübingen

,

Hans Tesch

¹⁸Oncology Practice at Bethanien Hospital, Frankfurt am Main

,

Nina Ditsch

¹⁹Department of Gynecology and Obstetrics, University Hospital Augsburg, Augsburg

,

Michael P. Lux

²⁰Klinik für Gynäkologie und Geburtshilfe, Frauenklinik St. Louise, Paderborn, St. Josefs-Krankenhaus, Salzkotten, St. Vincenz Krankenhaus GmbH, Paderborn

,

Achim Wöckel

²¹Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg

,

Bahriye Aktas

²²Klinik und Poliklinik für Gynäkologie, Universitätsklinikum Leipzig, Leipzig

,

Andreas Schneeweiss

²³National Center for Tumor Diseases (NCT), Heidelberg University Hospital and German Cancer Research Center, Heidelberg

,

Rachel Würstlein

²⁴Breast Center, Department of Gynecology and Obstetrics and CCC Munich LMU, LMU University Hospital, Munich

› Author Affiliations

Abstract

Zusammenfassung

Im vergangenen Jahr wurden für viele Patientinnen mit Mammakarzinom in frühem Krankheitsstadium neue und effektive Optionen für eine weitere Verbesserung der Behandlungsergebnisse gezeigt. Für Patientinnen mit hormonrezeptorpositiver Erkrankung zeigte sich ein signifikanter Zusatzeffekt durch den Einsatz des CDK4/6-Inhibitors Abemaciclib zusätzlich zur endokrinen adjuvanten Therapie. Bei triple-negativer Erkrankung wurden Daten für 2 Therapieprinzipien gezeigt. Patientinnen mit fortgeschrittener Erkrankung (Stadium 2 und 3) profitieren von dem neoadjuvanten Einsatz des Immuncheckpoint-Inhibitors Pembrolizumab unabhängig von der PD‑L1-Expression in Kombination mit einer Standardchemotherapie. Bei BRCA1- oder BRCA2-Mutation wurde ein eindrucksvoller Benefit durch den Einsatz des PARP-Inhibitors Olaparib gezeigt, wenn die neoadjuvante Therapie nicht zur gewünschten Remission geführt hat. Weitere Daten betreffen translationale Fragestellungen beim HER2-positiven Mammakarzinom sowie neoadjuvante Therapieansätze mit dem oralen SERD Giredestrant und dem PARP-Inhibitor Talazoparib. In dieser Übersichtsarbeit werden die Ergebnisse der wichtigsten Studienergebnisse dieses Jahres vorgestellt und bewertet.

Abstract

This past year has seen new and effective options for further improving treatment outcome in many patients with earlystage breast cancer. Patients with hormone receptor-positive disease benefited significantly from the addition of the CDK4/6 inhibitor abemaciclib to endocrine adjuvant therapy. In triple-negative disease, data were presented for two treatment regimens. Patients with advanced disease (stage 2 and 3) benefit from neoadjuvant treatment with the immune checkpoint inhibitor pembrolizumab in combination with standard chemotherapy, regardless of PD‑L1 expression. When neoadjuvant therapy has failed to achieve the desired remission in BRCA1 and BRCA2 mutations, the administration of the PARP inhibitor olaparib has demonstrated an impressive response. Other data address translational issues in HER2-positive breast cancer and neoadjuvant therapy approaches with the oral SERD giredestrant and the PARP inhibitor talazoparib. This review presents and analyses the findings of this yearʼ s most important study outcomes.

Schlüsselwörter

BRCA (breast cancer associated gene) - Brust - Mamma - Genetik - Her‑2/neu (humaner epidermaler Wachstumsfaktor‑Rezeptor) - Hormonrezeptor - Mammakarzinom

Key words

BRCA (breast cancer associated gene) - breast - genetics - Her‑2/neu (human epidermal growth factor receptor) - hormonal receptor - breast cancer

Full Text

References

Literatur
1 Foulkes WD. The ten genes for breast (and ovarian) cancer susceptibility. Nat Rev Clin Oncol 2021; 18: 259-260
2 Hu C, Hart SN, Gnanaolivu R. et al. A Population-Based Study of Genes Previously Implicated in Breast Cancer. N Engl J Med 2021; 384: 440-451
3 Dorling L, Carvalho S, Allen J. Breast Cancer Association Consortium. et al. Breast Cancer Risk Genes – Association Analysis in More than 113000 Women. N Engl J Med 2021; 384: 428-439
4 Ramus SJ, Song H, Dicks E. et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst 2015; 107: djv214
5 Easton DF, Lesueur F, Decker B. et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J Med Genet 2016; 53: 298-309
6 Hahnen E, Lederer B, Hauke J. et al. Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial. JAMA Oncol 2017; 3: 1378-1385
7 Wunderle M, Gass P, Häberle L. et al. BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients. Breast Cancer Res Treat 2018; 171: 85-94
8 Fasching PA, Loibl S, Hu C. et al. BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the Gepar-Quinto Study. J Clin Oncol 2018; 36: 2281-2287
9 Copson ER, Maishman TC, Tapper WJ. et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol 2018; 19: 169-180
10 Schmidt MK, Hogervorst F, van Hien R. et al. Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers. J Clin Oncol 2016; 34: 2750-2760
11 Weischer M, Nordestgaard BG, Pharoah P. et al. CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer. J Clin Oncol 2012; 30: 4308-4316
12 Cybulski C, Kluźniak W, Huzarski T. et al. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol 2015; 16: 638-644
13 Tung NM, Robson ME, Ventz S. et al. TBCRC048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes. J Clin Oncol 2020; 38: 4274-4282
14 Fasching PA, Yadav S, Hu C. et al. Mutations in BRCA1/2 and Other Panel Genes in Patients With Metastatic Breast Cancer-Association With Patient and Disease Characteristics and Effect on Prognosis. J Clin Oncol 2021; 39: 1619-1630
15 Schmid P, Cortes J, Dent R. et al. KEYNOTE‑522: Phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early-stage TNBC. Ann Oncol 2021; 32: 1198-1200
16 Tutt ANJ, Garber JE, Kaufman B. et al. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. N Engl J Med 2021; 384: 2394-2405
17 Schmid P, Cortes J, Pusztai L. et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med 2020; 382: 810-821
18 Merck Sharp & Dohme Corp., FDA. Pembrolizumab: Combined FDA and Applicant ODAC Briefing Document for the Oncologic Drugs Advisory Committee (ODAC) Meeting on February 9, 2021. Online (Stand: 20.02.2021): https://www.fda.gov/media/145654/download
19 Loibl S, Schneeweiss A, Huober JB. et al. Durvalumab improves long-term outcome in TNBC: results from the phase II randomized GeparNUEVO study investigating neodjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC). J Clin Oncol 2021; 39 (15) 506
20 Litton JK, Scoggins M, Ramirez DL. et al. A feasibility study of neoadjuvant talazoparib for operable breast cancer patients with a germline BRCA mutation demonstrates marked activity. NPJ Breast Cancer 2017; 3: 49
21 Litton JK, Beck JT, Jones JM. et al. Neoadjuvant talazoparib in patients with germline BRCA1/2 (gBRCA1/2) mutation-positive, early HER2-negative breast cancer (BC): Results of a phase 2 study. J Clin Oncol 2021; 39 (15) 505
22 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
23 von Minckwitz G, Schneeweiss A, Loibl S. et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 2014; 15: 747-756
24 Sikov WM, Berry DA, Perou CM. et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 2015; 33: 13-21
25 Loibl S, Weber KE, Timms KM. et al. Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response – final results from GeparSixto. Ann Oncol 2018; 29: 2341-2347
26 Sikov WM, Polley MY, Twohy E. et al. CALGB (Alliance) 40603: Long-term outcomes (LTOs) after neoadjuvant chemotherapy (NACT) ± carboplatin (Cb) and bevacizumab (Bev) in triple-negative breast cancer (TNBC). J Clin Oncol 2019; 37 (15) 591
27 Loibl S, Sikov W, Huober J. et al. Event-free survival (EFS), overall survival (OS), and safety of adding veliparib (V) plus carboplatin (Cb) or carboplatin alone to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) after ≥ 4 years of follow-up: BrighTNess, a randomized phase III trial. Ann Oncol 2021; 32 (Suppl. 05) S407-S446
28 Slamon D, Eiermann W, Robert N. et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365: 1273-1283
29 Perez EA, Romond EH, Suman VJ. et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B‑31. J Clin Oncol 2011; 29: 3366-3373
30 Piccart-Gebhart MJ, Procter M, Leyland-Jones B. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353: 1659-1672
31 Goldhirsch A, Gelber RD, Piccart-Gebhart MJ. et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013; 382: 1021-1028
32 Conte P, Frassoldati A, Bisagni G. et al. Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study‡. Ann Oncol 2018; 29: 2328-2333
33 Joensuu H, Fraser J, Wildiers H. et al. Effect of Adjuvant Trastuzumab for a Duration of 9 Weeks vs. 1 Year With Concomitant Chemotherapy for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: The SOLD Randomized Clinical Trial. JAMA Oncol 2018; 4: 1199-1206
34 Mavroudis D, Saloustros E, Malamos N. et al. Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol 2015; 26: 1333-1340
35 Mavroudis D, Saloustros E, Malamos N. et al. Corrigendum to Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG): Annals of Oncology, Volume 26, Issue 7, July 2015, Pages 1333-1340. Ann Oncol 2020; 31: 444-445
36 Pivot X, Romieu G, Debled M. et al. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial. Lancet 2019; 393: 2591-2598
37 Earl HM, Hiller L, Vallier AL. et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol 2018; 36 (15) 506
38 Earl HM, Hiller L, Dunn JA. et al. LBA11 – Individual patient data metaanalysis of 5 non-inferiority RCTs of reduced duration single agent adjuvant trastuzumab in the treatment of HER2 positive early breast cancer. Ann Oncol 2021; 32 (Suppl. 05) S1283
39 Harbeck N, Gluz O, Christgen M. et al. De-escalated neoadjuvant pertuzumab+ trastuzumab with or without paclitaxel weekly in HR-/HER2+ early breast cancer: ADAPT‑HR-/HER2+ biomarker and survival results. J Clin Oncol 2021; 39 (15) 503
40 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
41 Harbeck N, Rastogi P, Martin M. et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol 2021; 32: 1571-1581
42 Yerushalmi R, Woods R, Ravdin PM. et al. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol 2010; 11: 174-183
43 Fasching PA, Gass P, Häberle L. et al. Prognostic effect of Ki-67 in common clinical subgroups of patients with HER2-negative, hormone receptor-positive early breast cancer. Breast Cancer Res Treat 2019; 175: 617-625
44 Fasching PA, Heusinger K, Haeberle L. et al. Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment. BMC Cancer 2011; 11: 486
45 Nielsen TO, Leung SCY, Rimm DL. et al. Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group. J Natl Cancer Inst 2021; 113: 808-819
46 Bardia A, Kaklamani V, Wilks S. et al. Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer. J Clin Oncol 2021; 39: 1360-1370
47 Lim E, Beeram M, Prawira A. et al. EMBER: A phase 1a/b trial of LY3484356, a novel, oral selective estrogen-receptor degrader (SERD), in advanced ER plus breast cancer and endometroid endometrial cancer. Cancer Res 2021;
48 Linden HM, Campone M, Bardia A. et al. Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA‑1. Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium, San Antonio, TX, USA. December 8-11 2020;
49 Baird R, Oliveira M, Ciruelos Gil EM. et al. Abstract PS11-05: Updated data from SERENA‑1: A Phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer. Cancer Res 2021; 81 (04) PS11-05
50 Jhaveri KL, Lim E, Hamilton EP. et al. A first-in-human phase 1a/b trial of LY3484356, an oral selective estrogen receptor (ER) degrader (SERD) in ER+ advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): Results from the EMBER study. J Clin Oncol 2021; 39 (15) 1050
51 Hamilton EP, Wang JS, Pluard T. et al. Abstract PD8-06: Phase I/II trial of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium, San Antonio, TX, USA. December 8-11 2020;
52 ClinicalTrials.gov. NCT04961996. A Study Evaluating the Efficacy and Safety of Adjuvant Giredestrant Compared With Physicianʼs Choice of Adjuvant Endocrine Monotherapy in Participants With Estrogen Receptor-Positive, HER2-Negative Early Breast Cancer (lidERA Breast Cancer). Online (Stand: 17.10.2021): https://clinicaltrials.gov/ct2/show/NCT04961996
53 Sanofi Aventis Groupe. Sanofi partnering with leading academic cooperative groups to study amcenestrant in the adjuvant setting for patients with estrogen receptor positive breast cancer. Online (Stand: 16.10.2021): https://www.sanofi.com/en/media-room/press-releases/2021/2021-06-04-07-00-00-2241809
54 Snyder LB, Flanagan JJ, Qian Y. et al. Abstract 44: The discovery of ARV‑471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer. Cancer Res 2021; 81 (13) 44
55 Arvinas. Arvinas and Pfizer Announce Global Collaboration to Develop and Commercialize PROTAC^® Protein Degrader ARV‑471. Online (Stand: 16.10.2021): https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizer-announce-global-collaboration-develop-and