Translationale Highlights Mamma- und Ovarialkarzinom 2019 – Immuntherapien, DNA-Reparatur, PI3K-Inhibition und CDK4/6-Therapien

Andreas D. Hartkopf; Volkmar Müller; Achim Wöckel; Michael P. Lux; Wolfgang Janni; Johannes Ettl; Erik Belleville; Florian Schütz; Peter A. Fasching; Hans-Christian Kolberg; Manfred Welslau; Friedrich Overkamp; Florin-Andrei Taran; Sara Y. Brucker; Markus Wallwiener; Hans Tesch; Tanja N. Fehm; Andreas Schneeweiss; Diana Lüftner

doi:10.1055/a-1098-2357

Senologie - Zeitschrift für Mammadiagnostik und -therapie, Inhaltsverzeichnis

Senologie - Zeitschrift für Mammadiagnostik und -therapie 2020; 17(01): 31-41
DOI: 10.1055/a-1098-2357

Wissenschaftliche Arbeit

Translationale Highlights Mamma- und Ovarialkarzinom 2019 – Immuntherapien, DNA-Reparatur, PI3K-Inhibition und CDK4/6-Therapien

Translational Highlights in Breast and Ovarian Cancer 2019 – Immunotherapy, DNA Repair, PI3K Inhibition and CDK4/6 Therapy

Andreas D. Hartkopf

¹Department of Obstetrics and Gynecology, University of Tübingen, Tübingen

,

Volkmar Müller

²Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg

,

Achim Wöckel

³Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg

,

Michael P. Lux

⁴Klinik für Gynäkologie und Geburtshilfe, Frauenklinik St. Louise, Paderborn, St. Josefs-Krankenhaus, Salzkotten

,

Wolfgang Janni

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

,

Johannes Ettl

⁶Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich, Munich

,

Erik Belleville

⁷ClinSol GmbH & Co KG, Würzburg

,

Florian Schütz

⁸Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg

,

Peter A. Fasching

⁹Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen

,

Hans-Christian Kolberg

¹⁰Department of Gynecology and Obstetrics, Marienhospital Bottrop, Bottrop

,

Manfred Welslau

¹¹Onkologie Aschaffenburg, Aschaffenburg

,

Friedrich Overkamp

¹²OncoConsult Hamburg GmbH, Hamburg

,

Florin-Andrei Taran

¹³Universitätsspital Zürich, Klinik für Gynäkologie, Zürich, Schweiz

,

Sara Y. Brucker

¹Department of Obstetrics and Gynecology, University of Tübingen, Tübingen

,

Markus Wallwiener

⁸Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg

,

Hans Tesch

¹⁴Oncology Practice at Bethanien Hospital Frankfurt, Frankfurt

,

Tanja N. Fehm

¹⁵Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf

,

Andreas Schneeweiss

¹⁶National Center for Tumor Diseases, Division Gynecologic Oncology, University Hospital Heidelberg, Heidelberg

,

Diana Lüftner

¹⁷Charité University Hospital, Campus Benjamin Franklin, Department of Hematology, Oncology and Tumour Immunology, Berlin

› Institutsangaben

Abstract

Zusammenfassung

Im Rahmen von derzeit laufenden Studien werden in naher Zukunft wichtige translationale Fragestellungen von klinischer Relevanz geklärt werden. Zum einen muss die Rolle der PD‑L1-Expression, nachdem sie für die Indikationsstellung für Atezolizumab in der 1. Therapielinie bei Patientinnen mit einem metastasierten triplenegativen Mammakarzinom (TNBC) von Relevanz ist, weiter geklärt werden. In einer neoadjuvanten Studie beim TNBC mit Pembrolizumab konnte kein Zusammenhang zwischen Wirksamkeit und PD‑L1-Expression gefunden werden. Sowohl mit als auch ohne Expression war die pCR höher, wenn Pembrolizumab zur Chemotherapie hinzugefügt wurde. Des Weiteren wird für die bei Keimbahnmutation von BRCA1/2 zugelassenen PARP-Inhibitoren nach weiteren Patientengruppen gesucht, in denen eine Wirksamkeit besteht. Dieses sind z. B. Patientinnen mit Mutationen in anderen Genen, die an der homologen Rekombination beteiligt sind, oder Patientinnen mit Tumoren, die bei globalen Tests zu homologen Rekombinationsdefizienzen (HRDTests) eine Auffälligkeit zeigen. Auch die Frage, ob und mit welchen Chemotherapie-Kombinationspartnern eine PARP-Inhibition zusammen gegeben werden kann, wird derzeit sowohl beim Mamma- als auch beim Ovarialkarzinom untersucht. Während sich die Daten zum verbesserten Gesamtüberleben bei den CDK4/6-Inhibitoren konsolidieren, wächst auch das Wissen um molekulare Veränderungen unter der Therapie und bei der Progression unter der Therapie. Sowohl die Anhäufung von PI3K-Mutationen als auch PTEN-Veränderungen könnten bei der Planung von Folgetherapien eine Rolle spielen. Diese Übersichtsarbeit fasst diese aktuellen Entwicklungen beim Mammakarzinom und teilweise auch beim Ovarialkarzinom zusammen.

Abstract

In the near future, important translational questions of clinical relevance will be adressed by studies currently in progress. On the one hand, the role of PD‑L1 expression must be further understood, after it was found to be relevant in the use of atezolizumab in first-line therapy of patients with metastatic triple-negative breast cancer (TNBC). No association between efficacy and PD‑L1 expression was found in a neoadjuvant study that included pembrolizumab in TNBC. The pathological complete response rate (pCR) was higher in both patient groups with and without PD‑L1 expression when pembrolizumab was added to chemotherapy. Another future question is the identification of further patient groups in which efficacy of PARP inhibitors is seen, which are licensed for the pBRCA1/2 germline mutation. These include, for example, patients with mutations in other genes, which are involved in homologous recombination, or patients with tumours that show an abnormality in global tests of homologous recombination deficiencies (HRD tests). The question of whether a PARP inhibitor can be given and with which chemotherapy combination partners is currently being investigated in both breast and ovarian cancer. While the data on improved overall survival are being consolidated for the CDK4/6 inhibitors, knowledge of molecular changes during the therapy and during progression on the therapy is growing. Both the accumulation of PI3K mutations and also PTEN changes might play a part in planning subsequent therapies. This review article summarises these recent developments in breast cancer and in part also in ovarian cancer.

Schlüsselwörter

fortgeschrittenes Mammakarzinom - Metastasen - Therapie - Mutationstestung - Immuntherapie - PARP - CDK4/6 - BRCA1/2 - PD‑L1

Key words

advanced breast cancer - metastases - therapy - mutation testing - immunotherapy - PARP - CDK4/6 - BRCA1/2 - PD‑L1

Volltext

Referenzen

Literatur
1 Ventana. VENTANA PD‑L1 (SP142) Assay Interpretation Guide for Triple-Negative Breast Carcinoma (TNBC). 2018 Online: (Stand: 06.10.2019) https://diagnostics.roche.com/content/dam/diagnostics/us/en/resource-center/VENTANA-PDL1-(SP142)-Assay-Interpretation-Guide.pdf
2 Agilent DAKO. PD‑L1 IHC22C3 pharmDxInterpretation Manual – Urothelial Carcinoma (FDA-approved for in vitro diagnostic use). 2018 Online (Stand: 06.10.2019): https://www.agilent.com/cs/library/usermanuals/public/29276_22C3_pharmdx_uc_interpretation_manual_us.pdf
3 Rugo HS, Loi S, Adams S. et al Performance of PD‑L1 immunohistochemistry assays in unresectable locally advanced or metastatic triple-negative breast cancer: post hoc analysis of IMpassion130. Ann Oncol 2019; 30 (Suppl. 05) v851-v934 . doi:10.1093/annonc/mdz1394
4 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
5 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; pii: mdz158
6 Schmid P, Cortes J, Dent R. et al KEYNOTE-522: Phase 3 Study of Pembrolizumab + Chemotherapy versus Placebo + Chemotherapy as Neoadjuvant Treatment, Followed by Pembrolizumab versus Placebo as Adjuvant Treatment for Early Triple-Negative Breast Cancer (TNBC). Ann Oncol 2019; 30 (Suppl. 05) v851-v934 . doi:10.1093/annonc/mdz1394
7 Baselga J, Campone M, Piccart M. et al Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012; 366: 520-529
8 Piccart M, Hortobagyi GN, Campone M. et al Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†. Ann Oncol 2014; 25: 2357-2362
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 Sledge jr GW, 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;
11 Slamon DJ, Neven P, Chia S. et al Overall Survival Results from the Phase 3 MONALEESA‑3 Study of Fulvestrant ± Ribociclib in Postmenopausal Patients With HR+/HER2− Advanced Breast Cancer. Ann Oncol 2019; 30 (Suppl. 05) v851-v934 . doi:10.1093/annonc/mdz1394
12 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
13 Turner NC, Slamon DJ, Ro J. et al Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med 2018; 379: 1926-1936
14 OʼLeary B, Cutts RJ, Liu Y. et al The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA‑3 Trial. Cancer Discov 2018; 8: 1390-1403
15 Andre F, Ciruelos E, Rubovszky G. et al Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med 2019; 380: 1929-1940
16 Costa C, Wang Y, Ly A. et al PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer. Cancer Discov 2019; pii: CD-18-0830
17 Juric D, Castel P, Griffith M. et al Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature 2015; 518: 240-244
18 Hosford SR, Dillon LM, Bouley SJ. et al Combined Inhibition of Both p110α and p110β Isoforms of Phosphatidylinositol 3-Kinase Is Required for Sustained Therapeutic Effect in PTEN-Deficient, ER+ Breast Cancer. Clin Cancer Res 2017; 23: 2795-2805
19 Robson M, Im SA, Senkus E. et al Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017; 377: 523-533
20 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
21 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
22 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
23 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
24 Wunderle M, Gass P, Haberle 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
25 Byrski T, Gronwald J, Huzarski T. et al Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 2010; 28: 375-379
26 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
27 Fasching P, Jackisch C, Rhiem K. et al GeparOLA: A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel/carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients (pts) with HER2-negative early breast cancer (BC) and homologous recombination deficiency (HRD). J Clin Oncol 2019; 37 (Suppl.): Abstr. 506
28 Diéras V, Han HS, Kaufman B. et al Phase 3 study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic gBRCA-associated breast cancer: BROCADE3. Ann Oncol 2019; 30 (Suppl. 05) v851-v934 . doi:10.1093/annonc/mdz1394
29 Ray-Coquard I, Pautier P, Pignata S. et al Phase III PAOLA-1/ENGOT-ov25: maintenance olaparib with bevacizumab in patients with newly diagnosed, advanced ovarian cancer treated with platinum-based chemotherapy and bevacizumab as standard of care. Ann Oncol 2017; 30 (Suppl. 05) v851-v934 . doi:10.1093/annonc/mdz1394
30 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 . doi:10.1200/JCO.2017.77.2285
31 González-Martín A, Pothuri B, Vergote I. et al Niraparib Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer (PRIMA/ENGOT-OV26/GOG-3012). Ann Oncol 2019; 30 (Suppl. 05) v851-v934 . doi:10.1093/annonc/mdz1394
32 Coleman RL, Fleming GF, Brady MF. et al VELIA/GOG-3005: Integration of veliparib with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin. Ann Oncol 2019; 30 (Suppl. 05) v851-v934 . doi:10.1093/annonc/mdz1394
33 Lux MP, Janni W, Hartkopf AD. et al Update Breast Cancer 2017 – Implementation of Novel Therapies. Geburtsh Frauenheilk 2017; 77: 1281-1290
34 Pivot X, Bondarenko IM, Nowecki Z. et al One-year safety, immunogenicity, and survival results from a phase III study comparing SB3 (a proposed trastuzumab biosimilar) and originator trastuzumab in HER2-positive early breast cancer treated with neoadjuvant-adjuvant treatment. Ann Oncol 2017; 28 (Suppl. 05) v43-v67, 153PD
35 Pivot XB, Bondarenko I, Dvorkin M. et al A randomized, double-blind, phase III study comparing SB3 (trastuzumab biosimilar) with originator trastuzumab in patients treated by neoadjuvant therapy for HER2-positive early breast cancer. J Clin Oncol 2017; 35 (Suppl.): Abstr. 509
36 Pivot X, Pegram M, Cortes J. et al Three-year follow-up from a phase 3 study of SB3 (a trastuzumab biosimilar) versus reference trastuzumab in the neoadjuvant setting for human epidermal growth factor receptor 2-positive breast cancer. Eur J Cancer 2019; 120: 1-9
37 Kim S, Song J, Park S. et al Drifts in ADCC-related quality attributes of Herceptin(R): Impact on development of a trastuzumab biosimilar. MAbs 2017; 9: 704-714
38 Tresp V, Overhage JM, Bundschus M. et al Going Digital: A Survey on Digitalization and Large-Scale Data Analytics in Healthcare. P IEEE 2016; 104: 2180-2206
39 Luchini C, Bibeau F, Ligtenberg MJL. et al ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD‑1/PD‑L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol 2019; pii: mdz116
40 Kather JN, Pearson AT, Halama N. et al Deep learning can predict microsatellite instability directly from histology in gastrointestinal cancer. Nat Med 2019; 25: 1054-1056
41 Rodziewicz TL, Hipskind JE. Medical Error Prevention. StatPearls. Treasure Island (FL): StatPearls Publishing; 2019
42 Fasching PA, Brucker SY, Fehm TN. et al Biomarkers in Patients with Metastatic Breast Cancer and the PRAEGNANT Study Network. Geburtsh Frauenheilk 2015; 75: 41-50
43 Yang Y, Tresp V, Wunderle M. et al Explaining Therapy Predictions with Layer-wise Relevance Propagation in Neural Networks. IEEE International Conference on Healthcare Informatics (ICHI); 2018
44 Yang Y, Fasching PA, Wallwiener M. et al Predictive Clinical Decision Support System with RNN Encoding and Tensor Decoding. 30^th Conference on Neural Information Processing Systems (NIPS2016). Barcelona, Spain: 2016
45 Cortes J, Lipatov O, Im SA. et al KEYNOTE‑119: Phase 3 Study of Pembrolizumab versus Single-Agent Chemotherapy for Metastatic Triple-Negative Breast Cancer (mTNBC). Ann Oncol 2019; 30 (Suppl. 05) v851-v934 . doi:10.1093/annonc/mdz1394
46 Turner NC, Ro J, Andre F. et al Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med 2015; 373: 209-219
47 Tripathy D, Im SA, Colleoni M. et al Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol 2018; 19: 904-915 . doi:10.1016/S1470-2045(18)30292-4
48 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
49 Sledge jr GW, Toi M, Neven P. 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