Update Mammakarzinom 2019 Teil 5 – diagnostische und therapeutische Herausforderungen neuer personalisierter Therapien bei Patientinnen mit fortgeschrittenem Mammakarzinom

Zusammenfassung

Beim fortgeschrittenen Mammakarzinom sind in den letzten Jahren deutliche Fortschritte erzielt worden, fast alle auf dem Gebiet der zielgerichteten Therapie. Pertuzumab und Trastuzumab-Emtansin (T-DM1) konnten beim HER2-positiven Mammakarzinom eingeführt werden. Nun sind weitere Anti-HER2-Therapien in der Entwicklung (z. B. Margetuximab, DS-8201a, Pyrotinib), die weitere Resistenzmechanismen im HER2-Signalweg überwinden können. Auf dem Gebiet des hormonrezeptorpositiven Mammakarzinoms wurden in der Vergangenheit ein mTOR-Inhibitor und CDK4/6-Inhibitoren eingeführt. Nun steht die Einführung des ersten PI3K-Inhibitors bevor, die eine genetische Testung des Tumors auf eine Mutation im Gen PIK3CA mit sich bringen wird. Beim tripel-negativen Mammakarzinom gibt es ebenfalls deutliche Fortschritte: Durch Kombination von Chemo- mit Immuntherapie konnte ein Vorteil für das Gesamtüberleben in einer Subgruppe (Immunzellen PD-L1-positiv) gezeigt werden. Die PARP-Inhibitor-Therapie für HER2-negative Patientinnen mit einer Keimbahnmutation in BRCA1 oder BRCA2 war ebenfalls in einer Subgruppe mit einem verbesserten Gesamtüberleben assoziiert. Diese vielversprechenden, neuen Studienergebnisse werden in dieser Übersichtsarbeit zusammengefasst.

Abstract

Significant advancements have been made in recent years in advanced breast cancer and nearly all of them have been in the field of targeted therapy. Pertuzumab and trastuzumabemtansine (T-DM1) have been able to be introduced in HER2-positive breast cancer. Now other anti-HER2 therapies are being developed (e. g. margetuximab, DS-8201a, pyrotinib) which can overcome other resistance mechanisms in the HER2 signalling pathway. In the field of hormone-receptorpositive breast cancer, an mTOR inhibitor and CDK4/6 inhibitors were introduced in the past. Now the introduction of the first PI3K inhibitor is forthcoming and this inhibitor will involve genetic testing of the tumour for a mutation in the PIK3CA gene. There are also significant advancements in triple-negative breast cancer: By combining chemotherapy and immunotherapy, an advantage for overall survival was able to be demonstrated in a subgroup (immune cells PD-L1-positive). The PARP inhibitor therapy for HER2-negative patients with a germ line mutation in BRCA1 or BRCA2 was also associated with an improved overall survival in a subgroup. These promising new study results are summarised in this review.

Schlüsselwörter

fortgeschrittenes Mammakarzinom - Metastasen - Therapien - Mutationstestungen - Immuntherapie

Key words

advanced breast cancer - metastases - therapies - mutation testing - immunotherapy

• Literatur

• 1 Lux MP, Fasching PA, Schrauder MG. et al. The PI3K Pathway: Background and Treatment Approaches. Breast Care (Basel) 2016; 11: 398-404
• 2 Jones RH, Carucci M, Casbard AC. et al. Capivasertib (AZD5363) plus fulvestrant versus placebo plus fulvestrant after relapse or progression on an aromatase inhibitor in metastatic ER-positive breast cancer (FAKTION): A randomized, double-blind, placebo-controlled, phase II trial. J Clin Oncol 2019; 37: Abstr. 1005
• 3 Im SA, Lu YS, Bardia A. et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med 2019; DOI: 10.1056/NEJMoa1903765.
• 4 Novartis. Novartis Kisqali significantly prolongs life in women with HR +/HER2-advanced breast cancer now in two distinct Phase III trials. 2019 Online: https://www.novartis.com/news/media-releases/novartis-kisqali-significantly-prolongs-life-women-hrher2-advancedbreast-cancer-now-two-distinct-phase-iii-trials ; Stand: 03.08.2019
• 5 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
• 6 Park YH, Kim TY, Kim GM. et al. A randomized phase II study of palbociclib plus exemestane with GNRH agonist versus capecitabine in premenopausal women with hormone receptor-positive metastatic breast cancer (KCSG-BR 15-10, NCT02592746). J Clin Oncol 2019; DOI: 10.1200/JCO.2019.37.15_suppl.1007.
• 7 Hartkopf AD, Huober J, Volz B. et al. Treatment landscape of advanced breast cancer patients with hormone receptor positive HER2 negative tumors – Data from the German PRAEGNANT breast cancer registry. Breast 2018; 37: 42-51
• 8 Wallwiener M, Nabieva N, Feisst M. et al. Influence of patient and tumor characteristics on therapy persistence with letrozole in postmenopausal women with advanced breast cancer: results of the prospective observational EvAluate-TM study. BMC Cancer 2019; 19: 611
• 9 Tolaney SM, Barroso-Sousa R, Keenan T. et al. Randomized phase II study of eribulin mesylate (E) with or without pembrolizumab (P) for hormone receptor-positive (HR+) metastatic breast cancer (MBC). J Clin Oncol 2019; DOI: 10.1200/JCO.2019.37.15_suppl.1004.
• 10 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
• 11 Swain SM, Baselga J, Kim SB. et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015; 372: 724-734
• 12 Baselga J, Cortes J, Kim SB. et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012; 366: 109-119
• 13 Swain SM, Miles D, Kim SB. et al. End-of-study analysis from the phase III, randomized, double-blind, placebo (Pla)-controlled CLEOPATRA study of first-line (1L) pertuzumab (P), trastuzumab (H), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC). J Clin Oncol 2019; DOI: 10.1200/JCO.2019.37.15_suppl.1020.
• 14 Lux MP, Nabieva N, Hartkopf AD. et al. Therapy Landscape in Patients with Metastatic HER2-Positive Breast Cancer: Data from the PRAEGNANT Real-World Breast Cancer Registry. Cancers (Basel) 2018; DOI: 10.3390/cancers11010010.
• 15 Saura C, Oliveira M, Feng YH. et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. J Clin Oncol 2019; DOI: 10.1200/JCO.2019.37.15_suppl.1002.
• 16 Powell CA, Camidge DR, Gemma A. et al. Characterization, monitoring, and management of interstitial lung disease in patients with metastatic breast cancer: Analysis of data available from multiple studies of DS-8201a, a HER2-targeted antibody drug conjugate with a topoisomerase I inhibitor payload. San Antonio Breast Cancer Symposium 2018; Abstr. P6-17-06
• 17 Modi S, Tsurutani J, Takahashi S. et al. Safety and efficacy results from a phase 1 study of DS-8201a in patients with HER2 expressing breast cancers. Cancer Res 2018; DOI: 10.1158/1538-7445.SABCS17-PD3-07.
• 18 Iwata H, Tamura K, Doi T. et al. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing solid tumors: Long-term results of a large phase 1 study with multiple expansion cohorts. J Clin Oncol 2018; 36 (Suppl.): Abstr. 2501
• 19 Jiang Z, Yan M, Hu X. et al. Pyrotinib combined with capecitabine in women with HER2+ metastatic breast cancer previously treated with trastuzumab and taxanes: A randomized phase III study. J Clin Oncol 2019; DOI: 10.1200/JCO.2019.37.15_suppl.1001.
• 20 Rugo HS, Im SA, Wright GLS. et al. SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol 2019; DOI: 10.1200/JCO.2019.37.15_suppl.1000.
• 21 Musolino A, Naldi N, Bortesi B. et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 2008; 26: 1789-1796
• 22 Gavin PG, Song N, Kim SR. et al. Association of Polymorphisms in FCGR2A and FCGR3A With Degree of Trastuzumab Benefit in the Adjuvant Treatment of ERBB2 / HER2-Positive Breast Cancer: Analysis of the NSABP B-31 Trial. JAMA Oncol 2017; 3: 335-341
• 23 Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013; 39: 1-10
• 24 Nobel Media. The Nobel Prize in Physiology or Medicine 2018. 2018 Online: https://www.nobelprize.org/prizes/medicine/2018/summary/ ; Stand: 11.10.2018
• 25 Emens LA, Kok M, Ojalvo LS. Targeting the programmed cell death-1 pathway in breast and ovarian cancer. Curr Opin Obstet Gynecol 2016; 28: 142-147
• 26 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
• 27 Schmid P, Adams S, Rugo HS. et al. IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). J Clin Oncol 2019; DOI: 10.1200/JCO.2019.37.15_suppl.1003.
• 28 Emens LA, Loi S, Rugo HS. et al. IMpassion130: Efficacy in immune biomarker subgroups from the global, randomized, double-blind, placebocontrolled, phase III study of atezolizumab + nab-paclitaxel in patients with treatment-nave, locally advanced or metastatic triple-negative breast cancer. San Antonio Breast Cancer Symposium 2018; Abstr. GS1-04
• 29 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
• 30 Litton J, Rugo HS, Ettl J. et al. EMBRACA: A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physicianʼs choice of therapy in patients with advanced breast cancer and a germline BRCA mutation [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5–9; San Antonio, TX Philadelphia (PA): AACR. Cancer Res 2018; 78: Abstr. GS6-07
• 31 Robson ME, Tung N, Conte P. et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician ʼs choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol 2019; 30: 558-566
• 32 Fasching P, Hu C, Hart S. et al. Abstract PD1-02: Cancer predisposition genes in metastatic breast cancer – Association with metastatic pattern, prognosis, patient and tumor characteristics. Cancer Res 2018; 78: PD1-02-PD01-02
• 33 Schneeweiss A, Denkert C, Fasching PA. et al. Diagnosis and Therapy of Triple-Negative Breast Cancer (TNBC) – Recommendations for Daily Routine Practice. Geburtsh Frauenheilk 2019; 79: 605-617
• 34 Cardoso F, Bese N, Distelhorst SR. et al. Supportive care during treatment for breast cancer: resource allocations in low- and middle-income countries. A Breast Health Global Initiative 2013 consensus statement. Breast 2013; 22: 593-605
• 35 Ganz PA, Yip CH, Gralow JR. et al. Supportive care after curative treatment for breast cancer (survivorship care): resource allocations in lowand middle-income countries. A Breast Health Global Initiative 2013 consensus statement. Breast 2013; 22: 606-615
• 36 Harrison JD, Young JM, Price MA. et al. What are the unmet supportive care needs of people with cancer? A systematic review. Support Care Cancer 2009; 17: 1117-1128
• 37 Nabieva N, Kellner S, Fehm T. et al. Influence of patient and tumor characteristics on early therapy persistence with letrozole in postmenopausal women with early breast cancer: results of the prospective Evaluate-TM study with 3941 patients. Ann Oncol 2018; 29: 186-192
• 38 Nabieva N, Fehm T, Haberle L. et al. Influence of side-effects on early therapy persistence with letrozole in post-menopausal patients with early breast cancer: Results of the prospective EvAluate-TM study. Eur J Cancer 2018; 96: 82-90
• 39 Chirgwin JH, Giobbie-Hurder A, Coates AS. et al. Treatment Adherence and Its Impact on Disease-Free Survival in the Breast International Group 1–98 Trial of Tamoxifen and Letrozole, Alone and in Sequence. J Clin Oncol 2016; 34: 2452-2459
• 40 Van Poznak CH, Unger JM, Darke AK. et al. Osteonecrosis of the jaw in patients with cancer receiving zoledronic acid for bone metastases: SWOG S0702, NCT00874211. J Clin Oncol 2019; 37 (Suppl.): Abstr. 11502
• 41 Himelstein AL, Foster JC, Khatcheressian JL. et al. Effect of Longer-Interval vs. Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. JAMA 2017; 317: 48-58
• 42 Thill M, Liedtke C, Muller V. et al. AGO Recommendations for the Diagnosis and Treatment of Patients with Advanced and Metastatic Breast Cancer: Update 2018. Breast Care (Basel) 2018; 13: 209-215
• 43 Liedtke C, Jackisch C, Thill M. et al. AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2018. Breast Care (Basel) 2018; 13: 196-208
• 44 Klein-Schmeink M. Warten Kassenpatienten in NRW länger auf einen Facharzttermin als privat Versicherte?. 2017 Online: https://www.kleinschmeink.de/data/user/PDF-Dokumente/2017/Wartezeiten_NRW_2017.pdf ; Stand: 24.07.2017
• 45 Kopetsch T. Kassenärztliche Bundesvereinigung. Wartezeiten in der ambulanten Versorgung. 2014. Online: http://www.kbv.de/media/sp/wartezeiten_studie_kopetsch.pdf ; Stand: 24.07.2019
• 46 Bundesministerium für Gesundheit. E-Health – Digitalisierung im Gesundheitswesen. 2018 Online: https://www.bundesgesundheitsministerium.de/e-health-initiative.html ; Stand: 24.07.2019
• 47 Adamson BJS, Cohen AB, Estevez M. et al. Affordable Care Act (ACA) Medicaid expansion impact on racial disparities in time to cancer treatment. J Clin Oncol 2019; DOI: 10.1200/JCO.2019.37.18_suppl.LBA1.
• 48 Fasching PA, Hartkopf AD, Gass P. et al. Efficacy of neoadjuvant pertuzumab in addition to chemotherapy and trastuzumab in routine clinical treatment of patients with primary breast cancer: a multicentric analysis. Breast Cancer Res Treat 2019; 173: 319-328
• 49 Hartkopf AD, Graf J, Simoes E. et al. Electronic-Based Patient-Reported Outcomes: Willingness, Needs, and Barriers in Adjuvant and Metastatic Breast Cancer Patients. JMIR Cancer 2017; 3: e11
• 50 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
• 51 Wallwiener M, Heindl F, Brucker SY. et al. Implementation and Feasibility of Electronic Patient-Reported Outcome (ePRO) Data Entry in the PRAEGNANT Real-Time Advanced and Metastatic Breast Cancer Registry. Geburtsh Frauenheilk 2017; 77: 870-878
• 52 Wallwiener M, Matthies L, Simoes E. et al. Reliability of an e-PRO Tool of EORTC QLQ-C30 for Measurement of Health-Related Quality of Life in Patients With Breast Cancer: Prospective Randomized Trial. J Med Internet Res 2017; 19: e322
• 53 Finn RS, Crown JP, Lang I. et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as firstline 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
• 54 Finn RS, Martin M, Rugo HS. et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 2016; 375: 1925-1936
• 55 Verma S, Bartlett CH, Schnell P. et al. Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3). Oncologist 2016; 21: 1165-1175
• 56 Cristofanilli M, Turner NC, Bondarenko I. et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016; 17: 425-439
• 57 Hortobagyi GN, Stemmer SM, Burris HA. et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med 2016; 375: 1738-1748
• 58 Hortobagyi GN, Stemmer SM, Burris HA. et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol 2018; 29: 1541-1547
• 59 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; DOI: 10.1016/S1470-2045(18)30292-4.
• 60 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
• 61 Goetz MP, Toi M, Campone M. et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol 2017; 35: 3638-3646
• 62 Martins F, Sofiya L, Sykiotis GP. et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019; DOI: 10.1038/s41571-019-0218-0.