Personalisierte Medizin im Urothelkarzinom der Harnblase

Zusammenfassung

Während sich die zur Verfügung stehenden Therapieoptionen und die Prognose von Patienten mit Urothelkarzinom der Harnblase insbesondere im metastasierten Stadium über Jahrzehnte hinweg bisher kaum verbessert haben, hat der zunehmende Einsatz von Hochdurchsatzanalysen und das Wissen um den Einfluss des Immunsystems auf Tumorentstehung und -progression unser Verständnis von Tumorbiologie in den letzten Jahren grundlegend verändert.

Die Kenntnis von genetischen Mutationen und molekularen Subtypen bieten zunehmend die Möglichkeit maßgeschneiderter Therapieansätze für Patienten, die an einem Harnblasenkarzinom leiden. Veränderungen in DNA-Reparatur-Signalwegen stellen beispielsweise mögliche Prädiktoren für ein Chemotherapie-Ansprechen dar, zielgerichtete Therapien mittels FGFR- oder PARP-Inhibitoren befinden sich aktuell in klinischer Erprobung und könnten zukünftig die Therapie ergänzen. Inwieweit molekulare Subtypen Einzug in die klinisch-pathologische Routine halten werden, hängt von der prospektiven Evaluation ihres prognostischen und prädiktiven Stellenwerts ab. Insbesondere der Einzug von Immuncheckpoint-Inhibitoren ist die bedeutendste Erweiterung der zur Verfügung stehenden Therapieoptionen. Jedoch verdeutlicht sich angesichts des geringen Therapieansprechens von nur 25 % einmal mehr die dringende Notwendigkeit prädiktiver Biomarker.

Vor allem die große inter- und intratumorale Heterogenität stellt eine große Herausforderung für die klinische Implementierung personalisierter Therapieansätze im Harnblasenkarzinom dar. Insgesamt wurden in den letzten Jahren wichtige Schritte in Richtung personalisierter Medizin beim Urothelkarzinom der Harnblase unternommen, deren prospektive Evaluation größtenteils jedoch noch aussteht.

Abstract

Available treatment options and outcomes for patients suffering from urothelial bladder cancer, especially in the metastatic stage, have hardly improved over decades. However, the increasing use of high-throughput analyses and the concept of immune surveillance against tumours have recently changed our understanding of tumour biology in terms of tumour development and progression.

Our knowledge of genetic mutations and molecular subtypes provides the possibility of tailor-made therapeutic approaches for patients suffering from bladder cancer. For example, changes in DNA repair signalling pathways are possible predictors of chemotherapy response, and targeted therapies using FGFR or PARP inhibitors are currently being tested in clinical trials. The extent to which molecular subtypes will find their way into clinical practice depends on the prospective evaluation of their prognostic and predictive value. The introduction of immune checkpoint inhibitors is probably the most significant expansion of available treatment options in bladder cancer. Despite their promising results, however, a lot of questions remain to be answered, as only 25 % of patients respond. Again, this highlights the need for predictive biomarkers.

The large inter- and intratumoural heterogeneity represents a particular challenge for the clinical implementation of personalised treatment options in bladder cancer.

All in all, some important steps towards personalised medicine in urothelial bladder cancer have been taken in the past few years, but, for the most part, their prospective evaluation is still pending.

Schlüsselwörter

Urothelkarzinom - Immuncheckpoint-Inhibitor - zielgerichtete Therapie - Präzisionsmedizin

Keywords

urothelial cancer - immune checkpoint inhibitor - targeted therapy - precision medicine

• Literatur

• 1 Schwartzberg L, Kim ES, Liu D. et al. Precision Oncology: Who, How, What, When, and When Not?. Am Soc Clin Oncol Educ Book 2017; 37: 160-169
• 2 Sylvester RJ, van der Meijden AP, Oosterlinck W. et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. European urology 2006; 49: 466-465 ; discussion 75-77
• 3 Advanced Bladder Cancer Meta-analysis C. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. European urology 2005; 48: 202-205
• 4 Leow JJ, Martin-Doyle W, Fay AP. et al. A systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma. European urology 2014; 66: 529-541
• 5 Gupta S, Mahipal A. Role of systemic chemotherapy in urothelial urinary bladder cancer. Cancer Control 2013; 20: 200-210
• 6 De Santis M, Bellmunt J, Mead G. et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2012; 30: 191-199
• 7 Bellmunt J, de Wit R, Vaughn DJ. et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376: 1015-1026
• 8 Sharma P, Retz M, Siefker-Radtke A. et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017; 18: 312-322
• 9 Rosenberg JE, Hoffman-Censits J, Powles T. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387: 1909-1920
• 10 Zaid HB, Patel SG, Stimson CJ. et al. Trends in the utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer: results from the National Cancer Database. Urology 2014; 83: 75-80
• 11 Alfred Witjes J, Lebret T, Comperat EM. et al. Updated 2016 EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer. Eur Urol 2017; 71: 462-475
• 12 Van Allen EM, Mouw KW, Kim P. et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov 2014; 4: 1140-1153
• 13 Plimack ER, Dunbrack RL, Brennan TA. et al. Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer. Eur Urol 2015; 68: 959-967
• 14 Cancer Genome Atlas Research N. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014; 507: 315-322
• 15 Robertson AG, Kim J, Al-Ahmadie H. et al. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell 2017; 171: 540-556 e25
• 16 Siefker-Radtke AO, Necchi A, Park SH. et al. First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt). Journal of Clinical Oncology 2018; 36: 4503
• 17 Sweis RF, Heiss B, Segal J. et al. Clinical Activity of Olaparib in Urothelial Bladder Cancer With DNA Damage Response Gene Mutations. JCO Precision Oncology 2018; 2: 1-7
• 18 Patschan O, Sjodahl G, Chebil G. et al. A Molecular Pathologic Framework for Risk Stratification of Stage T1 Urothelial Carcinoma. Eur Urol 2015; 68: 824-832 ; discussion 35-36
• 19 Sjodahl G, Lauss M, Lovgren K. et al. A molecular taxonomy for urothelial carcinoma. Clin Cancer Res 2012; 18: 3377-3386
• 20 Hedegaard J, Lamy P, Nordentoft I. et al. Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma. Cancer Cell 2016; 30: 27-42
• 21 Damrauer JS, Hoadley KA, Chism DD. et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA 2014; 111: 3110-3115
• 22 Choi W, Porten S, Kim S. et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 2014; 25: 152-165
• 23 Choi W, Czerniak B, Ochoa A. et al. Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nature reviews Urology 2014; 11: 400-410
• 24 Seiler R, Ashab HAD, Erho N. et al. Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy. European urology 2017; 72: 544-554
• 25 Sharma P, Callahan MK, Bono P. et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. The Lancet Oncology 2016; 17: 1590-1598
• 26 Powles T, Eder JP, Fine GD. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014; 515: 558-562
• 27 Suzman DL, Agrawal S, Ning YM. et al. FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy. The oncologist 2018; DOI: 10.1634/theoncologist.2018-0084.
• 28 Eckstein M, Erben P, Kriegmair MC. et al. Performance of the Food and Drug Administration/EMA-approved programmed cell death ligand-1 assays in urothelial carcinoma with emphasis on therapy stratification for first-line use of atezolizumab and pembrolizumab. European journal of cancer 2019; 106: 234-243
• 29 Powles T, Duran I, van der Heijden MS. et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2018; 391: 748-757
• 30 Marcus L, Lemery SJ, Keegan P. et al. FDA Approval Summary: Pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clinical cancer research: an official journal of the American Association for Cancer Research 2019; DOI: 10.1158/1078-0432.CCR-18-4070.
• 31 Sternberg CN, Loriot Y, James N. et al. Primary Results from SAUL, a Multinational Single-arm Safety Study of Atezolizumab Therapy for Locally Advanced or Metastatic Urothelial or Nonurothelial Carcinoma of the Urinary Tract. European urology 2019; DOI: 10.1016/j.eururo.2019.03.015.
• 32 Faltas BM, Prandi D, Tagawa ST. et al. Clonal evolution of chemotherapy-resistant urothelial carcinoma. Nat Genet 2016; 48: 1490-1409