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Molecularly-driven precision medicine for advanced bladder cancer

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Abstract

Urothelial carcinoma of the bladder is a heterogeneous disease with many challenges for clinicians and patients alike. However, for the most part of the last three decades, treatment and outcomes for patients with this disease have not changed a lot. With recent advances in immunooncology leading to the approval of multiple agents for the metastatic setting, the treatment landscape started to change. With the emergent data from landmark multi-institutional sequencing projects as well as molecular data from recent trials, our understanding of the underlying disease biology, response patterns as well as definition of molecular subtypes has evolved tremendously. This review aims to summarize the currently available concepts of mutational profiles and molecular subtypes as well as their implications for management of urothelial carcinoma.

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References

  1. Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F (2016) Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol 71(1):96–108. https://doi.org/10.1016/j.eururo.2016.06.010

    Article  PubMed  Google Scholar 

  2. Kamat AM, Hegarty PK, Gee JR, Clark PE, Svatek RS, Hegarty N et al (2013) ICUD–EAU international consultation on bladder cancer 2012: screening, diagnosis, and molecular markers. Eur Urol 63:4–15

    Article  PubMed  Google Scholar 

  3. Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM et al (2017) EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol 71:447–461

    Article  PubMed  Google Scholar 

  4. Abida W, Bajorin DF, Rosenberg JE (2015) First-line treatment and prognostic factors of metastatic bladder cancer for platinum-eligible patients. Hematol Oncol Clin North Am 29:319–328 (ix-x)

    Article  PubMed  Google Scholar 

  5. Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D et al (1997) Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 15:2564–2569

    Article  CAS  PubMed  Google Scholar 

  6. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ et al (2000) Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18:3068–3077

    Article  PubMed  Google Scholar 

  7. Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL et al (2003) Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859–866

    Article  CAS  PubMed  Google Scholar 

  8. Alfred Witjes J, Lebret T, Comperat EM, Cowan NC, De Santis M, Bruins HM et al (2017) Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol 71:462–475

    Article  CAS  PubMed  Google Scholar 

  9. Dash A, JAt Pettus, Herr HW, Bochner BH, Dalbagni G, Donat SM et al (2008) A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer 113:2471–2477

    Article  PubMed  Google Scholar 

  10. Advanced Bladder Cancer Meta-analysis C (2005) Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 48:189–199 (discussion 99-201)

    Article  Google Scholar 

  11. Leow JJ, Martin-Doyle W, Rajagopal PS, Patel CG, Anderson EM, Rothman AT et al (2014) Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol 66:42–54

    Article  CAS  PubMed  Google Scholar 

  12. Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP et al (2014) Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol 32:3801–3809

    Article  PubMed  PubMed Central  Google Scholar 

  13. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R (2016) 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 387(10031):1909–1920. https://doi.org/10.1016/S0140-6736(16)00561-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L et al (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376:1015–1026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J et al (2017) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18:312–322

    Article  CAS  PubMed  Google Scholar 

  16. Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, Safran H, Stinchcombe TE, Srdanov M, Gelb AB, Schlichting M, Chin K, Gulley JL (2017) Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase Ib study. J Clin Oncol. 35(19):2117–2124. https://doi.org/10.1200/JCO.2016.71.6795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J et al (2016) Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol 34:3119–3125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J et al (2017) Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389:67–76

    Article  CAS  PubMed  Google Scholar 

  19. Balar AV, Castellano DE, O’Donnell PH, Grivas P, Vuky J, Powles T et al (2017) Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: results from the total KEYNOTE-052 study population. J Clin Oncol 35:284

    Article  Google Scholar 

  20. Boegemann M, Aydin AM, Bagrodia A, Krabbe LM (2017) Prospects and progress of immunotherapy for bladder cancer. Expert Opin Biol Ther 17:1417–1431

    CAS  PubMed  Google Scholar 

  21. FDA (2017) FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm

  22. Xylinas E, Kluth LA, Lotan Y, Daneshmand S, Rieken M, Karakiewicz PI, Shariat SF (2014) Blood- and tissue-based biomarkers for prediction of outcomes in urothelial carcinoma of the bladder. Urol Oncol 32(3):230–242. https://doi.org/10.1016/j.urolonc.2013.06.009

    Article  PubMed  Google Scholar 

  23. Nandagopal L, Sonpavde G (2016) Circulating biomarkers in bladder cancer. Bl Cancer. 2:369–379

    Article  PubMed  Google Scholar 

  24. Duquesne I, Weisbach L, Aziz A, Kluth LA, Xylinas E (2017) Young academic urologist urothelial carcinoma group of the European association of U. The contemporary role and impact of urine-based biomarkers in bladder cancer. Transl Androl Urol 6:1031–1042

    Article  PubMed  PubMed Central  Google Scholar 

  25. Knowles MA, Hurst CD (2015) Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 15:25–41

    Article  CAS  PubMed  Google Scholar 

  26. Hedegaard J, Lamy P, Nordentoft I, Algaba F, Hoyer S, Ulhoi BP et al (2016) Comprehensive transcriptional analysis of early-stage urothelial carcinoma. Cancer Cell 30:27–42

    Article  CAS  PubMed  Google Scholar 

  27. Cancer Genome Atlas Research N. (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315–322

    Article  CAS  Google Scholar 

  28. Hurst CD, Alder O, Platt FM, Droop A, Stead LF, Burns JE et al (2017) Genomic subtypes of non-invasive bladder cancer with distinct metabolic profile and female gender bias in KDM6A mutation frequency. Cancer Cell 32(701–15):e7

    Google Scholar 

  29. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752

    Article  CAS  PubMed  Google Scholar 

  30. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dyrskjot L, Thykjaer T, Kruhoffer M, Jensen JL, Marcussen N, Hamilton-Dutoit S et al (2003) Identifying distinct classes of bladder carcinoma using microarrays. Nat Genet 33:90–96

    Article  CAS  PubMed  Google Scholar 

  32. Blaveri E, Simko JP, Korkola JE, Brewer JL, Baehner F, Mehta K et al (2005) Bladder cancer outcome and subtype classification by gene expression. Clin Cancer Res 11:4044–4055

    Article  CAS  PubMed  Google Scholar 

  33. Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, Cordon-Cardo C (2006) Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol 24:778–789

    Article  CAS  PubMed  Google Scholar 

  34. Dyrskjot L, Kruhoffer M, Thykjaer T, Marcussen N, Jensen JL, Moller K et al (2004) Gene expression in the urinary bladder: a common carcinoma in situ gene expression signature exists disregarding histopathological classification. Cancer Res 64:4040–4048

    Article  CAS  PubMed  Google Scholar 

  35. Dyrskjot L, Zieger K, Kruhoffer M, Thykjaer T, Jensen JL, Primdahl H et al (2005) A molecular signature in superficial bladder carcinoma predicts clinical outcome. Clin Cancer Res 11:4029–4036

    Article  CAS  PubMed  Google Scholar 

  36. Dyrskjot L, Zieger K, Real FX, Malats N, Carrato A, Hurst C et al (2007) Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma: a multicenter validation study. Clin Cancer Res 13:3545–3551

    Article  CAS  PubMed  Google Scholar 

  37. Patschan O, Sjodahl G, Chebil G, Lovgren K, Lauss M, Gudjonsson S et al (2015) A Molecular pathologic framework for risk stratification of stage T1 urothelial carcinoma. Eur Urol 68:824–832 (discussion 35-6)

    Article  CAS  PubMed  Google Scholar 

  38. Lerner SP, Robertson AG (2016) Molecular subtypes of non-muscle invasive bladder cancer. Cancer Cell 30:1–3

    Article  CAS  PubMed  Google Scholar 

  39. Sjodahl G, Lauss M, Lovgren K, Chebil G, Gudjonsson S, Veerla S et al (2012) A molecular taxonomy for urothelial carcinoma. Clin Cancer Res 18:3377–3386

    Article  CAS  PubMed  Google Scholar 

  40. Damrauer JS, Hoadley KA, Chism DD, Fan C, Tiganelli CJ, Wobker SE et al (2014) Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA 111:3110–3115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J et al (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25:152–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD et al (2017) Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171(540–56):e25

    Google Scholar 

  43. Choi W, Ochoa A, McConkey DJ, Aine M, Hoglund M, Kim WY et al (2017) Genetic alterations in the molecular subtypes of bladder cancer: illustration in the cancer genome atlas dataset. Eur Urol 72:354–365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H et al (2014) Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov 4:1140–1153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Plimack ER, Dunbrack RL, Brennan TA, Andrake MD, Zhou Y, Serebriiskii IG et al (2015) Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Eur Urol 68:959–967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. McConkey DJ, Choi W, Shen Y, Lee IL, Porten S, Matin SF et al (2016) A prognostic gene expression signature in the molecular classification of chemotherapy-naive urothelial cancer is predictive of clinical outcomes from neoadjuvant chemotherapy: a Phase 2 trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with bevacizumab in urothelial cancer. Eur Urol 69:855–862

    Article  CAS  PubMed  Google Scholar 

  47. Seiler R, Ashab HAD, Erho N, van Rhijn BWG, Winters B, Douglas J et al (2017) Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur Urol 72:544–554

    Article  CAS  PubMed  Google Scholar 

  48. Sweis RF, Spranger S, Bao R, Paner GP, Stadler WM, Steinberg G et al (2016) Molecular drivers of the non-T-cell-inflamed tumor microenvironment in urothelial bladder cancer. Cancer Immunol Res 4:563–568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Szabados B, van Dijk N, Tang YZ, van der Heijden MS, Wimalasingham A, Gomez de Liano A et al (2018) Response rate to chemotherapy after immune checkpoint inhibition in metastatic urothelial cancer. Eur Urol 73:149–152

    Article  PubMed  Google Scholar 

  50. Bensalah K, Montorsi F, Shariat SF (2007) Challenges of cancer biomarker profiling. Eur Urol 52:1601–1609

    Article  PubMed  Google Scholar 

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Acknowledgements

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Author notes

  1. Kilian M. Gust and Martin Boegemann made equal contribution.

Authors and Affiliations

  1. Department of Urology, The University of Muenster Medical Center, Albert-Schweitzer, Campus 1, GB A1, 48149, Muenster, Germany

    Laura-Maria Krabbe, Andres Jan Schrader & Martin Boegemann

  2. Department of Urology, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    Laura-Maria Krabbe & Vitaly Margulis

  3. Department of Urology, Medical University of Vienna, Vienna, Austria

    Shahrokh F. Shariat & Kilian M. Gust

Authors
  1. Laura-Maria Krabbe
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  2. Vitaly Margulis
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  3. Andres Jan Schrader
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  4. Shahrokh F. Shariat
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  5. Kilian M. Gust
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  6. Martin Boegemann
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Contributions

LMK: literature search, manuscript writing, critical review and editing, supervision. VM, AJS, SFS: critical review and editing, supervision. MB, KMG: literature search, critical review and editing, supervision

Corresponding author

Correspondence to Laura-Maria Krabbe.

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Conflict of interest

LMK, VM, AJS and KMG have no conflict of interest. SFS holds patents (Method to determine prognosis after therapy for prostate cancer, granted 2002-09-06; Methods to determine prognosis after therapy for bladder cancer, granted 2003-06-19; Prognostic methods for patients with prostatic disease, granted 2004-08-05; Soluble Fas urinary marker for the detection of bladder transitional cell carcinoma, granted 2010-07-20) and has served on the advisory board/as a speaker for Astellas, Astra Zeneca, Bayer, BMS, Cepheid, Ferring`, Ipsen, Janssen, Lilly, MSD, Olympus, Pfizer, Pierre Fabre, Roche, Sanochemia, Sanofi, and Wolf. MB has served on the advisory board/as a speaker for MSD, BMS, Roche, Astra Zeneca, Janssen, Astellas, Amgen, Ipsen, Sanofi, ABX, Eisai, Bayer, Novartis, and Pfizer. As this is a review article, no research involving human participants and/or animals was carried out and no informed consent was needed.

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Krabbe, LM., Margulis, V., Schrader, A.J. et al. Molecularly-driven precision medicine for advanced bladder cancer. World J Urol 36, 1749–1757 (2018). https://doi.org/10.1007/s00345-018-2354-z

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  • DOI: https://doi.org/10.1007/s00345-018-2354-z

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