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Role of Targeted Therapies in Management of Metastatic Urothelial Cancer in the Era of Immunotherapy

  • Petros GrivasEmail author
  • Evan Y. Yu
Genitourinary Cancers (S Gupta, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Genitourinary Cancers

Opinion statement

Despite significant advances and the approval of immune checkpoint inhibitors, metastatic urothelial carcinoma (mUC) is still very hard to treat and has poor outcomes. Deeper understanding of the molecular underpinnings of mUC has identified potential biomarkers, biologic drivers, and relevant therapy targets. However, targeted therapies in mUC have had significant challenges due to molecular heterogeneity, clonal evolution, and genomic instability, and have not improved outcomes so far. Despite that, recent technological developments, clinical utilization of molecular biology, and discovery of new agents with preclinical and early clinical activity have signaled a new age of experimental therapeutics in mUC. The more frequent use of next-generation sequencing of tumor tissue and cell-free circulating tumor DNA, combined with novel agents tested in clinical trials, provides promise. There is a plethora of agents being tested in mUC, including inhibitors of receptors and signaling pathways (e.g., fibroblast growth factor receptor, human epidermal growth factor receptor, phosphatidylinositol 3-kinase/AKT/mTOR pathway), angiogenesis (e.g., vascular endothelial growth factor and its receptors), poly (ADP-ribose) polymerase (PARP) inhibitors, immuno-oncology agents, cytotoxic agents (e.g., chemotherapy, antibody drug conjugates), and epigenetic modulators, among others. Two agents, enfortumab-vedotin (antibody drug conjugate) and erdafitinib (fibroblast growth factor receptor inhibitor), have breakthrough designation by the FDA, but are not approved as of March 2019. Novel combinations with various modalities and optimal sequencing of active therapies are being investigated in clinical trials. More sophisticated patient selection, discovery and prospective validation of predictive (and prognostic) biomarkers with clinical utility, and relevant clinical trial designs are important parameters in that context. Based on the above, there is high potential for targeted therapies to be added in the growing armamentarium of mUC, and possibly complement chemotherapy and immuno-oncology agents.

Keywords

Urothelial carcinoma Bladder cancer Precision oncology Targeted therapeutics Biologic therapies Biomarkers 

Notes

Compliance with Ethical Standards

Conflict of Interest

Petros Grivas has received research funding (paid to Cleveland Clinic Foundation for conduction of clinical trials) from Genentech, Bayer, Merck & Co., Mirati Therapeutics, OncoGenex Pharmaceuticals, Pfizer, and AstraZeneca; has received research funding (paid to the University of Washington for conduction of clinical trials) from Pfizer, Clovis Oncology, Bavarian Nordic, and Immunomedics; has received compensation from Genentech, Dendreon, Bayer, Merck & Co., Pfizer, Bristol-Myers Squibb, Exelixis, AstraZeneca, Biocept, Clovis Oncology, EMD Serono, Seattle Genetics, Foundation Medicine, Driver, Inc., QED Therapeutics, Heron Therapeutics, and Janssen; and has participated in educational, unbranded, non-product-related speaker’s program (after providing direct input for content of slides) sponsored by Genentech and Bristol-Myers Squibb.

Evan Y. Yu has received research funding from Bayer, Dendreon, Merck, and Seattle Genetics and has received compensation from Amgen, AstraZeneca, Bayer, Churchill Pharmaceuticals, Dendreon, EMD Serono, Incyte Corporation, Janssen, Merck, Pharmacyclics, QED Therapeutics, Tolmar, Inc., and Seattle Genetics for service as a consultant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.PubMedGoogle Scholar
  2. 2.
    Koshkin VS, Grivas P. Emerging role of immunotherapy in advanced urothelial carcinoma. Curr Oncol Rep. 2018;20(6):48.PubMedGoogle Scholar
  3. 3.
    •• Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26 Landmark phase 3 trial of pembrolizumab vs. salvage chemotherapy in mUC.PubMedPubMedCentralGoogle Scholar
  4. 4.
    • 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 randomized controlled trial. Lancet. 2018;391(10122):748–57 Landmark phase 3 trial of atezolizumab vs. salvage chemotherapy in mUC.PubMedGoogle Scholar
  5. 5.
    Grivas P, Laliberte F, Doleh Y, et al. Economic burden of select adverse events in patients with metastatic urothelial cancer treated with first-line systemic therapy. J Clin Oncol. 2019;37(7_suppl (March 12,019)):363.  https://doi.org/10.1200/JCO.2019.37.7_suppl.363.Google Scholar
  6. 6.
    Sanli O, Dobruch J, Knowles MA, et al. Bladder cancer. Nat Rev Dis Primers. 2017;3:17022.PubMedGoogle Scholar
  7. 7.
    Hedegaard J, Lamy P, Nordentoft I, et al. Comprehensive transcriptional analysis of early-stage urothelial carcinoma. Cancer Cell. 2016;30(1):27–42.PubMedGoogle Scholar
  8. 8.
    Damrauer JS, Hoadley KA, Chism DD, et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. PNAS USA. 2014;111(8):3110–5.PubMedGoogle Scholar
  9. 9.
    Choi W, Ochoa A, McConkey DJ, et al. Genetic alterations in the molecular subtypes of bladder cancer: illustration in the cancer genome atlas dataset. Eur Urol. 2017;72(3):354–65.PubMedPubMedCentralGoogle Scholar
  10. 10.
    • Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315–22 Original version of the landmark TCGA molecular analysis of UC. Google Scholar
  11. 11.
    Sjodahl G, Lauss M, Lovgren K, et al. A molecular taxonomy for urothelial carcinoma. Clin Cancer Res. 2012;18(12):3377–86.PubMedGoogle Scholar
  12. 12.
    Warrick JI, Walter V, Yamashita H, et al. FOXA1, GATA3 and PPAR cooperate to drive luminal subtype in bladder cancer: a molecular analysis of established human cell lines. Sci Rep. 2016;6:38531.PubMedPubMedCentralGoogle Scholar
  13. 13.
    •• Robertson AG, Kim J, Al-Ahmadie H, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171(3):540–56.e25 Most updated version of the landmark TCGA analysis of UC.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Ross JS, Wang K, Khaira D, et al. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer. 2016;122(5):702–11.PubMedGoogle Scholar
  15. 15.
    Sfakianos JP, Cha EK, Iyer G, et al. Genomic characterization of upper tract urothelial carcinoma. Eur Urol. 2015;68(6):970–7.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Carlo MI, Vijai J, Mandelker D, et al. DNA damage repair (DDR) germline mutations in patients (Pts) with urothelial carcinoma (UC). J Clin Oncol. 2018(suppl_15):36, 1516.Google Scholar
  17. 17.
    Faltas BM, Vlachostergios PJ, Lam L, et al. Germline single nucleotide polymorphisms in DNA repair genes in urothelial cancer patients. 2017.  https://doi.org/10.1158/1538-7445.AM2017-1115.
  18. 18.
    Klek S, Heald B, Milinovich A, et al. Genetic counseling (GC) and germline (GL) testing rates after adoption of an integrated clinical cancer genetics (CCG) approach to genomics tumor board (GTB). J Clin Oncol. 2018;36(suppl_15):1511.Google Scholar
  19. 19.
    Sadaps M, Funchain P, Mahdi H, et al. Precision oncology in solid tumors: a longitudinal tertiary care center experience. J Clin Oncol. 2018;(2):1–11.Google Scholar
  20. 20.
    Agarwal N, Pal SK, Hahn AW, et al. Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA. Cancer. 2018;124(10):2115–24.PubMedGoogle Scholar
  21. 21.
    Grivas P, Lalani AA, Pond GR, et al. Circulating tumor DNA alterations in advanced urothelial carcinoma and association with clinical outcomes: a pilot study. Eur Urol Oncol. 2019.  https://doi.org/10.1016/j.euo.2019.02.004.
  22. 22.
    Barata PC, Koshkin VS, Funchain P, et al. Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance. Ann Oncol. 2017;28(10):2458–63.PubMedGoogle Scholar
  23. 23.
    Schiff JP, Barata PC, Yu EY, Grivas P. Precision therapy in advanced urothelial cancer. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT. 2019.  https://doi.org/10.1080/23808993.2019.1582298.Google Scholar
  24. 24.
    Mendiratta P, Grivas P. Emerging biomarkers and targeted therapies in urothelial carcinoma. Ann Transl Med. 2018;6(12):250.  https://doi.org/10.21037/atm.2018.05.49.PubMedPubMedCentralGoogle Scholar
  25. 25.
    •• Rosenberg JE, Srikala S, Zhang J, et al. Updated results from the enfortumab vedotin phase 1 (EV-101) study in patients with metastatic urothelial cancer (mUC). J Clin Oncol. 2018;36(suppl_15):4504. Important data with enfortumab-vedotin having breakthrough designation by FDA.Google Scholar
  26. 26.
    Tagawa S et al. Sacituzumab govitecan (IMMU-132) in patients with previously treated urothelial cancer: results from a phase I/II study. 2019.  https://doi.org/10.1200/JCO.2019.37.7_suppl.354.Google Scholar
  27. 27.
    Petrylak D, Heath E, Sonpavde G, et al. Interim analysis of a phase I dose escalation trial of the antibody drug conjugate (ADC) AGS15E (ASG-15ME) in patients (Pts) with metastatic urothelial cancer (mUC). Ann Oncol. 2016;27(suppl_6):780PD.Google Scholar
  28. 28.
    Yu EY. “Antibody drug conjugates for urothelial carcinoma, a cool technology with promising results.” UroToday 2018: https://www.urotoday.com/clinical-trials/from-the-editor/103205-antibody-drug-conjugates-or-urothelial-carcinoma-a-cool-technology-with-promising-results.html
  29. 29.
    Babina IS, Turner NC. Advances and challenges in targeting FGFR signaling in cancer. Nat Rev Cancer. 2017;17(5):318–32.PubMedGoogle Scholar
  30. 30.
    Hernandez S, Lopez-Knowles E, Lloreta J, et al. Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J Clin Oncol. 2006;24(22):3664–71.PubMedGoogle Scholar
  31. 31.
    van Rhijn BW, Vis AN, van der Kwast TH, et al. Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to pathologic grade for the prediction of clinical outcome. J Clin Oncol. 2003;21(10):1912–21.PubMedGoogle Scholar
  32. 32.
    Tabernero J, Bahleda R, Dienstmann R, et al. Phase I dose-escalation study of JNJ-42756493, an oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2015;33(30):3401–8.PubMedGoogle Scholar
  33. 33.
    •• 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). J Clin Oncol. 2018;36(suppl_15):4503 Important data with erdafitinib having breakthrough designation by FDA.Google Scholar
  34. 34.
    Joerger M, Cassier P, Penel N, et al. Rogaratinib treatment of patients with advanced urothelial carcinomas prescreened for tumor FGFR mRNA expression. J Clin Oncol. 2018;36(suppl_6):494.Google Scholar
  35. 35.
    Pal SK, Rosenberg JE, Hoffman-Censits JH, et al. Efficacy of BGJ398, a fibroblast growth factor receptor 1–3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations. Cancer Discov. 2018;8(7):812–21.PubMedGoogle Scholar
  36. 36.
    Necchi A, Pouessel D, Leibowitz-Amit R, et al. Interim results of Fight-201, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with metastatic or surgically unresectable urothelial carcinoma (UC) harboring fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations (GA). Ann Oncol. 2018;29(suppl_18):viii319–20.Google Scholar
  37. 37.
    Mazzola CR, Chin J. Targeting the VEGF pathway in metastatic bladder cancer. Expert Opin Investig Drugs. 2015;24(7):913–27.PubMedGoogle Scholar
  38. 38.
    Fus LP, Gornicka B. Role of angiogenesis in urothelial bladder carcinoma. Cent European J Urol. 2016;69(3):258–63.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Petrylak DP, de Wit R, Chi KN, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomized, double-blind, phase 3 trial. Lancet. 2017;390:2266–77.PubMedGoogle Scholar
  40. 40.
    Hahn NM, Stadler WM, Zon RT, et al. Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04–75. J Clin Oncol. 2011;29:1525–30.PubMedGoogle Scholar
  41. 41.
    Grivas PD, Daignault S, Tagawa ST, et al. Double-blind, randomized, phase 2 trial of maintenance sunitinib versus placebo after response to chemotherapy in patients with advanced urothelial carcinoma. Cancer. 2014;120:692–701.PubMedGoogle Scholar
  42. 42.
    Bellmunt J, Gonzalez-Larriba JL, Prior C, et al. Phase II study of sunitinib as first-line treatment of urothelial cancer patients ineligible to receive cisplatin-based chemotherapy: baseline interleukin-8 and tumor contrast enhancement as potential predictive factors of activity. Ann Oncol. 2011;22:2646–53.PubMedGoogle Scholar
  43. 43.
    Gallagher DJ, Milowsky MI, Gerst SR, et al. Phase II study of sunitinib in patients with metastatic urothelial cancer. J Clin Oncol. 2010;28:1373–9.PubMedGoogle Scholar
  44. 44.
    Apolo AB, Parnes HL, Francis DC, et al. A phase II study of cabozantinib in patients (pts) with relapsed or refractory metastatic urothelial carcinoma (mUC). J Clin Oncol. 2016;34(15_suppl):4534.  https://doi.org/10.1200/JCO.2016.34.15_suppl.4534.Google Scholar
  45. 45.
    Apolo ABMA, Stein MN, et al. A phase I study of cabozantinib plus nivolumab (CaboNivo) and cabonivo plus ipilimumab (CaboNivoIpi) in patients (pts) with refractory metastatic (m) urothelial carcinoma (UC) and other genitourinary (GU) tumors. J Clin Oncol. 2017;35(6_suppl):293.Google Scholar
  46. 46.
    Grivas PD, Day M, Hussain M. Urothelial carcinomas: a focus on human epidermal receptors signaling. Am J Transl Res. 2011;3:362–73.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Eriksson P, Sjodahl G, Chebil G, et al. HER2 and EGFR amplification and expression in urothelial carcinoma occurs in distinct biological and molecular contexts. Oncotarget. 2017;8(30):48905–14.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Wong YN, Litwin S, Vaughn D, et al. Phase II trial of cetuximab with or without paclitaxel in patients with advanced urothelial tract carcinoma. J Clin Oncol. 2012;30(28):3545–51.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Hussain M, Daignault S, Agarwal N, et al. A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma. Cancer. 2014;120(17):2684–93.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Powles T, Huddart RA, Elliott T, et al. Phase III, double-blind, randomized trial that compared maintenance lapatinib versus placebo after first-line chemotherapy in patients with human epidermal growth factor receptor 1/2–positive metastatic bladder cancer. J Clin Oncol. 2017;35(1):48–55.PubMedGoogle Scholar
  51. 51.
    Miller K, Morant R, Stenzl A, Zuna I, Wirth M. A phase II study of the Central European Society of Anticancer-Drug Research (CESAR) Group: results of an open-label study of gemcitabine plus cisplatin with or without concomitant or sequential gefitinib in patients with advanced or metastatic transitional cell carcinoma of the urothelium. Urol Int. 2016;96(1):5–13.PubMedGoogle Scholar
  52. 52.
    Choudhury NJ, Campanile A, Antic T, et al. Afatinib activity in platinum-refractory metastatic urothelial carcinoma in patients with ERBB alterations. J Clin Oncol. 2016;34(18):2165–71.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Koshkin VS, et al. Systematic review: targeting HER2 in bladder cancer. Bladder Cancer. 2019;5(1):1–12.Google Scholar
  54. 54.
    Bellmunt J, Werner L, Bamias A, et al. HER2 as a target in invasive urothelial carcinoma. Cancer Med. 2015;4(6):844–52.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Ross JS, Wang K, Gay LM, et al. A high frequency of activating extracellular domain ERBB2 (HER2) mutation in micropapillary urothelial carcinoma. Clin Cancer Res. 2014;20(1):68–75.PubMedGoogle Scholar
  56. 56.
    Mejri N, Sellami R, Lamia C, et al. Status of HER2 over expression in muscle invasive urothelial bladder carcinoma: report of 21 cases. Urol Ann. 2014;6(1):63–7.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Kiss B, Wyatt AW, Douglas J, et al. HER2 alterations in muscle-invasive bladder cancer: patient selection beyond protein expression for targeted therapy. Sci Rep. 2017;7:42713.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Pal SK, Agarwal N, Choueiri TK, et al. Comparison of tumor mutational burden (TMB) in relevant molecular subsets of metastatic urothelial cancer (MUC). Ann Oncol. 2017;28(suppl_5):v295–329.  https://doi.org/10.1093/annonc/mdx371.Google Scholar
  59. 59.
    Hussain MH, MacVicar GR, Petrylak DP, et al. Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II national cancer institute trial. J Clin Oncol. 2007;25(16):2218–24.PubMedGoogle Scholar
  60. 60.
    Bryce AH, Kurzrock R, Meric-Bernstam F, et al. Pertuzumab plus trastuzumab for HER2-positive metastatic urothelial cancer (mUC): preliminary data from mypathway. J Clin Oncol. 2017;35(suppl_6):348.Google Scholar
  61. 61.
    Ross RL, McPherson HR, Kettlewell L, et al. PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma. BMC Cancer. 2016;16(1):553.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Millis SZ, Bryant D, Basu G, et al. Molecular profiling of infiltrating urothelial carcinoma of bladder and nonbladder origin. Clin Genitourin Cancer. 2015;13(1):e37–49.PubMedGoogle Scholar
  63. 63.
    Sathe A, Nawroth R. Targeting the PI3K/AKT/mTOR pathway in bladder cancer. Methods Mol Biol. 2018;1655:335–50.PubMedGoogle Scholar
  64. 64.
    Bellmunt J, Werner L, Leow JJ, et al. Somatic copy number abnormalities and mutations in PI3K/AKT/mTOR pathway have prognostic significance for overall survival in platinum treated locally advanced or metastatic urothelial tumors. PLoS One. 2015;10(6):e0124711.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Kwiatkowski DJ, Choueiri TK, Fay AP, et al. Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2016;22(10):2445–52.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Iyer G, Hanrahan AJ, Milowsky MI, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012;338(6104):221.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Milowsky MI, Iyer G, Regazzi AM, et al. Phase II study of everolimus in metastatic urothelial cancer. BJU Int. 2013;112(4):462–70.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Niegisch G, Retz M, Thalgott M, et al. Second-line treatment of advanced urothelial cancer with paclitaxel and everolimus in a German phase II trial (AUO Trial AB 35/09). Oncology. 2015;89(2):70–8.PubMedGoogle Scholar
  69. 69.
    Nassim R, Mansure JJ, Chevalier S, et al. Combining mTOR inhibition with radiation improves antitumor activity in bladder cancer cells in vitro and in vivo: a novel strategy for treatment. PLoS One. 2013;8(6):e65257.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72(21):5588–99.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Duex JE, Swain KE, Dancik GM, et al. Functional impact of chromatin remodeling gene mutations and predictive signature for therapeutic response in bladder cancer. Mol Cancer Res. 2018;16:69–77.PubMedGoogle Scholar
  73. 73.
    Grivas P, Mortazavi A, Picus J, et al. Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes. Cancer. 2018;125(4):533–40.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Cheung EMQD, Tsao-Wei DD, et al. Phase II study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced transitional cell urothelial cancer after platinum-based therapy. J Clin Oncol. 2008;26(suppl 15):16058.Google Scholar
  75. 75.
    Ler LD, Ghosh S, Chai X, et al. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2. Sci Transl Med. 2017;9(378).Google Scholar
  76. 76.
    Bitler BG, Aird KM, Garipov A, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med. 2015;21:231–8.PubMedGoogle Scholar
  77. 77.
    Rose TL, Chism DD, Alva AS, et al. Phase II trial of palbociclib in patients with metastatic urothelial cancer after failure of first-line chemotherapy. Br J Cancer. 2018;119:801–7.PubMedGoogle Scholar
  78. 78.
    Grivas P. DNA damage response gene alterations in urothelial cancer: ready for practice? Clin Cancer Res. 2019;25(3):907–9.  https://doi.org/10.1158/1078-0432.CCR-18-2512.PubMedGoogle Scholar
  79. 79.
    Li Q, Damish A, Frazier ZJ, et al. ERCC2 helicase domain mutations confer nucleotide excision repair deficiency and drive cisplatin sensitivity in muscle-invasive bladder cancer. Clin Cancer Res. 2019;25(3):977–88.  https://doi.org/10.1158/1078-0432.CCR-18-1001.PubMedGoogle Scholar
  80. 80.
    Liu D, Plimack ER, Hoffman-Censits J, et al. Clinical validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder carcinoma. JAMA Oncol. 2016;2:1094–6.PubMedPubMedCentralGoogle Scholar
  81. 81.
    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;68:959–67.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Teo MY, Bambury RM, Zabor EC, et al. DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma. Clin Cancer Res. 2017;23:3610–8.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Teo MY, Seier K, Ostrovnaya I, et al. Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers. J Clin Oncol. 2018;36(17):1685–94.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Gopalakrishnan D, Koshkin VS, Ornstein MC, et al. Immune checkpoint inhibitors in urothelial cancer: recent updates and future outlook. Ther Clin Risk Manag. 2018;14:1019–40.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Tsimberidou AM, Hong DS, Wheler JJ, et al. Precision medicine: clinical outcomes including long-term survival according to the pathway targeted and treatment period–the impact study. J Clin Oncol. 2018;36(suppl_18):LBA2553.Google Scholar
  86. 86.
    Massard C, Michiels S, Ferté C, et al. High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 trial. Cancer Discov. 2017;7(6):586–95.PubMedGoogle Scholar
  87. 87.
    Le Tourneau C, Delord JP, Goncalves A, et al. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (shiva): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol. 2015;16(13):1324–34.PubMedGoogle Scholar
  88. 88.
    Hovelson DH, Udager AM, McDaniel AS, et al. Targeted DNA and RNA sequencing of paired urothelial and squamous bladder cancers reveals discordant genomic and transcriptomic events and unique therapeutic implications. Eur Urol. 2018;74(6):741–53.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Oncology, Department of MedicineUniversity of WashingtonSeattleUSA
  2. 2.Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleUSA
  3. 3.Genitourinary Cancers ProgramUniversity of WashingtonSeattleUSA
  4. 4.Seattle Cancer Care AllianceSeattleUSA

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