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Molecular and histopathology directed therapy for advanced bladder cancer

  • Review Article
  • Published:

From Nature Reviews Urology

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Abstract

Bladder cancer is a heterogeneous group of tumours with at least 40 histological subgroups. Patients with localized disease can be cured with surgical resection or radiotherapy, but such curative options are limited in the setting of recurrent disease or distant spread, in which case systemic therapy is used to control disease and palliate symptoms. Cytotoxic chemotherapy has been the mainstay of treatment for advanced bladder cancer, but high-quality evidence is lacking to inform the management of rare subgroups that are often excluded from studies. Advances in molecular pathology, the development of targeted therapies and the resurgence of immunotherapy have led to the reclassification of bladder cancer subgroups and rigorous efforts to define predictive biomarkers for cancer therapies. In this Review, we present the current evidence for the management of conventional, variant and divergent urothelial cancer subtypes, as well as non-urothelial bladder cancers, and discuss how the integration of genomic, transcriptomic and proteomic characterization of bladder cancer could guide future therapies.

Key points

  • Combining sequencing and transcriptomic technologies might improve the identification of clinically relevant bladder cancer subgroups.

  • Molecular subtyping has helped us to identify bladder tumours that respond well to cytotoxic chemotherapy.

  • Targeted therapies have had a limited role in bladder cancer management, but the next generation of specific targets are showing promise, as exemplified by fibroblast growth factor receptor 3.

  • Immune checkpoint inhibition leads to deep and durable responses in a small subgroup of patients.

  • Composite molecular signatures are showing promise as predictors of treatment response and should be tested in prospective clinical trials.

  • Real-time serial biopsies during the course of treatment will be required to help direct therapy in an evolving tumour landscape.

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Fig. 1: Timeline of discoveries and therapeutics relevant to advanced bladder cancer.
Fig. 2: Immunohistochemistry of bladder cancer.
Fig. 3: The major classifications of urothelial carcinoma.
Fig. 4: Signalling pathways for targeted therapies in urothelial carcinoma.

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References

  1. Ferlay, J. et al. (eds) GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012 v1.0: IARC CancerBase No. 11 (International Agency for Research on Cancer, Lyon, 2012).

  2. Alanee, S. et al. Update of the International Consultation on Urological Diseases on bladder cancer 2018: non-urothelial cancers of the urinary bladder. World J. Urol. 37, 107–114 (2019).

    Article  PubMed  Google Scholar 

  3. Humphrey, P. A., Moch, H., Cubilla, A. L., Ulbright, T. M. & Reuter, V. E. The 2016 WHO classification of tumours of the urinary system and male genital organs-part B: prostate and bladder tumours. Eur. Urol. 70, 106–119 (2016).

    Article  PubMed  Google Scholar 

  4. Garraway, L. A. Genomics-driven oncology: framework for an emerging paradigm. J. Clin. Oncol. 31, 1806–1814 (2013).

    Article  PubMed  Google Scholar 

  5. Dinney, C. P. et al. Focus on bladder cancer. Cancer Cell 6, 111–116 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Dadhania, V. et al. Meta-analysis of the luminal and basal subtypes of bladder cancer and the identification of signature immunohistochemical markers for clinical use. EBioMedicine 12, 105–117 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Choi, W. et al. Genetic alterations in the molecular subtypes of bladder cancer: illustration in the Cancer Genome Atlas Dataset. Eur. Urol. 72, 354–365 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Damrauer, J. S. et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc. Natl Acad. Sci. USA 111, 3110–3115 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sjodahl, G. et al. Toward a molecular pathologic classification of urothelial carcinoma. Am. J. Pathol. 183, 681–691 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Choi, W. et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25, 152–165 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Biton, A. et al. Independent component analysis uncovers the landscape of the bladder tumor transcriptome and reveals insights into luminal and basal subtypes. Cell Rep. 9, 1235–1245 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Lerner, S. P. et al. Bladder cancer molecular taxonomy: summary from a consensus meeting. Bladder Cancer 2, 37–47 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Robertson, A. G. et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171, 540–556 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chan, K. et al. An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nat. Genet. 47, 1067–1072 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Roberts, S. A. et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat. Genet. 45, 970–976 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Iyer, G. et al. Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J. Clin. Oncol. 31, 3133–3140 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315–322 (2014).

    Article  CAS  Google Scholar 

  18. van Oers, J. M. et al. FGFR3 mutations indicate better survival in invasive upper urinary tract and bladder tumours. Eur. Urol. 55, 650–657 (2009).

    Article  PubMed  CAS  Google Scholar 

  19. Leiserson, M. D. et al. Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes. Nat. Genet. 47, 106–114 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Kolluri, K. K. et al. Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells. eLife 7, e30224 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Miller, R. E. et al. Synthetic lethal targeting of ARID1A-mutant ovarian clear cell tumors with dasatinib. Mol. Cancer Ther. 15, 1472–1484 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Vandekerkhove, G. et al. Circulating tumor DNA reveals clinically actionable somatic genome of metastatic bladder cancer. Clin. Cancer Res. 23, 6487–6497 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Togneri, F. S. et al. Genomic complexity of urothelial bladder cancer revealed in urinary cfDNA. Eur. J. Hum. Genet. 24, 1167–1174 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wong, Y. N. S. et al. Urine-derived lymphocytes as a non-invasive measure of the bladder tumor immune microenvironment. J. Exp. Med. 215, 2748–2759 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Amin, M. B. et al. Update for the practicing pathologist: the International Consultation on Urologic Disease-European Association of Urology consultation on bladder cancer. Mod. Pathol. 28, 612–630 (2015).

    Article  PubMed  Google Scholar 

  26. Moschini, M. et al. Characteristics and clinical significance of histological variants of bladder cancer. Nat. Rev. Urol. 14, 651 (2017).

    Article  PubMed  Google Scholar 

  27. von der Maase, H. et al. 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 (2000).

    Article  PubMed  Google Scholar 

  28. Sternberg, C. N. et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J. Urol. 133, 403–407 (1985).

    Article  CAS  PubMed  Google Scholar 

  29. Loehrer, P. J. Sr. et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J. Clin. Oncol. 10, 1066–1073 (1992).

    Article  PubMed  Google Scholar 

  30. Sternberg, C. N. et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer 64, 2448–2458 (1989).

    Article  CAS  PubMed  Google Scholar 

  31. von der Maase, H. et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J. Clin. Oncol. 23, 4602–4608 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Sternberg, C. N. et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer protocol no. 30924. J. Clin. Oncol. 19, 2638–2646 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Bellmunt, J. et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J. Clin. Oncol. 30, 1107–1113 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. De Santis, M. et al. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer “unfit” for cisplatin-based chemotherapy: phase II—results of EORTC study 30986. J. Clin. Oncol. 27, 5634–5639 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Bellmunt, J. et al. A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN). Ann. Oncol. 28, 1517–1522 (2017).

    Article  CAS  PubMed  Google Scholar 

  36. Bellmunt, J. et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J. Clin. Oncol. 27, 4454–4461 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Sonpavde, G. et al. Second-line systemic therapy and emerging drugs for metastatic transitional-cell carcinoma of the urothelium. Lancet Oncol. 11, 861–870 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Grossman, H. B. et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N. Engl. J. Med. 349, 859–866 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Necchi, A. et al. Efficacy and safety of gemcitabine plus either taxane or carboplatin in the first-line setting of metastatic urothelial carcinoma: a systematic review and meta-analysis. Clin. Genitourin. Cancer 15, 23–30 (2017).

    Article  PubMed  Google Scholar 

  40. Necchi, A. et al. Cisplatin-based first-line therapy for advanced urothelial carcinoma after previous perioperative cisplatin-based therapy. Clin. Genitourin. Cancer 13, 178–184 (2015).

    Article  PubMed  Google Scholar 

  41. Sjodahl, G., Jackson, C. L., Bartlett, J. M., Siemens, D. R. & Berman, D. M. Molecular profiling in muscle-invasive bladder cancer: more than the sum of its parts. J. Pathol. 247, 563–573 (2019).

    Article  PubMed  Google Scholar 

  42. Seiler, R. et al. Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur. Urol. 72, 544–554 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Felsenstein, K. M. & Theodorescu, D. Precision medicine for urothelial bladder cancer: update on tumour genomics and immunotherapy. Nat. Rev. Urol. 15, 92–111 (2018).

    Article  CAS  PubMed  Google Scholar 

  44. Plimack, E. R. et al. Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Eur. Urol. 68, 959–967 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Morales, A., Eidinger, D. & Bruce, A. W. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol. 116, 180–183 (1976).

    Article  CAS  PubMed  Google Scholar 

  46. Ishida, Y., Agata, Y., Shibahara, K. & Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11, 3887–3895 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bardhan, K. et al. PD-1 inhibits the TCR signaling cascade by sequestering SHP-2 phosphatase, preventing its translocation to lipid rafts and facilitating Csk-mediated inhibitory phosphorylation of Lck [abstract]. J. Immunol. 196 (Suppl. 1), 128.15 (2016).

    Google Scholar 

  48. Nakanishi, J. et al. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol. Immunother. 56, 1173–1182 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Fessas, P., Lee, H., Ikemizu, S. & Janowitz, T. A molecular and preclinical comparison of the PD-1-targeted T cell checkpoint inhibitors nivolumab and pembrolizumab. Semin. Oncol. 44, 136–140 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bellmunt, J. et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N. Engl. J. Med. 376, 1015–1026 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Balar, A. V. et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 18, 1483–1492 (2017).

    Article  CAS  PubMed  Google Scholar 

  53. Sharma, P. et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol. 17, 1590–1598 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sharma, P. et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 18, 312–322 (2017).

    Article  CAS  PubMed  Google Scholar 

  55. Tan, S. et al. Distinct PD-L1 binding characteristics of therapeutic monoclonal antibody durvalumab. Protein Cell 9, 135–139 (2018).

    Article  CAS  PubMed  Google Scholar 

  56. Rosenberg, J. E. 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 387, 1909–1920 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Powles, T. et al. Inhibition of PD-L1 by MPDL3280A and clinical activity in pts with metastatic urothelial bladder cancer (UBC) [abstract]. J. Clin. Oncol. 32 (Suppl. 5), 5011 (2014).

    Article  Google Scholar 

  58. Powles, T. 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 391, 748–757 (2018).

    Article  CAS  PubMed  Google Scholar 

  59. Massard, C. et al. 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 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Powles, T. et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 3, e172411 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Apolo, A. B. et al. 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, 2117–2124 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Patel, M. R. et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN solid tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 19, 51–64 (2018).

    Article  CAS  PubMed  Google Scholar 

  63. Powles, T. & Morrison, L. Biomarker challenges for immune checkpoint inhibitors in urothelial carcinoma. Nat. Rev. Urol. 15, 585–587 (2018).

    Article  PubMed  Google Scholar 

  64. Plimack, E. R. et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Lancet Oncol. 18, 212–220 (2017).

    Article  CAS  PubMed  Google Scholar 

  65. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mariathasan, S. et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Robbins, P. F. et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19, 747–752 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. van Rooij, N. et al. Tumor exome analysis reveals neoantigen-specific T cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31, e439–442 (2013).

    Article  PubMed  Google Scholar 

  70. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Teo, M. Y. 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. 36, 1685–1694 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. van der Post, R. S. et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J. Med. Genet. 47, 464–470 (2010).

    Article  PubMed  Google Scholar 

  73. Akhurst, R. J. & Hata, A. Targeting the TGFβ signalling pathway in disease. Nat. Rev. Drug Discov. 11, 790–811 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Balar, A. V. et al. 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 (2017).

    Article  CAS  PubMed  Google Scholar 

  75. Pond, G. R. et al. A nomogram including baseline prognostic factors to estimate the activity of second-line therapy for advanced urothelial carcinoma. BJU Int. 113, E137–E143 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Pond, G. R. et al. New 6-factor prognostic model for patients (pts) with advanced urothelial carcinoma (UC) receiving post-platinum atezolizumab [abstract]. J. Clin. Oncol. 36 (Suppl. 6), 413 (2018).

    Article  Google Scholar 

  77. Garcia, J. A. & Danielpour, D. Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies. Mol. Cancer Ther. 7, 1347–1354 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Motzer, R. J. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–456 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Averous, J. & Proud, C. G. When translation meets transformation: the mTOR story. Oncogene 25, 6423–6435 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Mansure, J. J. et al. Inhibition of mammalian target of rapamycin as a therapeutic strategy in the management of bladder cancer. Cancer Biol. Ther. 8, 2339–2347 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Milowsky, M. I. et al. Phase II study of everolimus in metastatic urothelial cancer. BJU Int. 112, 462–470 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wulfing, C. et al. A single-arm, multicenter, open-label phase 2 study of lapatinib as the second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma. Cancer 115, 2881–2890 (2009).

    Article  PubMed  CAS  Google Scholar 

  83. Powles, 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. 35, 48–55 (2017).

    Article  CAS  PubMed  Google Scholar 

  84. Turner, N. & Grose, R. Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer 10, 116–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal 6, pl1 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Iyer, G. & Milowsky, M. I. Fibroblast growth factor receptor-3 in urothelial tumorigenesis. Urol. Oncol. 31, 303–311 (2013).

    Article  CAS  PubMed  Google Scholar 

  87. Milowsky, M. I. et al. Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma. Eur. J. Cancer 50, 3145–3152 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Nogova, L. et al. Evaluation of BGJ398, a fibroblast growth factor receptor 1–3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J. Clin. Oncol. 35, 157–165 (2017).

    Article  CAS  PubMed  Google Scholar 

  89. Loriot, Y. et al. Erdafitinib (ERDA; JNJ-42756493), a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRa): phase 2 continuous versus intermittent dosing. J. Clin. Oncol. 36, 411–411 (2018).

    Article  Google Scholar 

  90. Petrylak, D. P. et al. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet 390, 2266–2277 (2017).

    Article  CAS  PubMed  Google Scholar 

  91. Wit, R. D. et al. Ramucirumab (RAM) exposure-response (ER) relationship in RANGE: a randomized phase III trial of RAM plus docetaxel (DOC) versus placebo (P) plus DOC in advanced platinum-refractory urothelial carcinoma (UC) patients (pts). J. Clin. Oncol. 37, 353–353 (2019).

    Article  Google Scholar 

  92. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 68, 7–30 (2018).

    Article  PubMed  Google Scholar 

  93. Sui, W. et al. Micropapillary bladder cancer: insights from the National Cancer Database. Bladder Cancer 2, 415–423 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Comperat, E. et al. Micropapillary urothelial carcinoma of the urinary bladder: a clinicopathological analysis of 72 cases. Pathology 42, 650–654 (2010).

    Article  PubMed  Google Scholar 

  95. Meeks, J. J. et al. Pathological response to neoadjuvant chemotherapy for muscle-invasive micropapillary bladder cancer. BJU Int. 111, E325–E330 (2013).

    Article  PubMed  Google Scholar 

  96. Rosenblatt, R. et al. Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer. Eur. Urol. 61, 1229–1238 (2012).

    Article  PubMed  Google Scholar 

  97. Guo, C. C. et al. Gene expression profile of the clinically aggressive micropapillary variant of bladder cancer. Eur. Urol. 70, 611–620 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sahin, A. A. et al. Plasmacytoid transitional cell carcinoma. Report of a case with initial presentation mimicking multiple myeloma. Acta Cytol. 35, 277–280 (1991).

    CAS  PubMed  Google Scholar 

  99. Raspollini, M. R. et al. Plasmacytoid urothelial carcinoma of the urinary bladder: clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of a case series. Hum. Pathol. 42, 1149–1158 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Kaimakliotis, H. Z. et al. Plasmacytoid bladder cancer: variant histology with aggressive behavior and a new mode of invasion along fascial planes. Urology 83, 1112–1116 (2014).

    Article  PubMed  Google Scholar 

  101. Li, Q. et al. The impact of plasmacytoid variant histology on the survival of patients with urothelial carcinoma of bladder after radical cystectomy. Eur. Urol. Focus 5, 104–108 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Dayyani, F. et al. Plasmacytoid urothelial carcinoma, a chemosensitive cancer with poor prognosis, and peritoneal carcinomatosis. J. Urol. 189, 1656–1661 (2013).

    Article  PubMed  Google Scholar 

  103. Wang, J., Gillaspie, C., Kunadharaju, R., Talmon, G. A. & Enke, C. Sarcomatoid urothelial carcinoma: a single cancer center experience. World J. Oncol. 2, 175–180 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Sung, M. T. et al. Histogenesis of sarcomatoid urothelial carcinoma of the urinary bladder: evidence for a common clonal origin with divergent differentiation. J. Pathol. 211, 420–430 (2007).

    Article  PubMed  Google Scholar 

  105. Froehner, M., Gaertner, H. J., Manseck, A. & Wirth, M. P. Durable complete remission of metastatic sarcomatoid carcinoma of the bladder with cisplatin and gemcitabine in an 80-year-old man. Urology 58, 799 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Powell, M. A. et al. Phase II evaluation of paclitaxel and carboplatin in the treatment of carcinosarcoma of the uterus: a Gynecologic Oncology Group study. J. Clin. Oncol. 28, 2727–2731 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Shokeir, A. A. Squamous cell carcinoma of the bladder: pathology, diagnosis and treatment. BJU Int. 93, 216–220 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Royce, T. J. et al. Clinical characteristics and outcomes of nonurothelial cell carcinoma of the bladder: results from the National Cancer Data Base. Urol. Oncol. 36, 78.e1–78.e12 (2018).

    Article  Google Scholar 

  109. Mostafa, M. H., Sheweita, S. A. & O’Connor, P. J. Relationship between schistosomiasis and bladder cancer. Clin. Microbiol. Rev. 12, 97–111 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Willis, D. & Kamat, A. M. Nonurothelial bladder cancer and rare variant histologies. Hematol. Oncol. Clin. North Am. 29, 237–252 (2015).

    Article  PubMed  Google Scholar 

  111. Abdollah, F. et al. Survival after radical cystectomy of non-bilharzial squamous cell carcinoma versus urothelial carcinoma: a competing-risks analysis. BJU Int 109, 564–569 (2012).

    Article  PubMed  Google Scholar 

  112. Kassouf, W. et al. Outcome and patterns of recurrence of nonbilharzial pure squamous cell carcinoma of the bladder: a contemporary review of The University of Texas M D Anderson Cancer Center experience. Cancer 110, 764–769 (2007).

    Article  PubMed  Google Scholar 

  113. Kastritis, E. et al. The outcome of patients with advanced pure squamous or mixed squamous and transitional urothelial carcinomas following platinum-based chemotherapy. Anticancer Res. 26, 3865–3869 (2006).

    CAS  PubMed  Google Scholar 

  114. Khaled, H. M., Hamza, M. R., Mansour, O., Gaafar, R. & Zaghloul, M. S. A phase II study of gemcitabine plus cisplatin chemotherapy in advanced bilharzial bladder carcinoma. Eur. J. Cancer 36 (Suppl. 2), 34–37 (2000).

    Article  Google Scholar 

  115. Samlowski, W. E. et al. Evaluation of the combination of docetaxel/carboplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN): a Southwest Oncology Group phase II study. Cancer Invest. 25, 182–188 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Shepherd, F. A. et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J. Clin. Oncol. 18, 2095–2103 (2000).

    Article  CAS  PubMed  Google Scholar 

  117. Galsky, M. D. et al. Prospective trial of ifosfamide, paclitaxel, and cisplatin in patients with advanced non-transitional cell carcinoma of the urothelial tract. Urology 69, 255–259 (2007).

    Article  PubMed  Google Scholar 

  118. Molitor, M. et al. Comparison of structural genetics of non-schistosoma-associated squamous cell carcinoma of the urinary bladder. Int. J. Clin. Exp. Pathol. 8, 8143–8158 (2015).

    PubMed  PubMed Central  Google Scholar 

  119. Hovelson, D. H. et al. Targeted DNA and RNA sequencing of paired urothelial and squamous bladder cancers to reveal discordant genomic and transcriptomic events and unique therapeutic opportunities. J. Clin. Oncol. 35, 296–296 (2017).

    Article  Google Scholar 

  120. Dotto, G. P. & Rustgi, A. K. Squamous cell cancers: a unified perspective on biology and genetics. Cancer Cell 29, 622–637 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Abrahams, N. A., Moran, C., Reyes, A. O., Siefker-Radtke, A. & Ayala, A. G. Small cell carcinoma of the bladder: a contemporary clinicopathological study of 51 cases. Histopathology 46, 57–63 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Koay, E. J., Teh, B. S., Paulino, A. C. & Butler, E. B. A. Surveillance, epidemiology, and end results analysis of small cell carcinoma of the bladder: epidemiology, prognostic variables, and treatment trends. Cancer 117, 5325–5333 (2011).

    Article  PubMed  Google Scholar 

  123. Choong, N. W., Quevedo, J. F. & Kaur, J. S. Small cell carcinoma of the urinary bladder. The Mayo Clinic experience. Cancer 103, 1172–1178 (2005).

    Article  PubMed  Google Scholar 

  124. Lohrisch, C., Murray, N., Pickles, T. & Sullivan, L. Small cell carcinoma of the bladder: long term outcome with integrated chemoradiation. Cancer 86, 2346–2352 (1999).

    Article  CAS  PubMed  Google Scholar 

  125. Siefker-Radtke, A. O. et al. Evidence supporting preoperative chemotherapy for small cell carcinoma of the bladder: a retrospective review of the M. D. Anderson cancer experience. J. Urol. 172, 481–484 (2004).

    Article  PubMed  Google Scholar 

  126. Pakkala, S. & Owonikoko, T. K. Immune checkpoint inhibitors in small cell lung cancer. J. Thorac Dis. 10, S460–S467 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Comperat, E., Varinot, J., Moroch, J., Eymerit-Morin, C. & Brimo, F. A practical guide to bladder cancer pathology. Nat. Rev. Urol. 15, 143–154 (2018).

    Article  PubMed  Google Scholar 

  128. Lughezzani, G. et al. Adenocarcinoma versus urothelial carcinoma of the urinary bladder: comparison between pathologic stage at radical cystectomy and cancer-specific mortality. Urology 75, 376–381 (2010).

    Article  PubMed  Google Scholar 

  129. Wright, J. L., Porter, M. P., Li, C. I., Lange, P. H. & Lin, D. W. Differences in survival among patients with urachal and nonurachal adenocarcinomas of the bladder. Cancer 107, 721–728 (2006).

    Article  PubMed  Google Scholar 

  130. Szarvas, T. et al. Clinical, prognostic, and therapeutic aspects of urachal carcinoma—a comprehensive review with meta-analysis of 1,010 cases. Urol. Oncol. 34, 388–398 (2016).

    Article  PubMed  Google Scholar 

  131. Roy, S. et al. Next-generation sequencing-based molecular characterization of primary urinary bladder adenocarcinoma. Mod. Pathol. 30, 1133–1143 (2017).

    Article  CAS  PubMed  Google Scholar 

  132. Collazo-Lorduy, A. et al. Urachal carcinoma shares genomic alterations with colorectal carcinoma and may respond to epidermal growth factor inhibition. Eur. Urol. 70, 771–775 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Gopalan, A. et al. Urachal carcinoma: a clinicopathologic analysis of 24 cases with outcome correlation. Am. J. Surg. Pathol. 33, 659–668 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Siefker-Radtke, A. Urachal adenocarcinoma: a clinician’s guide for treatment. Semin. Oncol. 39, 619–624 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00082706 (2018).

  136. Loh, K. P. et al. Targeted therapy based on tumor genomic analyses in metastatic urachal carcinoma. Clin. Genitourin. Cancer 14, e449–452 (2016).

    Article  Google Scholar 

  137. Wang, J. Primary sarcoma and sarcomatoid carcinoma of the urinary bladder: comparison of clinical features, treatment, and survival [abstract]. J. Clin. Oncol. 34 (Suppl. 2), 381 (2016).

    Article  CAS  Google Scholar 

  138. Spiess, P. E. et al. Review of the M. D. Anderson experience in the treatment of bladder sarcoma. Urol. Oncol. 25, 38–45 (2007).

    Article  PubMed  Google Scholar 

  139. Linch, M., Miah, A. B., Thway, K., Judson, I. R. & Benson, C. Systemic treatment of soft-tissue sarcoma-gold standard and novel therapies. Nat. Rev. Clin. Oncol. 11, 187–202 (2014).

    Article  CAS  PubMed  Google Scholar 

  140. Judson, I. et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 15, 415–423 (2014).

    Article  CAS  PubMed  Google Scholar 

  141. Seddon, B. et al. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol. 18, 1397–1410 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Mai, K. T., Bateman, J., Djordjevic, B., Flood, T. A. & Belanger, E. C. Clear cell urothelial carcinoma. Int. J. Surg. Pathol. 25, 18–25 (2017).

    Article  PubMed  Google Scholar 

  143. Oliva, E., Amin, M. B., Jimenez, R. & Young, R. H. Clear cell carcinoma of the urinary bladder: a report and comparison of four tumors of mullerian origin and nine of probable urothelial origin with discussion of histogenesis and diagnostic problems. Am. J. Surg. Pathol. 26, 190–197 (2002).

    Article  PubMed  Google Scholar 

  144. Teo, M. Y. & Rosenberg, J. E. EMA and FDA prune the checkpoint inhibitor treatment landscape. Nat. Rev. Urol. 15, 596–597 (2018).

    Article  CAS  PubMed  Google Scholar 

  145. Gourd, E. EMA restricts use of anti-PD-1 drugs for bladder cancer. Lancet Oncol. 19, e341 (2018).

    Article  PubMed  Google Scholar 

  146. Balar, A. V. et al. Abstract CT112: durvalumab + tremelimumab in patients with metastatic urothelial cancer [abstract]. Cancer Res. 78 (Suppl. 13), CT112 (2018).

    Google Scholar 

  147. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02516241 (2019).

  148. [No authors listed]. Companies scaling back IDO1 inhibitor trials. Cancer Discov. 8, OF5 (2018).

  149. Gandhi, L. et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med. 378, 2078–2092 (2018).

    Article  CAS  PubMed  Google Scholar 

  150. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02853305 (2018).

  151. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02807636 (2019).

  152. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02546661 (2019).

  153. Peyton, C. C. et al. Downstaging and survival outcomes associated with neoadjuvant chemotherapy regimens among patients treated with cystectomy for muscle-invasive bladder cancer. JAMA Oncol. 4, 1535–1542 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Powles, T. et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS) [abstract]. J. Clin. Oncol. 36 (Suppl. 15), 4506 (2018).

    Article  Google Scholar 

  155. Necchi, A. et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase II study. J. Clin. Oncol. 36, 3353–3360 (2018).

    Article  CAS  PubMed  Google Scholar 

  156. Strauss, J. et al. Safety and activity of M7824, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with HPV associated cancers [abstract]. J. Clin. Oncol. 36 (Suppl. 15), 3007 (2018).

    Article  Google Scholar 

  157. Challita-Eid, P. M. et al. Enfortumab vedotin antibody–drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res. 76, 3003–3013 (2016).

    Article  CAS  PubMed  Google Scholar 

  158. Rosenberg, J. E. et al. EV-201 study: a single-arm, open-label, multicenter study of enfortumab vedotin for treatment of patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor therapy. J. Clin. Oncol. 36 (Suppl. 15), TPS4590 (2018).

    Article  Google Scholar 

  159. US Food and Drug Administration. FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-erdafitinib-metastatic-urothelial-carcinoma (updated 12 Apr 2019).

  160. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03474107 (2019).

  161. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03390504 (2019).

  162. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).

    Article  CAS  PubMed  Google Scholar 

  163. Coley, W. B. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin. Orthop. Relat. Res. 262, 3–11 (1991).

    Article  Google Scholar 

  164. Bulkley, G. B., Cohen, M. H., Banks, P. M., Char, D. H. & Ketcham, A. S. Long-term spontaneous regression of malignant melanoma with visceral metastases. Report of a case with immunologic profile. Cancer 36, 485–494 (1975).

    CAS  PubMed  Google Scholar 

  165. Weber, J. et al. Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2’-deoxycytidine. Cancer Res. 54, 1766–1771 (1994).

    CAS  PubMed  Google Scholar 

  166. Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).

    Article  CAS  PubMed  Google Scholar 

  167. Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).

    Article  CAS  PubMed  Google Scholar 

  168. Simons, M., Gordon, E. & Claesson-Welsh, L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat. Rev. Mol. Cell Biol. 17, 611–625 (2016).

    Article  CAS  PubMed  Google Scholar 

  169. Moch, H., Humphrey, P. A., Ulbright, T. M. & Reuter, V. E. WHO Classification of Tumours of the Urinary System and Male Genital Organs 4th edn (International Agency for Research on Cancer, Lyon, 2016).

  170. Centre for Evidence-Based Medicine. Oxford Centre for Evidence-based Medicine – levels of evidence (March 2009). CEBM https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009 (2009).

  171. Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).

    Article  CAS  PubMed  Google Scholar 

  172. Petrylak, D. P. et al. Atezolizumab (MPDL3280A) monotherapy for patients with metastatic urothelial cancer. JAMA Oncol. 4, 537 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

M.L. and A.F. are supported by the National Institute for Health Research and the University College London Hospitals Biomedical Research Centre (no grant numbers apply). M.L. receives funding from Cancer Research UK, the Rosetrees Trust and a Bristol-Myers Squibb II-ON grant (no grant numbers apply).

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  1. Department of Oncology, University College London Hospital, London, UK

    Constantine Alifrangis, Ursula McGovern & Mark Linch

  2. Department of Pathology, University College London Hospital, London, UK

    Alex Freeman

  3. Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UK

    Thomas Powles

  4. Department of Oncology, University College London Cancer Institute, London, UK

    Mark Linch

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M.L. has received research funding from Bristol-Myers Squibb, AstraZeneca/MedImmune and Astellas, and has received consulting fees from Janssen Pharmaceuticals. T.P. receives research funding from AstraZeneca/MedImmune, Genentech/Roche and Novartis, and consulting fees from Genentech/Roche, Pfizer, GlaxoSmithKline and Merck. The other authors declare no competing interests.

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Glossary

Non-urothelial carcinomas

The minority of urothelial carcinomas that arise from cells other than urothelial cells, most commonly pure squamous cell carcinomas or pure adenocarcinomas.

Conventional urothelial carcinoma

The most common type of bladder carcinoma, arising from urothelial cells lining the bladder and urinary tract, also known as the transitional epithelium.

Urothelial carcinoma with divergent differentiation

Also known as variant urothelial carcinoma. A urothelial carcinoma with varying amounts of differentiation to other histological entities, of which 13 are currently recognized, including sarcomatoid and squamous differentiation.

Luminal

In gene expression studies, ‘luminal’ describes a group of bladder cancers expressing epithelial markers.

Basal

In gene expression studies, ‘basal’ describes a group of bladder cancers lacking epithelial markers but expressing markers of mesenchymal or sarcomatoid differentiation.

Liquid biopsies

The use of circulating (dynamic) tumour-derived nucleic acids to inform tumour-specific somatic mutations.

T cell exhaustion

A state of T cell dysfunction that exists in many chronic diseases and cancer due to prolonged antigen stimulation; defined by expression of inhibitory receptors and loss of effector function in T cells.

Lynch syndrome

Also known as hereditary non-polyposis colorectal cancer. An inherited autosomal dominant condition that increases the risk of certain solid tumours such as colorectal and endometrial cancer; caused by mutations in DNA mismatch repair genes, such as MLH1 and MSH2.

Keratinizing squamous metaplasia

A precancerous condition of squamous cells.

Bilharzial-associated bladder cancer

Bladder cancer arising following chronic infection with schistosomiasis (infection also known as snail fever and bilharzia).

Leiomyosarcoma

A malignant tumour arising from smooth muscle.

Angiosarcoma

A malignant tumour arising from blood vessels.

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Alifrangis, C., McGovern, U., Freeman, A. et al. Molecular and histopathology directed therapy for advanced bladder cancer. Nat Rev Urol 16, 465–483 (2019). https://doi.org/10.1038/s41585-019-0208-0

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