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  • Review Article
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Precision medicine for urothelial bladder cancer: update on tumour genomics and immunotherapy

Nature Reviews Urology volume 15, pages 92–111 (2018)Cite this article

Subjects

Key Points

  • Mutations in the DNA repair pathway genes ERCC2, FANCC, ATM, and RB1 correlate with complete pathological response to neoadjuvant chemotherapy and should be further evaluated for their utility in clinical decision making

  • Gene mutations, copy number variations, and rearrangements in receptor tyrosine kinase (RTK)– MAPK and PI3K–MTOR pathways are found in ∼70% of bladder tumours; recent studies show that these alterations, in addition to having prognostic significance, can be predictive of response

  • Several ongoing, large pan-cancer trials match patients to a targeted agent (or agents) on the basis of molecular and genetic tumour features, testing for increased efficacy of this personalized medicine approach

  • Immune checkpoint inhibitors that target programmed cell death protein 1 (PD1) and its ligand PDL1 show promise in clinical trials and are approved for bladder cancer treatment; further research is required to personalize the use of these agents

  • Personalized peptide vaccines that are created on the basis of patient leukocyte antigen immune subtypes are currently being tested in clinical trials

Abstract

Effective management of advanced urothelial bladder cancer is challenging. New discoveries that improve our understanding of molecular bladder cancer subtypes have revealed numerous potentially targetable genomic alterations and demonstrated the efficacy of treatments that harness the immune system. These findings have begun to change paradigms of bladder cancer therapy. For example, DNA repair pathway mutations in genes such as ERCC2, FANCC, ATM, RB1, and others can predict responses to neoadjuvant platinum-based chemotherapies and to targeted therapies on the basis of mutation status. Furthermore, an increasing number of pan-cancer clinical trials (commonly referred to as basket or umbrella trials) are enrolling patients on the basis of molecular and genetic predictors of response. These studies promise to provide improved insight into the true utility of personalized medicine in the treatment of bladder cancer and many other cancer types. Finally, therapies that modulate immune responses have shown great benefit in many cancer types. Several immune checkpoint inhibitors that target programmed cell death protein 1 (PD1), its ligand PDL1, and cytotoxic T lymphocyte-associated protein 4 (CTLA4) have already been approved for use in bladder cancer, representing the most important change to the urological oncologist's tool-kit in over a decade. These advances also provide opportunities for personalization of bladder cancer therapy.

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Figure 1: Potentially actionable mutations are frequent in bladder cancer.
Figure 2: Personalized immunotherapy for the treatment of bladder cancer.

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Acknowledgements

The authors thank R. T. Jones for his significant input and helpful suggestions to this work and all members of the Theodorescu laboratory.

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Authors and Affiliations

  1. Department of Surgery (Urology), University of Colorado, 12631 E. 17th Avenue, Aurora, 80045, Colorado, USA

    Kenneth M. Felsenstein & Dan Theodorescu

  2. Department of Pharmacology, University of Colorado, 12800 E. 19th Avenue, Aurora, 80045, Colorado, USA

    Kenneth M. Felsenstein & Dan Theodorescu

  3. University of Colorado Medical Scientist Training Program (MSTP), 12631 E. 17th Avenue, Aurora, 80045, Colorado, USA

    Kenneth M. Felsenstein

  4. Department of Molecular, Cellular, and Developmental Biology, University of Colorado, 347 UCB Boulder, 80309, Colorado, USA

    Kenneth M. Felsenstein

  5. University of Colorado Comprehensive Cancer Center, 13001 East 17th Place, Aurora, 80045, Colorado, USA

    Dan Theodorescu

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K.F. researched data for the article. Both authors made substantial contributions to discussion of the manuscript content and wrote the article. D.T. reviewed and/or edited the manuscript before submission.

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Correspondence to Dan Theodorescu.

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Competing interests

D.T. is co-founder of Aurora Oncology and has stock options in and is on the scientific advisory boards of Machavert, Precision Profile, and Urogen. D.T. also holds intellectual property (through the University of Colorado) that has been licensed to NantHealth. K.M.F. declares no competing interests.

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Felsenstein, K., Theodorescu, D. Precision medicine for urothelial bladder cancer: update on tumour genomics and immunotherapy. Nat Rev Urol 15, 92–111 (2018). https://doi.org/10.1038/nrurol.2017.179

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