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  • Review Article
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Molecular and histopathology directed therapy for advanced bladder cancer

Nature Reviews Urology volume 16, pages 465–483 (2019)Cite this article

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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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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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