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Molecular biomarkers of progression in non-muscle-invasive bladder cancer — beyond conventional risk stratification

  • Review Article
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From Nature Reviews Urology

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Abstract

The global incidence of bladder cancer is more than half a million diagnoses each year. Bladder cancer can be categorized into non-muscle-invasive bladder cancer (NMIBC), which accounts for ~75% of diagnoses, and muscle-invasive bladder cancer (MIBC). Up to 45% of patients with NMIBC develop disease progression to MIBC, which is associated with a poor outcome, highlighting a clinical need to identify these patients. Current risk stratification has a prognostic value, but relies solely on clinicopathological parameters that might not fully capture the complexity of disease progression. Molecular research has led to identification of multiple crucial players involved in NMIBC progression. Identified biomarkers of progression are related to cell cycle, MAPK pathways, apoptosis, tumour microenvironment, chromatin stability and DNA-damage response. However, none of these biomarkers has been prospectively validated. Reported gene signatures of progression do not improve NMIBC risk stratification. Molecular subtypes of NMIBC have improved our understanding of NMIBC progression, but these subtypes are currently unsuitable for clinical implementation owing to a lack of prospective validation, limited predictive value as a result of intratumour subtype heterogeneity, technical challenges, costs and turnaround time. Future steps include the development of consensus molecular NMIBC subtypes that might improve conventional clinicopathological risk stratification. Prospective implementation studies of biomarkers and the design of biomarker-guided clinical trials are required for the integration of molecular biomarkers into clinical practice.

Key points

  • A thorough understanding of molecular mechanisms that drive disease progression is crucial to improve non-muscle invasive bladder cancer (NMIBC) risk stratification.

  • Independent genomic and transcriptomic biomarkers of progression have been reported and hold the potential to improve risk stratification, but lack prospective validation.

  • One gene signature of progression (12-gene PCR panel) was prospectively validated, but this signature did not improve conventional risk stratification.

  • Transcriptomic molecular subtyping could be a strategy for predicting NMIBC progression and might also provide molecular targets for precision medicine approaches.

  • Future investigations should explore mechanisms underlying NMIBC progression after BCG treatment, as the current guideline-recommended treatment for patients with BCG-unresponsive tumours is a radical cystectomy, but a subset of patients might be candidates for alternative bladder-sparing therapies.

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Fig. 1: Overview of genes and mechanisms associated with progressive disease in non-muscle-invasive bladder cancer.
Fig. 2: Transcriptomic subtypes in non-muscle invasive bladder cancer.

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Acknowledgements

The authors would like to thank S. Meertens-Gunput, M. Udo and C. Niehot from the Erasmus MC Medical Library for their assistance in the literature search, and F. Khoraminia for conceptualizing figures.

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  1. These authors contributed equally: Mitchell Olislagers, Florus C. de Jong.

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  1. Department of Urology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

    Mitchell Olislagers, Florus C. de Jong, Vera C. Rutten, Joost L. Boormans, Tokameh Mahmoudi & Tahlita C. M. Zuiverloon

  2. Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands

    Tokameh Mahmoudi

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Contributions

M.O., F.C.D.J. and V.C.R. researched data for the article. T.C.M.Z., M.O. and F.C.D.J. contributed substantially to discussion of the content. M.O. and F.C.D.J. wrote the article. T.C.M.Z., M.O., F.C.D.J., J.L.B. and T.M. reviewed and/or edited the manuscript before submission.

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Competing interests

T.M. has a research collaboration with HUB Organoids, Gilead and Viiv. J.L.B. receives consultancy fees (all paid to Erasmus MC) from Janssen, BMS, AstraZeneca, Merck AG/Pfizer, MSD and Bayer. He also has research collaborations with Merck AG/Pfizer, MSD, Janssen, and VitroScan and has done book writing for Astellas. T.C.M.Z. has research collaborations with Vitroscan, HUB Organoids and Valar Labs. The other authors declare no competing interests.

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Olislagers, M., de Jong, F.C., Rutten, V.C. et al. Molecular biomarkers of progression in non-muscle-invasive bladder cancer — beyond conventional risk stratification. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-024-00914-7

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