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Urine biomarkers in bladder cancer — current status and future perspectives

Nature Reviews Urology volume 20, pages 597–614 (2023)Cite this article

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Abstract

Urine markers to detect bladder cancer have been the subject of research for decades. The idea that urine — being in continuous contact with tumour tissue — should provide a vector of tumour information remains an attractive concept. Research on this topic has resulted in a complex landscape of many different urine markers with varying degrees of clinical validation. These markers range from cell-based assays to proteins, transcriptomic markers and genomic signatures, with a clear trend towards multiplex assays. Unfortunately, the number of different urine markers and the efforts in research and development of clinical grade assays are not reflected in the use of these markers in clinical practice, which is currently limited. Numerous prospective trials are in progress with the aim of increasing the quality of evidence about urinary biomarkers in bladder cancer to achieve guideline implementation. The current research landscape suggests a division of testing approaches. Some efforts are directed towards addressing the limitations of current assays to improve the performance of urine markers for a straightforward detection of bladder cancer. Additionally, comprehensive genetic analyses are emerging based on advances in next-generation sequencing and are expected to substantially affect the potential application of urine markers in bladder cancer.

Key points

  • Urine cytology remains the only urine marker for bladder cancer detection recommended in guidelines as an adjunct to cystoscopy, although the sensitivity of this technique for the detection of low-grade tumours is limited, and numerous other markers are available.

  • Single protein-based markers such as nuclear matrix protein 22 (NMP22) and bladder tumour antigen (BTA) are susceptible to interference by benign conditions (such as inflammation), which lead to increased concentration of these proteins in urine.

  • The development of commercially available markers in the past decade has focused on assays based on multiplex protein, mRNA and DNA.

  • Non-coding RNA forms (microRNA, long non-coding RNA, circular RNA) and extracellular vesicles are growing areas of research on novel urinary biomarkers.

  • Genomic markers provide molecular insight into tumour biology and will expand the future application of biomarkers beyond diagnosis and surveillance.

  • The main obstacle to the implementation of urine markers in clinical practice is the lack of high-quality evidence from prospective randomized trials.

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Fig. 1: Biomarkers detectable in urine.

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Acknowledgements

M.M. (MA 9796/1-1) is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation).

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Authors and Affiliations

  1. Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

    Moritz Maas & Peter C. Black

  2. Department of Urology, University of Tübingen, Tübingen, Germany

    Moritz Maas

  3. Clinical Trials Unit Studienpraxis Urologie, Nürtingen, Germany

    Tilman Todenhöfer

  4. Eberhard-Karls-University, Tübingen, Germany

    Tilman Todenhöfer

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M.M. researched data for the article. All authors contributed substantially to discussion of the content. M.M. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Peter C. Black.

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P.C.B. has consulted for AbbVie, Astellas Pharma, AstraZeneca, Bayer, Biosyent, Bristol-Myers Squibb, EMD-Serono, Ferring, Janssen Oncology, Merck, Nanology, Nonagen, Pfizer, Prokarium, Protara, QED, Roche Canada, Sanofi Canada, STIMIT, Urogen Pharma and Verity, has received research funding from iProgen, and shares a patent with Veracyte. M.M. is an adviser for VitaDx. T.T. is a speaker/adviser for Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, Roche and Sanofi.

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Maas, M., Todenhöfer, T. & Black, P.C. Urine biomarkers in bladder cancer — current status and future perspectives. Nat Rev Urol 20, 597–614 (2023). https://doi.org/10.1038/s41585-023-00773-8

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