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Circulating and urinary tumour DNA in urothelial carcinoma — upper tract, lower tract and metastatic disease

Nature Reviews Urology volume 20, pages 406–419 (2023)Cite this article

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An Author Correction to this article was published on 22 May 2023

This article has been updated

Abstract

Precision medicine has transformed the way urothelial carcinoma is managed. However, current practices are limited by the availability of tissue samples for genomic profiling and the spatial and temporal molecular heterogeneity observed in many studies. Among rapidly advancing genomic sequencing technologies, non-invasive liquid biopsy has emerged as a promising diagnostic tool to reproduce tumour genomics, and has shown potential to be integrated in several aspects of clinical care. In urothelial carcinoma, liquid biopsies such as plasma circulating tumour DNA (ctDNA) and urinary tumour DNA (utDNA) have been investigated as a surrogates for tumour biopsies and might bridge many shortfalls currently faced by clinicians. Both ctDNA and utDNA seem really promising in urothelial carcinoma diagnosis, staging and prognosis, response to therapy monitoring, detection of minimal residual disease and surveillance. The use of liquid biopsies in patients with urothelial carcinoma could further advance precision medicine in this population, facilitating personalized patient monitoring through non-invasive assays.

Key points

  • Genomic profiling in urothelial carcinoma has enabled precision medicine to transform the management of this malignancy.

  • Liquid biopsies are non-invasive genomic assays that serve as surrogates for the primary tumour biopsy. In urothelial carcinoma, liquid biopsies include urinary tumour DNA (utDNA) and circulating tumour DNA (ctDNA).

  • Advances in genomic sequencing techniques have enabled researchers to detect utDNA and ctDNA at previously undetectable levels. Genomic profiling of the primary tumour facilitates the creation of bespoke utDNA and ctDNA panels for patients with urothelial carcinoma.

  • In urothelial carcinoma, utDNA and ctDNA are very promising in multiple areas of care including diagnosis, risk stratification and prognostication, monitoring of response to systemic therapy, detection of minimal residual disease and surveillance.

  • Results from different studies have shown that utDNA and ctDNA outperform conventional markers for diagnosis and surveillance, showing promise for the integration of these factors into management paradigms. For example, utDNA and ctDNA consistently outperform urine cytology, and the detection of these markers identifies recurrence seen through cross-sectional imaging, holding implications for early and personalized systemic therapies.

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Fig. 1: Cell-free DNA assays in urothelial carcinoma.

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Authors and Affiliations

  1. Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Kyle M. Rose, Heather L. Huelster, Philippe E. Spiess, Rohit K. Jain & Roger Li

  2. Department of Urology, Northwestern University, Chicago, IL, USA

    Joshua J. Meeks

  3. Department of Hematology/Oncology, Weill-Cornell Medicine, New York, NY, USA

    Bishoy M. Faltas

  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Guru P. Sonpavde

  5. Department of Urology, Baylor College of Medicine, Houston, TX, USA

    Seth P. Lerner

  6. Foundation Medicine, Inc, Cambridge, MA, USA

    Jeffrey S. Ross

  7. Departments of Urology and Pathology, Upstate Medical University, Syracuse, NY, USA

    Jeffrey S. Ross

  8. Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Philippe E. Spiess & G. Daniel Grass

  9. Department of Urology, MD Anderson Cancer Center, Houston, TX, USA

    Ashish M. Kamat

  10. Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Aram Vosoughi

  11. Department of Tumour Biology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Liang Wang

  12. Department of Biostatistics/Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Xuefeng Wang

  13. Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Roger Li

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Contributions

K.M.R., H.L.H., P.E.S., R.K.J. and R.L. researched data for the article. K.M.R., H.L.H., J.J.M., B.M.F., S.P.L., P.E.S., R.K.J. and R.L. contributed substantially to discussion of the content. K.M.R., H.L.H., B.M.F., S.P.L., J.S.R., P.E.S., G.D.G., R.K.J., A.V. and R.L. wrote the article. K.M.R., H.L.H., J.J.M., B.M.F., G.P.S., S.P.L., J.S.R., G.D.G., A.M.K., A.V., L.W., X.W. and R.L. reviewed and/or edited the manuscript before submission.

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Correspondence to Roger Li.

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Competing interests

K.M.R. is a consultant for Urogen Inc. J.J.M. is a consultant for Merck, AstraZeneca, Ferring, Incyte, Janssen, Foundation Medicine, BMS, UroGen, receives research funding from Epizyme, Hope Foundation, VHA, NIH, DoD; receives compensation for talks/educational courses from AUA, OncLive, Olympus, UroToday; clinical trials: SWOG, Genentech, Merck, AstraZeneca, Incyte; has two patents for T1 and TCGA classifier. B.M.F. is on the advisory board of Guardant, Janssen, Gilead, Merck, Immunomedics/Gilead, QED therapeutics; is a consultant for QED therapeutics, Boston gene; has patent royalties for Immunomedics/Gilead; receives honoraria from Urotoday; receives research support from Eli-Lilly. G.P.S. is an advisory board member for BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Infinity Pharmaceuticals, Lucence Health, IMV; receives research support from Sanofi, Astrazeneca, Gilead, QED, Lucence, Predicine, BMS, EMD Serono, Jazz Therapeutics; is in the steering committee of the following studies: BMS, Bavarian Nordic, Seattle Genetics, QED, G1 Therapeutics (all unpaid), and Astrazeneca, EMD Serono, Debiopharm (paid); is on the data safety monitoring committee of Mereo; his spouse is employed by Myriad; travel costs: BMS, Astrazeneca; had writing/editor fees from Uptodate; is the Editor of Elsevier Practice Update Bladder Cancer Center of Excellence; receives speaking fees from Physicians Education Resource (PER), Onclive, Research to Practice, Medscape, Cancer Network, Masters Lecture Series (MLS). S.P.L. is a consultant/ advisory board member for Aura Bioscience, BMS, C2iGenomics, FerGene, Genentech, Merck, Pfizer/EMD Serono, Stimit, UroGen, Vaxiion, Verity; clinical trials: Endo, FKD, JBL (SWOG), Genentech (SWOG), QED Therapeutics, UroGen, Vaxiion, Viventia; has a patent for TCGA classifier; receives honoraria from Annenberg, Clinical Care Options, Grand Rounds Urology, Ology, UroToday. J.S.R. is an employee and equity holder in Foundation Medicine; is a consultant and equity holder in Tango Therapeutics and Celsius Therapeutics. P.E.S. is the NCCN bladder and penile cancer panel vice chair (leadership position, non-financially incentivized). R.K.J. is an advisory board member for Pfizer; is in the speakers bureau of Astellas/Seattle Genetics. A.M.K. is a consultant for Arquer Diagnostics, Asieris, Biological Dynamics, Bristol Myers Squibb, CG Oncology, H3 Biomedicine/Eisai, Engene, FerGene, Imagin Medical, Janssen, Medac, Merck, Photocure, ProTara, Seattle Genetics, Sessen Bio, Theralase, US Biotest, Urogen Inc, Roche, TMC Innovation; receives grants/research support from Adolor, BMS, FKD Industries, FerGene, Heat Biologics, Merck, Photocure, SWOG, NIH/GU SPORE, AIBCCR, Janssen (+ Taris), Seattle Genetics; has a patent for CyPRIT (Cytokine Predictors of Response to Intravesical Therapy); is a board member of the International Bladder Cancer Group (IBCG). R.L. receives research support from Predicine; Veracyte; CG Oncology; Valar labs; is in the clinical trial protocol committee of CG Oncology; is a scientific advisor/consultant for BMS, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology.

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Rose, K.M., Huelster, H.L., Meeks, J.J. et al. Circulating and urinary tumour DNA in urothelial carcinoma — upper tract, lower tract and metastatic disease. Nat Rev Urol 20, 406–419 (2023). https://doi.org/10.1038/s41585-023-00725-2

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