We developed UroScout, a high volume (up to 100 mL) urine tumor DNA assay detecting mutations in 25 urothelial cancer associated genes. The assay demonstrated state-of-the-art sensitivity in detecting urothelial cancer and its recurrence in an all-comers urothelial cancer cohort with in-mail collection.
We analyzed a total of 497 urine samples from 281 patients, using UroScout to look for somatic alterations indicative of cancer. The assay achieved a sensitivity of 100% for ≥T1 and carcinoma in situ bladder cancer, 94% for Ta bladder cancer, 92% for upper tract urothelial cancer (UTUC), and 100% for ≥T1 or high grade UTUC in blinded analysis.
High-grade, muscle-invasive, and carcinoma in situ tumors showed enrichment of TP53 mutations and depletion of FGFR3 mutations. Consequently, these mutations were prognostic for overall survival and time to recurrence after TURBT. To further investigate utDNA as a potential predictive biomarker for bladder-preserving treatment, we studied 10 patients who provided a post-TURBT urine sample before cystectomy. utDNA fraction was correlated with pathological findings from cystectomy tissue: the three patients with the lowest utDNA fractions (< 3%) had pT0 (n=2) or low grade Ta. The remaining seven patients with utDNA fractions >3% had T≥1 or Tis in the cystectomy specimen.
We also demonstrate that utDNA offers a non-invasive approach to detect underlying Lynch syndrome (LS) and high tumor mutational burden in UC. In theory, this information could be tested as a tool to guide decisions on immunotherapy. utDNA may also provide a sensitive approach for UC screening in LS, and the 10-25% lifetime risk of UC in LS mutation carriers likely justifies this.1 We have an ongoing clinical trial utilizing the UroScout assay for UC screening in LS individuals (NCT06218433).
As a part of UC diagnostics and surveillance, millions of cystoscopies are performed annually, but only 10% result in a cancer diagnosis.2 The procedure itself leads to unpleasant post-operative symptoms, in addition to the burden on healthcare systems. Therefore, the performance of contemporary utDNA assays calls for consideration of when utDNA testing becomes a viable method for avoiding cystoscopies.
Our study introduces a three-tier risk classification for urine DNA analysis, based on the level of evidence for utDNA using the UroScout assay:
- Low risk: A sensitive utDNA assay can identify patients with a very low likelihood of UC allowing them to avoid cystoscopy.
- Medium risk: Cystoscopy required for further evaluation.
- High risk: A stringent utDNA threshold can be used to direct patients to operating room procedures.
utDNA testing has also the ability to identify clinically undetectable or pre-malignant tumors, and utDNA-informed cystoscopies can detect more cancers.3,4 Adoption of utDNA testing in the clinic could eliminate most diagnostic cystoscopies while providing valuable prognostic and predictive biomarkers for targeted therapies.5
In conclusion, a non-invasive, cost-effective urine test that detects cancer alterations offers an alternative to invasive cystoscopy exams, helps reduce the workload of urological units, improves patients’ quality of life, expedites access to treatment, offers opportunities for precision cancer medicine, and identifies undiagnosed cancer syndromes. These findings are currently being validated in the international multicenter UROSCOUT-1 study, where patients collect urine samples at home and mail them to the laboratory before undergoing cystoscopy (NCT06310759).
Written by: Jussi Nikkola,1,2,3 Lauri Ryyppö,1 Juuso Vuorinen,1 Heini Kallio,1 Hanna Selin,1 Pyry Jämsä,2 Jonne Åkerla,2 Tuomo Virtanen,1 Tarmo Pekkarinen,2 Antti Kaipia,2 Johanna Pulkkinen,4 Gillian Vandekerkhove,3 David C. Müller,3 Alexander W. Wyatt,3 Peter C. Black,3 Matti Nykter,1 Thea Veitonmäki,2 Matti Annala1
- Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland
- Department of Urology, Tampere University Hospital, Tampere, Finland
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
- Department of Pathology, Fimlab Laboratories, Tampere, Finland
References:
- Møller P, Seppälä T, Bernstein I, Holinski-Feder E, Sala P, Evans DG, et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: First report from the prospective Lynch syndrome database. Gut 2017;66:464–72.
- 2. Woldu SL, Ng CK, Loo RK, Slezak JM, Jacobsen SJ, Tan WS, et al. Evaluation of the New American Urological Association Guidelines Risk Classification for Hematuria. J Urol 2021;205:1387–93.
- Hosen MI, Sheikh M, Zvereva M, Scelo G, Forey N, Durand G, et al. Urinary TERT promoter mutations are detectable up to 10 years prior to clinical diagnosis of bladder cancer: Evidence from the Golestan Cohort Study. EBioMedicine 2020;53:102643.
- van der Aa MNM, Steyerberg EW, Bangma C, van Rhijn BWG, Zwarthoff EC, van der Kwast TH. Cystoscopy revisited as the gold standard for detecting bladder cancer recurrence: diagnostic review bias in the randomized, prospective CEFUB trial. J Urol 2010;183:76–80.
- Catto JWF, Tran B, Rouprêt M, Gschwend JE, Loriot Y, Nishiyama H, et al. Erdafitinib in BCG-treated high-risk non-muscle-invasive bladder cancer. Ann Oncol 2024;35:98–106.