Noninvasive Early Detection and Recurrence Monitoring for Non-Muscle-Invasive Bladder Cancer via Urine Tumor DNA: A Prospective Clinical Study

Abstract

Conventional approaches for the detection and surveillance of non-muscle invasive bladder cancer (NMIBC) remain invasive, burdensome, and costly. The utLIFE-UC assay, designed to identify mutations and large copy number variations in urine, has demonstrated high accuracy in detecting urothelial carcinoma. Here, we assessed its efficacy in early detection of NMIBC, identifying minimal residual disease, and monitoring recurrence. Among 108 consecutive NMIBC patients evaluated, utLIFE-UC exhibited a sensitivity of 90.5% in diagnosing NMIBC, with comparable performance in detecting both de novo and recurrent NMIBC. For patients undergoing repeat transurethral resection of bladder tumor (Re-TURBT), the assay accurately identified all cases with residual tumor, achieving a 100% negative predictive value. Positive postoperative utLIFE-UC results before the first follow-up cystoscopy predicted a higher risk of future relapse. A positive test result at any time following TURBT was correlated with poorer recurrence-free survival, whereas sustained negative test results indicated recurrence-free status. Moreover, utLIFE-UC could predict recurrence with a median lead time of 73.5 days prior to clinical confirmation. As the first prospective, longitudinal analysis of urinary tumor DNA in NMIBC, this study highlights the potential of utLIFE-UC to enable earlier recurrence detection and improve risk stratification, potentially obviating unnecessary Re-TURBT and surveillance cystoscopies.

Keywords

early detection / minimal residual disease / non-muscle-invasive bladder cancer / recurrence monitoring / urine tumor DNA

References

[1] J. Ferlay, M. Ervik, F. Lam, et al., Global Cancer Observatory: Cancer Today (International Agency for Research on Cancer, 2024), https://gco.iarc.who.int/today.

[2] M. Burger, J. W. Catto, G. Dalbagni, et al., “Epidemiology and Risk Factors of Urothelial Bladder Cancer,” European Urology 63, no. 2 (2013): 234–241.

[3] P. Gontero, A. Birtle, O. Capoun, et al., “European Association of Urology Guidelines on Non-Muscle-Invasive Bladder Cancer (TaT1 and Carcinoma In Situ)-A Summary of the 2024 Guidelines Update,” European Urology 86, no. 6 (2024): 531–549.

[4] J. Y. Teoh, A. M. Kamat, P. C. Black, et al., “Recurrence Mechanisms of Non-Muscle-Invasive Bladder Cancer-a Clinical Perspective,” Nature Reviews Urology 19, no. 5 (2022): 280–294.

[5] K. D. Sievert, B. Amend, U. Nagele, et al., “Economic Aspects of Bladder Cancer: What Are the Benefits and Costs?,” World Journal of Urology 27, no. 3 (2009): 295–300.

[6] P. S. Chauhan, K. Chen, R. K. Babbra, et al., “Urine Tumor DNA Detection of Minimal Residual Disease in Muscle-Invasive Bladder Cancer Treated With Curative-Intent Radical Cystectomy: A Cohort Study,” Plos Medicine 18, no. 8 (2021): e1003732.

[7] F. Soria, M. J. Droller, Y. Lotan, et al., “An Up-To-Date Catalog of Available Urinary Biomarkers for the Surveillance of Non-Muscle Invasive Bladder Cancer,” World Journal of Urology 36, no. 12 (2018): 1981–1995.

[8] K. Ng, A. Stenzl, A. Sharma, et al., “Urinary Biomarkers in Bladder Cancer: A Review of the Current Landscape and Future Directions,” Urologic Oncology 39, no. 1 (2021): 41–51.

[9] R. Chou, J. L. Gore, D. Buckley, et al., “Urinary Biomarkers for Diagnosis of Bladder Cancer: A Systematic Review and Meta-Analysis,” Annals of Internal Medicine 163, no. 12 (2015): 922–931.

[10] H. Huang, A. Liu, Y. Liang, et al., “A Urinary Assay for Mutation and Methylation Biomarkers in the Diagnosis and Recurrence Prediction of Non-Muscle Invasive Bladder Cancer Patients,” BMC Medicine 21, no. 1 (2023): 357.

[11] K. Yang, H. Hu, J. Wu, et al., “Letter to the Editor: Clinical Utility of Urine DNA for Noninvasive Detection and Minimal Residual Disease Monitoring in Urothelial Carcinoma,” Molecular Cancer 22, no. 1 (2023): 25.

[12] W. Ouyang, R. Xu, H. Yao, et al., “Urinary DNA Methylation-Based Risk Stratification Model to Triage Patients for Repeat Transurethral Resection of Bladder Tumors,” Clinical and Translational Medicine 14, no. 1 (2024): e1549.

[13] H. W. Herr, “Role of Repeat Resection in Non-Muscle-Invasive Bladder Cancer,” Journal of the National Comprehensive Cancer Network: JNCCN 13, no. 8 (2015): 1041–1046.

[14] M. G. K. Cumberbatch, B. Foerster, J. W. F. Catto, et al., “Repeat Transurethral Resection in Non-Muscle-Invasive Bladder Cancer: A Systematic Review,” European Urology 73, no. 6 (2018): 925–933.

[15] M. A. Zurkirchen, T. Sulser, A. Gaspert, et al., “Second Transurethral Resection of Superficial Transitional Cell Carcinoma of the Bladder: A Must Even for Experienced Urologists,” Urologia Internationalis 72, no. 2 (2004): 99–102.

[16] J. C. Dudley, J. Schroers-Martin, D. V. Lazzareschi, et al., “Detection and Surveillance of Bladder Cancer Using Urine Tumor DNA,” Cancer Discovery 9, no. 4 (2019): 500–509.

[17] H. Huang, A. Liu, Y. Liang, et al., “A Urinary Assay for Mutation and Methylation Biomarkers in the Diagnosis and Recurrence Prediction of Non-Muscle Invasive Bladder Cancer Patients,” BMC Medicine 21, no. 1 (2023): 357.

[18] J. T. Zhang, S. Y. Liu, W. Gao, et al., “Longitudinal Undetectable Molecular Residual Disease Defines Potentially Cured Population in Localized Non-Small Cell Lung Cancer,” Cancer Discovery 12, no. 7 (2022): 1690–1701.

[19] S. Mo, L. Ye, D. Wang, et al., “Early Detection of Molecular Residual Disease and Risk Stratification for Stage I to III Colorectal Cancer via Circulating Tumor DNA Methylation,” JAMA Oncology 9, no. 6 (2023): 770–778.

[20] A. Astram, A. Khadijah, P. Yuri, et al., “Effective Dose and Adverse Effects of Maintenance Bacillus Calmette-Gue'Rin in Intermediate and High Risk Non-Muscle Invasive Bladder Cancer: A Meta-Analysis of Randomized Clinical Trial,” Acta Medica Indonesiana 46, no. 4 (2014): 298–307.

[21] T. Austin, R. Robinson, D. Wilby, et al., “Day Case Primary Trans-Urethral Resection of Bladder Tumor (turbt) as Standard in a Single UK Centre. Should This be the New Norm?,” Journal of Clinical Urology 13, no. 4 (2020): 205141581989047.

RIGHTS & PERMISSIONS

2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.