Urinary Tumor <scp>DNA</scp> to Identify Candidates for Repeat Transurethral Resection in Non‐Muscle‐Invasive Bladder Cancer

Repeat transurethral resection of bladder tumor (re-TURBT) is commonly recommended for patients with non-muscle-invasive bladder cancer (NMIBC) with high-risk features, although many individuals may undergo unnecessary procedures that increase morbidity without clear benefit. Urinary tumor DNA (utDNA) has emerged as a promising biomarker, and we evaluated the performance of a multidimensional utDNA assay (utLIFE) in this context. In a retrospective cohort of 161 patients who underwent re-TURBT between May 2020 and May 2025, urine samples collected 2-6 weeks after initial TURBT were analyzed using utLIFE, which integrates shallow whole-genome sequencing and targeted sequencing of 155 genes with machine learning-based classification. Residual tumor was identified in 35% of patients, and utLIFE demonstrated high diagnostic accuracy, with sensitivity of 80.7%, specificity of 96.2%, and overall accuracy of 90.7%, markedly outperforming urine cytology. A positive utLIFE result was the strongest independent predictor of residual disease (OR = 77.5, 95% CI: 22.4-268.2, p < 0.001). During a median follow-up of 32.5 months, recurrence occurred in 20.5% of patients; recurrence was defined as urothelial tumor relapse within the urinary tract and did not include distant metastasis. utLIFE positivity was significantly associated with shorter recurrence-free survival (HR = 16.4, 95% CI: 2.7-101.8, p = 0.003). Longitudinal testing further revealed that utDNA positivity frequently preceded cystoscopic evidence of recurrence by several months. These findings highlight the strong diagnostic and prognostic value of utDNA in identifying residual disease and predicting recurrence, supporting its potential role in refining postoperative management strategies for NMIBC.