Circulating Plasma and Urine Tumor DNA in Non–muscle-invasive Bladder Cancer: A Promising Biomarker to Guide Therapeutic Intensification

Circulating tumor DNA (ctDNA) in plasma and urine is a promising noninvasive biomarker in non–muscle-invasive bladder cancer (NMIBC), with potential implications for early detection, risk stratification, and therapeutic decisions. Plasma ctDNA is detectable in 52% of Ta and 85% of T1 tumors, and a higher molecular tumor burden index is correlated with shorter disease-free survival. Retrospective analyses using personalized assays have identified ctDNA months before clinical recurrence, particularly in the bacillus Calmette-Guérin–unresponsive setting, which can thus guide timely interventions. Urinary tumor DNA (utDNA) profiling detected 69% of high-risk cases and predicted lower 6-mo complete response and 18-mo event-free survival rates. In addition, utDNA often precedes clinical or radiographic recurrence and correlates with tumor size, grade, and progression risk, and DNA methylation-based scores can further refine prognostic stratification. Collectively, ctDNA and utDNA represent complementary tools for early detection, risk-adapted surveillance, and personalized management in NMIBC, with potential to guide therapeutic intensification strategies. Patient summary: Blood and urine tests for tumor DNA can add information for identifying patients with non–muscle-invasive bladder cancer at high risk of disease recurrence or progression. These test results could be added to tools for treatment decision-making to target the patients who are most likely to benefit from intensified treatment.