The evolving landscape and clinical utility of circulating tumor DNA across the spectrum of urothelial carcinoma: A systematic review and framework for clinical integration

Abstract Urothelial carcinoma (UC) is a significant global health challenge with heterogeneous clinical presentations from nonmuscle‐invasive to metastatic disease. Circulating tumor DNA (ctDNA) has emerged as promising noninvasive biomarker for risk classification, treatment monitoring and recurrence detection. Systematic searches of PubMed identified 390 articles; 61 met inclusion criteria for plasma ctDNA analysis in UC. Independent dual screening, Joanna Briggs Institute assessment, and stratification by disease stage (nonmuscle‐invasive bladder cancer [NMIBC], muscle‐invasive bladder cancer [MIBC], metastatic urothelial carcinoma [mUC], and upper tract urothelial carcinoma [UTUC]) were performed. Simple pooled detection rates were calculated. ctDNA detection rates increased with disease advancement: NMIBC (53.2%), MIBC (47.6%), mUC (85.9%), and UTUC (50.5%). TERT promoter mutations predominated, followed by genomic alterations in TP53 . Assays varied widely across studies with next‐generation sequencing (22.4%) being most common. In NMIBC, ctDNA enabled risk stratification and recurrence detection. In MIBC, IMvigor010 demonstrated patients with positive ctDNA had worse overall survival (OS) (hazard ratio, 6.3); IMvigor011 showed that patients with negative ctDNA managed without adjuvant therapy had excellent outcomes (98% OS at 18 months). Post‐surgical monitoring achieved 94%–100% sensitivity for recurrence with 96‐ to 131‐day lead times. In mUC, KEYNOTE‐361 showed ctDNA reductions at 6 weeks predicted improved OS ( p < 10 –4 ), whereas fibroblast growth factor receptor 3 mutations tracked resistance. Preoperative ctDNA fraction >2% in UTUC predicted worse OS ( p < 10 –3 ). ctDNA is a critical precision oncology tool in UC management, with TERT mutations as the predominant alteration. Stage‐tailored strategies are emerging, including risk assessment in NMIBC, refining adjuvant decisions in MIBC, and treatment monitoring in mUC. Integration of ctDNA‐guided approaches should proceed alongside prospective validation to ensure safe and effective adoption.