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

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.