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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\u2010invasive bladder cancer [NMIBC], muscle\u2010invasive 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%).\n                    <jats:italic>TERT<\/jats:italic>\n                    promoter mutations predominated, followed by genomic alterations in\n                    <jats:italic>TP53<\/jats:italic>\n                    . Assays varied widely across studies with next\u2010generation 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\u2010surgical monitoring achieved 94%\u2013100% sensitivity for recurrence with 96\u2010 to 131\u2010day lead times. In mUC, KEYNOTE\u2010361 showed ctDNA reductions at 6 weeks predicted improved OS (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0&lt;\u00a010\n                    <jats:sup>\u20134<\/jats:sup>\n                    ), whereas fibroblast growth factor receptor 3 mutations tracked resistance. Preoperative ctDNA fraction &gt;2% in UTUC predicted worse OS (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0&lt;\u00a010\n                    <jats:sup>\u20133<\/jats:sup>\n                    ). ctDNA is a critical precision oncology tool in UC management, with TERT mutations as the predominant alteration. Stage\u2010tailored strategies are emerging, including risk assessment in NMIBC, refining adjuvant decisions in MIBC, and treatment monitoring in mUC. Integration of ctDNA\u2010guided approaches should proceed alongside prospective validation to ensure safe and effective adoption.\n                  <\/jats:p>","DOI":"10.1002\/cncr.70448","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T16:56:03Z","timestamp":1781024163000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The evolving landscape and clinical utility of circulating tumor DNA across the spectrum of urothelial carcinoma: A systematic review and framework for clinical integration"],"prefix":"10.1002","volume":"132","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7110-3527","authenticated-orcid":false,"given":"Sanchit","family":"Mehta","sequence":"first","affiliation":[{"name":"B.J. 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