Prognostic Value of Perioperative Circulating Tumor DNA in Pure Urothelial Carcinoma and Histological Subtypes of Bladder Cancer.

BACKGROUND AND OBJECTIVE: Pure urothelial carcinoma (UC) and histological subtypes (HS) in bladder cancer (BC) are associated with distinct pathological features and oncologic outcomes across disease stages. Circulating tumor DNA (ctDNA) is a promising perioperative biomarker, but its prognostic performance across histologic subtypes remains unclear. We evaluated the prognostic value of perioperative tumor-informed ctDNA in patients with pure UC and HS. METHODS: We analyzed a database of consecutive patients with BC who underwent radical cystectomy with available preoperative or postoperative ctDNA between 2021 and 2025. Patients were stratified into four groups according to histology status and ctDNA detectability at both preoperative and postoperative time points. Disease-free survival (DFS) was estimated using the Kaplan-Meier method and compared with log-rank tests. Associations between groups and DFS were evaluated using uni- and multivariable Cox regression analyses. KEY FINDINGS AND LIMITATIONS: Among 138 patients with preoperative ctDNA, negative ctDNA status was associated with significantly higher 24-mo DFS compared with positive ctDNA in both pure UC (89% vs 49%, p < 0.001) and HS (79% vs 43%, p = 0.012). Multivariable Cox regression confirmed positive preoperative ctDNA as an independent predictor of recurrence or death in pure UC (hazard ratio [HR] = 4.07, 95% confidence interval [CI] = 1.29-12.81, p = 0.020) and HS groups (HR = 3.99, 95% CI = 1.24-12.82, p = 0.023). Similarly, among 144 patients with postoperative ctDNA, negative ctDNA status predicted higher 24-mo DFS in pure UC (81% vs 30%, p < 0.001) and HS (66% vs 29%, p < 0.001), with positive postoperative ctDNA independently associated with disease recurrence or death in pure UC (HR = 4.38, 95% CI = 1.66-11.52, p < 0.01) and HS groups (HR = 4.52, 95% CI = 1.86-11.03, p < 0.001). Limitations include the retrospective design and relatively short follow-up. CONCLUSIONS AND CLINICAL IMPLICATIONS: Perioperative ctDNA is a robust biomarker with consistent prognostic value and can refine perioperative risk stratification in patients with BC with pure UC or HS.