Preoperative ctDNA Predicts Upstaging and Recurrence in High-Risk Non-Muscle-Invasive Bladder Cancer Undergoing Radical Cystectomy.

Abstract

To assess if precystectomy circulating tumor DNA (ctDNA) status predicts recurrence-free survival (RFS) and correlates with disease upstaging in patients with high-risk non-muscle-invasive bladder cancer (NMIBC) undergoing radical cystectomy (RC). A bicenter analysis of patients with high-risk NMIBC (N0M0) who underwent RC between 2021 and 2023 and had prospective serial tumor-informed ctDNA analyses performed before and after RC. The molecular residual disease (MRD) window was defined as the initial 90 days after RC. The primary end point RFS was analyzed with the Kaplan-Meier method. A total of 56 patients with NMIBC with a median follow-up time of 14 months (IQR 6-18) and a median age of 67 years (IQR 62-72) were included; among them, 45 patients had pre-RC ctDNA status available, 15 patients (33.3%) had detectable, and 30 patients (66.7%) had undetectable ctDNA. Twelve patients had Bacillus Calmette-Guérin unresponsive disease (26.8%). The most common pre-RC pathology was T1HG (60%) and T1HG + carcinoma in situ (28.9%). Detectable pre-RC ctDNA were more commonly upstaged (≥pT2) 66.7% vs 13.3%, and 33.3% vs 0% had pN+ (odds ratio = 13.0 [3.13-66.1], <i>P</i> < .001). Among patients with undetectable ctDNA, 20% had pT0 and none had ≥ pT3 or pN+ disease. On survival analysis, detectable pre-RC ctDNA had worse RFS than undetectable ctDNA (log-rank, <i>P</i> < .0001, HR = 11 [2.27-53.8]), with worse 6-month RFS of 64.3% [43.5-95] vs 100% and 12-month RFS of 38.6% [17.1-87.2] vs 95.7% [87.7-100], respectively. Detectable MRD ctDNA was associated with worse RFS than undetectable ctDNA (log-rank, <i>P</i> < .0001, HR = 14.1 [3.12-63.7], <i>P</i> = .001). Detectable ctDNA status for high-risk NMIBC pre-RC was associated with worse RFS, increased risk of pathological upstaging, and locally advanced disease with lymph node metastasis.