Longitudinal analysis of circulating tumor DNA in localized and metastatic urothelial cancer.

4587 Background: Circulating tumor DNA (ctDNA)-based minimal residual disease has been established as a prognostic biomarker in advanced urothelial carcinoma (UC). Despite the confirmed utility of ctDNA in muscle-invasive non-metastatic UC (nmUC), validation in patients with metastatic UC (mUC) remains unexplored. This study aims to prospectively assess the utility of ctDNA in nmUC and mUC Methods: This prospective study analyzed the results of longitudinal ctDNA testing in a single academic center of patients with UC. A personalized, tumor-informed, multiple PCR-NGS assay (Signatera, Natera, Inc) was used for the detection and quantification of ctDNA. A total of 203 samples were analyzed (median: 3 samples/patient) with a median follow up (mFU) from first ctDNA of 12months. nmUC and mUC patients with >1 ctDNA sample were included for analysis. Disease progression was assessed by clinical/radiographic exams. ctDNA dynamics were categorized based on clearance (ctDNA-), residual (ctDNA+), ≥50% quantitative reduction (≥50%ctDNAr), and 50%ctDNAr remained progression free at analysis (mFU:11mo) and mTTP in 8/31 patients was 9.5months. Notably, 5/9 patients with ≥50%ctDNAr who underwent treatment breaks due to adverse events remained progression free (median treatment break: 7 months, mFU:19 months). Patients with ≥50%ctDNAr and ctDNA-had significantly improved mTTP when compared to patients with <50%ctDNAr (HR 0.18, p=0.02 and HR 0.11, p=0.009 respectively). Conclusions: Our findings underscore the potential for personalized assessment of tumor-informed ctDNA dynamics as a promising prognostic biomarker in patients with both localized and metastatic UC. Further prospective studies are necessary to validate utility for ctDNA guided treatment de-escalation in mUC.