Utility of circulating tumor DNA in patients with renal cell carcinoma at increased risk of recurrence after resection.

519 Background: Despite approval of adjuvant pembrolizumab for high-risk renal cell carcinoma (RCC), risk of disease recurrence persists for many patients after surgical resection, without proven biomarkers for minimal residual disease (MRD). Circulating tumor DNA (ctDNA) testing is utilized in other malignancies to identify MRD and monitor treatment response. Here we aim to investigate whether detection of ctDNA in patients with localized RCC after resection can predict disease recurrence and help guide patient management. Methods: We conducted a retrospective analysis of patients with localized RCC at high-risk for recurrence after resection from May 2022 to August 2025. Inclusion criteria was similar to Keynote-564, including pT2 with grade 4 or sarcomatoid features, pT3, pT4, or any pathological lymph node involvement. Post-nephrectomy and surveillance ctDNA testing were performed using tumor-informed, whole exosome sequencing-based Signatera assays. Disease-free survival (DFS) was performed using Kaplan-Meier and univariable Cox-regression analyses. Results: A cohort of 97 patients were included in the study, with median follow up 15.0 months. Of these, 92 (94.8%) patients had pT3 disease, 85 (87.6%) had clear cell RCC, and 39 (40.2%) received adjuvant therapy. Eleven (11.3%) patients had a positive initial post-operative ctDNA within 3 months of surgery; 12 (12.4%) had ctDNA conversion to positive outside of the 3-month window (median time from surgery to positive ctDNA was 3.5 months). ctDNA positivity has a sensitivity of 73.1% and a specificity of 94.4% for developing radiological progression. Median lead time from ctDNA positivity to radiographic progression was 3.5 (range: 0.9-7.9) months. Any positive ctDNA was associated with a significantly shorter DFS than ctDNA negative group (median 5.5m vs not reached, HR 15.0; 95%CI 5.2-43.5; p