Ultra-sensitive whole-genome sequencing-based molecular residual disease detection in resectable renal cell carcinoma: Preliminary results from the MONSTAR-SCREEN-3 study.

Abstract

421 Background: Circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection has shown promise across various malignancies, yet limited data exist for renal cell carcinoma (RCC), a traditionally low-shedding tumor type. Whole-exome sequencing (WES)-based approaches often lack sufficient sensitivity for effective MRD surveillance in RCC. The prospective, multicenter MONSTAR-SCREEN-3 study evaluates an ultra-sensitive whole-genome sequencing (WGS)-based MRD assay in patients with resectable solid tumors undergoing curative-intent therapy. Here, we report preliminary results from patients with resectable RCC enrolled in the definitive cohort (target n=1,100). Methods: Personalized ctDNA panels were generated using a WGS-based tumor-informed platform (Myriad Genetics), incorporating up to 1,000 tumor-specific variants identified through WGS of matched tumor tissue. Serial plasma samples were collected at baseline, 1 month post-surgery, quarterly during the first year, and biannually thereafter for up to two years. Results: As of September 2025, 30 patients with resectable RCC were enrolled; MRD results were available for 54 samples from 16 patients. Median age was 68 years (range: 41-88), with male predominance (87.5%). Clinical staging distribution included Stage I (6.3%), Stage II (6.3%), and Stage III (87.5%). All patients underwent upfront radical nephrectomy. Personalized panel creation succeeded in 100% of patients (16/16), identifying a median of 4,054 highly confident tumor-specific alterations per patient (range: 902-7712), yielding bespoke panels containing 518-1,000 alterations. The assay demonstrated 100% baseline ctDNA detection (16/16), with 56.3% (9/16) detected at ultra-sensitive levels (tumor fraction <100 parts per million [ppm]; minimum detection: 12.0 ppm). Post-surgical MRD positivity rates were 13.3% (2/15) at 1 month, 15.4% (2/13) at 3 months, and 10.0% (1/10) at 6 months. Among 16 evaluable patients, one developed radiographic recurrence, with MRD detection preceding imaging by 4.4 months. Extended follow-up and comprehensive longitudinal ctDNA dynamics will be presented. Conclusions: The WGS-based personalized ctDNA assay achieved high technical feasibility in RCC, with over half of patients demonstrating baseline ctDNA detection below 100 ppm, highlighting the critical importance of ultra-sensitive platforms for low-shedding tumors like RCC. Early data suggest potential clinical utility for recurrence surveillance. Updated molecular correlates and clinical outcomes will be presented.