Prognostic impact of MRD positivity at ultra-sensitive ctDNA levels using a WGS-based personalized assay: A pan-cancer analysis from MONSTAR-SCREEN-3.

Abstract

3044 Background: While circulating tumor DNA (ctDNA) demonstrates promise as a molecular residual disease (MRD) biomarker, its clinical implementation has been primarily limited to tumors with favorable ctDNA shedding characteristics. The MONSTAR-SCREEN-3 evaluates a whole-genome sequencing (WGS)-based MRD assay to assess MRD positivity at ultra-sensitive level beyond conventional WES-based MRD, including traditionally low-shedding tumors. Methods: MONSTAR-SCREEN-3 is a prospective multicenter study targeting 1,100 patients with solid tumors undergoing curative-intent treatment. Personalized panels were constructed using Precise MRD (Myriad Genetics), incorporating up to 1,000 tumor-specific alterations identified through WGS of matched tumor tissue. Serial plasma samples were collected at baseline, post-neoadjuvant treatment (NAT) (when applicable), 1-month (1M) post-surgery, every 3 months in year 1, and every 6 months thereafter up to 2 years. Assay performance was evaluated across multiple cancer types for ctDNA detection and recurrence monitoring. Results: Between May 2024 and November 2025, 1,088 patients across over 20 cancer types were enrolled, including colorectal (n=250), breast (n=156), cervical (n=95), gastric (n=88), and pancreatic (n=69) cancers. Treatment strategies included upfront surgery (n=704), NAT (n=296), and definitive chemoradiotherapy (n=96). Median follow-up was 5.3 months (range, 0–18.1). Baseline ctDNA detection was achieved in 96.2% (684/711), with 16.4% at ultra-sensitive levels (tumor fraction <100 parts per million [ppm]). Post-operative MRD positivity was 26.4% (163/617) at 1M and 23.8% (120/504) at 3M, with 46.0% and 41.7% detected at ultra-sensitive levels, respectively. Among 91 patients who received NAT and underwent pathological assessment, post-NAT MRD status demonstrated a sensitivity of 74.3% (55/74) and a specificity of 100% (17/17) for predicting pathological complete response (P<0.01). Among patients with available survival data, post-1M MRD positivity was associated with significantly worse disease-free survival (DFS) compared with MRD negativity (HR, 16.9; 95% CI, 8.2–34.8; P < 0.001). Furthermore, post-1M MRD positivity at levels below 100 ppm was associated with significantly inferior DFS compared with MRD negativity (HR, 8.2; 95% CI, 3.4–19.4; P < 0.001), whereas post-1M MRD positivity at levels ≥100 ppm was associated with significantly worse DFS compared with MRD positivity below 100 ppm (HR, 3.4; 95% CI, 1.7–6.7; P < 0.001). Conclusions: The WGS-based MRD assay demonstrated high baseline detection sensitivity and robust ultra-sensitive detection across diverse cancer types. Our findings show that post-1M MRD positivity below 100 ppm at ultra-sensitive level is prognostic for recurrence risk. Updated molecular and clinical outcome data will be presented. Clinical trial information: UMIN000053975.