AbstractPurpose:Analysis of ctDNA may enable early identification of patients likely to relapse, presenting an opportunity for early interventions and improved outcomes. Tumor-naïve plasma-only approaches for minimal residual disease (MRD) assessment accelerate turnaround time, enabling rapid treatment decisions and ongoing surveillance.Experimental Design:Plasma samples were obtained from 80 study participants with stage II or III colorectal cancer selected from CIRCULATE-Japan GALAXY. MRD status was assessed using a tumor-naïve ctDNA assay (xM) that integrates methylation and genomic variant data, delivering a binary call. MRD was assessed at 4 weeks postsurgery [landmark time point (LMT)] using methylation and genomic variant data and longitudinally (median, 22.1 months) using only methylation data.Results:At LMT, 69/80 study participants were evaluable (36 recurrent; 33 nonrecurrent). Of recurrent study participants, 22/36 had detectable ctDNA (MRD-positive) at LMT and 29/33 nonrecurrent study participants had undetectable ctDNA (MRD-negative), yielding a clinical sensitivity of 61.1% and specificity of 87.9%. Additionally, 74 study participants were evaluable for longitudinal performance with a clinical sensitivity of 83.3% and specificity of 89.5%. The median lead time from the first MRD-positive result to recurrence was 4.77 months overall, and 5.30 months for study participants with no adjuvant treatment. At 12 weeks postsurgery, MRD status strongly correlated with disease-free survival (adjusted HR, 9.69), outperforming carcinoembryonic antigen correlation (HR, 2.13).Conclusions:This tumor-naïve MRD assay demonstrated clinically meaningful performance at LMT and longitudinally, accurately predicting clinical recurrence. MRD status was a stronger prognostic biomarker for disease-free survival compared with standard-of-care carcinoembryonic antigen.