A tumor-naive ctDNA assay detects minimal residual disease in resected stage II or III colorectal cancer and predicts recurrence: subset analysis from the GALAXY study in CIRCULATE-Japan

Purpose: Analysis of circulating tumor DNA (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 molecular 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 (CRC) 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 post-surgery (landmark timepoint (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 non-recurrent). Of recurrent study participants, 22/36 had detectable ctDNA (MRD+) at LMT and 29/33 non-recurrent study participants had undetectable ctDNA (MRD-), yielding 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%. Median lead time from first MRD+ result to recurrence was 4.77 months overall, and 5.30 months for study participants with no adjuvant treatment. At 12 weeks post-surgery, MRD status strongly correlated with disease-free survival (DFS) [adj. HR 9.69], outperforming carcinoembryonic antigen (CEA) 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 to DFS compared to standard of care CEA.