Postoperative circulating tumor DNA combined with consensus molecular subtypes can better predict outcomes in stage III colon cancers: A prospective cohort study

Precise methods for risk stratification to guide adjuvant chemotherapy for stage III colon cancers are needed. Here, we combined circulating tumor DNA (ctDNA) with consensus molecular subtype (CMS) to improve risk stratification in stage III colon cancers.We conducted a prospective, observational cohort study of 165 patients with stage III colon cancers. Somatic variants in tumor tissues and plasmas collected pre- and post-chemo were detected via a targeted sequencing panel of 197 cancer-related genes. CMSs classification was characterized using a targeted RNA sequencing panel of 788 genes.We analyzed 151 pre-chemo and 124 post-chemo plasmas, while 130 patients were CMSs classified. ctDNA was detectable in 15.9% pre-chemo and 8.9% post-chemo samples. Significantly worse recurrence-free survival (RFS) was seen if ctDNA was detectable in pre-chemo samples (hazard ratio [HR], 3.585; P < 0.001) or in post-chemo samples (HR, 3.337; P = 0.005). Pre-chemo ctDNA (HR, 5.538; P < 0.001) and post-chemo ctDNA status (HR, 3.272; P = 0.037) remained independently associated with RFS in multivariate analysis. According to the redefined recurrence risk stratification, mid-risk patients (ctDNA-negative with CMS4/T4 or N2 tumors) were 5.3 times (HR, 5.269; P = 0.025) more likely to relapse than low-risk patients (ctDNA-negative with CMS1-3/T3N1 tumors), while high-risk patients (ctDNA-positive) were 14.6 times (HR, 14.590; P < 0.001) more likely to relapse.Postoperative ctDNA indicating residual disease, combined with CMSs classification and clinical risk reflecting the intrinsic characteristics of tumors, can redefine risk stratification of stage III colon cancers and better predict relapse.