Prognostic value of circulating tumor DNA in a phase 3 trial of FOLFOX-based adjuvant chemotherapy for stage III colon cancer

Detection of molecular residual disease using circulating tumor DNA (ctDNA) may enable postoperative risk stratification to guide adjuvant therapy. Post hoc analysis of the Alliance N0147 trial evaluated the prognostic value of a tissue-free, epigenomic ctDNA assay (739-gene panel) in stage III colon cancer (CC) patients receiving adjuvant FOLFOX with or without cetuximab.Among 2,260 evaluable patients, 461 (20.4%) were ctDNA-positive. At a median follow-up of 6.1 years, ctDNA positivity was indepedently associated with shorter time to recurrence (HR 5.96; 95% CI 5.11-6.96), disease-free survival (5.03; 4.36-5.81), and overall survival (4.45;3.76-5.27). The 5-year DFS was 27.7% versus 77.1% in ctDNA-positive versus ctDNA-negative patients, and adverse prognostic impact was greater in lower T/N stage, low-risk, and dMMR subsets. Among ctDNA-positive patients, tumor fraction was nearly double in those who recurred or died (p=0.0002) and stratified patients for TTR, DFS, and OS. The authors conclude that evaluation of ctDNA in resected stage III CC using a tissue-free assay provided robust and independent prognostic value.