Physical activity and molecular residual disease in stage III colon cancer: Findings from Cancer and Leukemia Group B (Alliance)/SWOG 80702

BACKGROUND: Postoperative circulating tumor DNA (ctDNA) is a highly prognostic marker of residual disease among patients with stage III colon cancer, and physical activity has been associated with improved survival after curative resection. Whether physical activity predicts outcomes according to postoperative ctDNA status remains unknown. METHODS: We conducted a post hoc analysis of CALGB/SWOG 80702, a phase III study evaluating adjuvant celecoxib vs. placebo and 3 vs. 6 months of chemotherapy. Total physical activity volume was assessed using validated and quantified in metabolic equivalent task hours per week (MET-h/week). ctDNA status was determined using a clinically validated, tumor-informed assay (SignateraTM, Natera, Inc.). RESULTS: Among 763 patients (median follow-up 6.0 years), 32.3% were inactive (<3.0 MET-h/week), 24.4% were highly active (≥18.0), and 17.8% were ctDNA-positive. Among patients who were ctDNA-negative, moderate (adjusted hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.37-0.91) and high physical activity (HR 0.49, 95% CI 0.27-0.86) were associated with improved disease-free survival (DFS) compared to inactivity, with similar trends in overall survival (OS). Physical activity was not associated with DFS/OS in the ctDNA-positive subcohort (P > 0.05 for all), though interactions were not statistically significant. Among patients who were physically active (≥9.0 MET-h/week) and received adjuvant celecoxib, improved DFS was observed in both ctDNA-negative (HR 0.41, 95% CI 0.22-0.77) and ctDNA-positive (Ref: inactive, placebo; HR 0.29, 95% CI 0.15-0.57) subgroups. CONCLUSIONS: Greater physical activity was associated with improved DFS among patients who were ctDNA-negative. Physical activity and adjuvant celecoxib was associated with favorable survival outcomes regardless of ctDNA status.