Data from Plasma 25-hydroxyvitamin D levels and survival in stage III colon cancer: Findings from CALGB/SWOG 80702 (Alliance)

Abstract Purpose: To assess whether higher plasma 25-hydroxyvitamin D (25[OH]D) are associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. Patients and Methods: Plasma samples were collected from 1437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of CRP, IL-6, and sTNF-R2. Results: Vitamin D deficiency (25(OH)D<12 ng/ml) was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, non-deficient vitamin D status (≥12 ng/ml) was significantly associated with improved DFS, OS and TTR (all Plog-rank<0.05), with multivariable-adjusted hazard ratios of 0.68 (95% confidence interval [CI], 0.51-0.92) for DFS, 0.57 (0.40-0.80) for OS, and 0.71 (0.52-0.98) for TTR. A U-shaped dose-response pattern was observed for DFS and OS (both Pnon-linearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (P mediation=0.04) for DFS and 11.8% (P mediation=0.05) for OS, whereas CRP and IL-6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. Conclusions: Non-deficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate if adjuvant vitamin D supplementation improves patient outcomes.