Effect of vitamin D on relapse-free survival in a subgroup of patients with p53 protein-positive digestive tract cancer: A post hoc analysis of the AMATERASU trial.

Background: The AMATERASU randomized trial of vitamin D3 supplementation (2,000 IU/day; UMIN000001977) showed the potential benefit of vitamin D in a subgroup of patients with digestive tract cancer. By conducting post hoc analyses of this trial, we further explored whether subgroups stratified by expression levels of p53, vitamin D receptor (VDR), and Ki-67 modify the effect of vitamin D supplementation. Methods: The primary outcome was relapse-free survival (RFS). On IHC using pathologic specimens, the degree of p53 protein expression parallel with TP53 missense mutations was classified as p53 positive (>10%) and p53 negative (<= 10%). In addition, VDR and Ki-67 expression levels were divided into quartiles. Results: The p53 status of 372 patients' pathologic specimens was evaluated. In a subgroup of patients with p53-positive cancer n = 226), 5-year RFS was 79% in the vitamin D group, which was significantly higher than the 57% in the placebo group (HR, 0.52; 95% confidence interval, 0.31-0.88; P = 0.02). In the subgroup of patients with p53-negative cancer, 5-year RFS in the vitamin D group versus placebo group was 72% versus 84% (not significantly different), respectively. Effect modification by p53 positivity was significant (P-interaction = 0.02). However, no significant effect modification by either VDR or Ki-67 was observed. Conclusions: These results generate a hypothesis that vitamin D supplementation may improve RFS in patients with p53-positive digestive tract cancer. Impact: The results are still preliminary, but potentially important, because TP53 is the most frequently mutated gene across cancers at all sites.