Vitamin D Receptor Genotype, Tumor Expression, and Outcomes After Vitamin D Supplementation in Digestive Tract Cancer: An Exploratory Post Hoc Analysis of the AMATERASU Trial

Background/Objectives: Vitamin D supplementation effects may vary according to receptor genotype and tumor receptor abundance. We examined whether treatment effects differed according to FokI genotype and tumor nuclear vitamin D receptor (VDR) expression after surgery for digestive tract cancer. Methods: This exploratory post hoc analysis used data from the double-blind AMATERASU randomized trial (UMIN000001977), which assigned 417 patients with resected stage I–III digestive tract cancers to vitamin D3 (2000 IU/day) or placebo. FokI genotype was determined by sequencing and nuclear VDR expression by immunohistochemistry. Unadjusted Cox analyses were supplemented by pooled treatment-by-subgroup interaction models adjusted for age, sex, and pathological stage, with baseline hazards stratified by tumor site. Results: The joint analysis included 359 patients (213 vitamin D; 146 placebo). VDR expression varied across tumor sites. Among patients with the FokI CC genotype and VDR expression in quintiles 2–5 (n = 110), the unadjusted treatment hazard ratio (HR) for relapse or death was 0.30 (95% confidence interval [CI], 0.12–0.73), compared with 1.02 (95% CI, 0.61–1.71) in the complementary subgroup (n = 249; nominal interaction p = 0.02). After adjustment, the HR in the CC/VDR Q2–5 subgroup was 0.44 (95% CI, 0.18–1.10; interaction p = 0.211). For all-cause mortality, the adjusted HR was 0.46 (95% CI, 0.14–1.51; interaction p = 0.135). Conclusions: The unadjusted exploratory findings were attenuated after accounting for clinicopathological factors. Differential supplementation benefit according to the joint classification was not established. Independent validation is required before clinical use.