A post-hoc analysis of a randomized trial found that daily vitamin D3 supplementation was associated with reduced risk of relapse or death in patients with digestive tract cancer who were p53 immunoreactive. These findings were published in JAMA Network Open.
The AMATERASU study was a randomized, double-blind, controlled clinical trial that included 417 patients with digestive tract cancer (stages I to III) who underwent curative surgery. Participants were randomized to oral vitamin D3 supplementation (2000 IU/day) postoperatively or placebo. Treatment continued until relapse or death. Median follow-up was 3.5 years.
Survival or Relapse With Vitamin D Supplementation
For the post-hoc analysis, 392 patients were included. The primary outcome was relapse or all-cause death. The median age was 66 years and 66.3% were male. The vitamin D supplementation group comprised 241 patients, and 151 patients comprised the placebo group. Thirty-six percent of patients were positive for p53 antibodies in serum and p53 protein in pathological specimens (the p53-Ab–positive group), and 250 patients made up the p53-Ab–negative group.
The makeup of cancer types in the population were as follows: esophageal cancer (9.4%), gastric cancer (43.4%), small bowel cancer (0.5%), and colorectal cancer (46.7%). Regarding staging, 44.1% were stage I, 26.5% were stage II, and 29.4% were stage III. Ten percent of patients had missing histopathology specimens.
In the p53-Ab–positive group, 19.8% of the vitamin D group (n=17 of 86 patients) experienced relapse or death compared with 33.9% (n=19 of 56) of the placebo group. Five-year relapse-free survival (RFS) rates were 77.2% in the vitamin D group and 60.0% in the placebo group. This difference was found to be significant when controlling for age and history of cardiovascular disease (hazard ratio [HR], 0.47; 95% CI, 0.23-0.95).
In the group of patients who were p53-Ab–negative, relapse or death occurred in 21.3% of the vitamin D group (n=33 of 155 patients) and 22.1% of the placebo group (n=21 of 95). Five-year RFS was 75.9% and 72.5%, respectively, which was not a statistically significant difference (HR, 0.98; 95% CI, 0.56-1.69).
Outcomes in p53-Immunoreactive Patients
The researchers conducted a subgroup analysis of 80 patients who were p53 immunoreactive (eg, those who had p53 antibodies and overexpressed p53 immunohistochemistry). Relapse or death occurred in 16.7% of the vitamin D group and 53.8% of the placebo group. Five-year RFS was significantly higher in the vitamin D versus placebo groups (80.9% vs 30.6%; HR, 0.27; 95% CI, 0.11-0.61; P=.002). This effect remained significant after adjusting for age and history of cardiovascular disease (HR, 0.20; 95% CI, 0.08-0.50).
Among patients who were not p53 immunoreactive (n=272), relapse or death was 22.2% in the vitamin D group and 21.1% in the placebo group, with 5-year RFS rates of 74.7% and 74.1%, respectively, which was not a significant difference (HR, 1.09; 95% CI, 0.65-1.84). When compared between p53-immunoractive and non-immunoreactive subgroups, 5-year RFS rates were significantly different (P=.005).
“The main findings of this study were that daily supplementation of 2000 IU of vitamin D reduced the risk of relapse or death by 27% compared with placebo in the p53-immunoreactive subgroup,” the authors concluded. “Although further research is needed, these results suggest that cancer immunotherapy targeting mutated p53 proteins should be developed.”
In 272 patients in the non–p53-immunoreactive group (eg, patients who were p53-Ab [−] or p53-IHC [2+, 1+, or 0] negative), relapse or death occurred in 35 of 158 patients (22.2%) in the vitamin D group and 24 of 114 patients (21.1%) in the placebo group; the 5-year RFS was 37 patients (74.7%) in the vitamin D group and 24 patients (74.1%) in the placebo group, indicating no significant difference (HR, 1.09; 95% CI, 0.65-1.84), which was significantly different from the effect of vitamin D in the p53-immunoreactive subgroup (P for interaction=.005).
