'Game Changer' Data for Vitamin D in Digestive Tract Cancers

Megan Brooks

August 25, 2023

Vitamin D supplementation significantly reduced the risk of relapse or death in a subgroup of patients with digestive tract cancer who were p53-immunoreactive, a recent analysis found.

In the p53-immunoreactive subgroup, daily vitamin D supplementation reduced the risk of relapse or death by 73%. Overall, the 5-year relapse-free survival (RFS) among those receiving vitamin D was 81% vs nearly 31% in the placebo group.

Vitamin D supplementation, however, had no effect on survival outcomes in the non-p53-immunoreactive subgroup.

These findings represent a "game changer" for vitamin D and cancer, Michael Holick, PhD, MD, with Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, said in an editorial accompanying the study, published online August 22 in JAMA Network Open. The AMATERASU trial "provides an additional variable in our understanding of whether improving vitamin D status has any benefit for reducing risk of developing cancer as well as improving relapse-free and mortality outcomes."

A growing body of research suggests that vitamin D supplementation may reduce the risk of cancer mortality, but the evidence remains mixed and efficacy may hinge on a patient's tumor biology, specifically the p53 protein, the authors of the current analysis explained.

A 2019 randomized controlled trial from the research team found vitamin D supplements of 2000 IU/day did not improve RFS at 5 years in patients with digestive tract cancers. However, a post hoc analysis of the AMATERASU trial, published in 2020, suggested that vitamin D supplementation improved RFS in a subgroup of patients with p53-positive digestive tract cancers, as seen using immunohistochemistry (IHC) staining (79% vs 57% in the placebo group; hazard ratio [HR], 0.52; P = .02).

In the current post hoc analysis of the AMATERASU trial, the research team explored whether vitamin D supplementation reduced the risk of relapse or death in the subgroup of patients who were p53 immunoreactive, defined as positivity for both nuclear accumulation of the p53 protein in more than 99% of cancer cells, as seen on IHC staining, as well as anti-p53 antibodies in serum.

In the trial, patients with stage I-III luminal gastrointestinal cancer who had undergone complete tumor resection were randomly assigned to receive placebo or oral vitamin D supplements of 2000 IU/day from their first postoperative visit through the end of the trial, up to 8 years.

The current post hoc analysis by p53-immunoreactive status included 392 patients, 47% of whom had colorectal cancer, 43% had gastric cancer, 9% had esophageal cancer, and 0.5% had small bowel cancer.

The post hoc analysis found that, among the p53-immunoreactive subgroup of 80 patients, relapse or death occurred in nine of 54 patients (17%) in the vitamin D group and 14 of 26 patients (54%) in the placebo group. The 5-year RFS was significantly higher in the vitamin D group than the placebo group (81% vs 31%; HR, 0.27; P = .002).

This was not the case in the 272 patients in the non-p53-immunoreactive subgroup. In this group, vitamin D supplementation had no apparent effect on 5-year RFS compared with placebo (22% vs 21%; HR, 1.09; 95% CI, 0.65-1.84).

The main findings of this study were that daily supplementation of 2000 IU of vitamin D reduced the risk of relapse or death compared with placebo in the p53-immunoreactive subgroup, and "suggest the importance of developing cancer immunotherapy targeting mutated p53 proteins," study investigator Mitsuyoshi Urashima, MD, PhD, MPH, with Jikei University School of Medicine, Tokyo, Japan, and colleagues concluded.

Support for the study was provided by the Japan-Supported Program for the Strategic Research Foundation at Private Universities and a grant from the Japan Society for the Promotion of Science of the Ministry of Education, Culture, Sports, Science, and Technology. The authors report no relevant financial relationships . Holick reported grants from Carbogen Amcis and Solius; personal fees from Biogena, Sanofi, Faes Farma, Eric Anthony Nepute, and others; nonfinancial support from Ontometrics outside the submitted work; and had a patent for Novel Use of 25 hydroxy vitamin D pending for Carbogen Amcis BV and Aamanya AG.

JAMA Netw Open. Published online August 22, 2023. Full text; editorial.

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