A recently analysis led by scientists in Tokyo, Japan, found that daily vitamin D supplementation appeared to significantly reduce – by 75% – the risk of relapse or death in a subgroup of patients with digestive tract cancer who were p53-immuno-reactive.
Overall, they said, the five-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-immuno-reactive subgroup.
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 tumour biology, specifically the p53 protein, said study investigator Mitsuyoshi Urashima, MD, PhD, MPH, with Jikei University School of Medicine, Tokyo.
Medscape reports that a 2019 randomised controlled trial from the research team had found vitamin D supplements of 2000 IU/day did not improve RFS at five 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 immuno-histochemistry (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 immuno-reactive, 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 tumour 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 eight years.
The current post hoc analysis by p53-immuno-reactive status included 392 patients, 47% of whom had colorectal cancer, 43% had gastric cancer, 9% had oesophageal cancer, and 0.5% had small bowel cancer.
The post hoc analysis found that, among the p53-immuno-reactive 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 five-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-immuno-reactive subgroup. In this group, vitamin D supplementation had no apparent effect on five-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”, Urashima and colleagues concluded.
In an editorial accompanying the study, which was published in JAMA Network Open, Dr Michael Holick, PhD, described the findings as a “game changer” for vitamin D and cancer.
Holick, from Boston University Chobanian & Avedisian School of Medicine, said 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”.
Study details
Effect of Vitamin D Supplements on Relapse or Death in a p53-Immunoreactive Subgroup With Digestive Tract Cancer: Post Hoc Analysis of the AMATERASU Randomised Clinical Trial
Kazuki Kanno, Taisuke Akutsu, Hironori Ohdaira, et al.
Published in JAMA Network Open on 22 August 2022
Key Points
Question Can vitamin D supplementation reduce the risk of relapse or death in a subgroup of patients with digestive tract cancer who were p53 immuno-reactive, defined by positivity for anti-p53 antibodies in serum and p53 protein in more than 99% of cancer cells?
Findings In this post hoc analysis of a randomized clinical trial including 392 patients with digestive tract cancer, 5-year relapse-free survival was significantly higher in the vitamin D group (80.9%) than the placebo group (30.6%) among patients in the p53-immuno-reactive subgroup but not in the non–p53-immunoreactive subgroup.
Meaning These findings suggest that vitamin D supplementation may reduce the risk of relapse or death in this subgroup of patients.
Abstract
Importance
Recent meta-analyses of randomised clinical trials found that daily vitamin D3 supplementation had beneficial effects on cancer mortality, although the results are still controversial.
Objective
To examine whether vitamin D supplementation reduces the risk of relapse or death in a subgroup of patients with digestive tract cancer who were p53 immuno-reactive.
Design, Setting, and Participants
This was a post hoc subgroup analysis of the AMATERASU randomised, double-blind, placebo-controlled clinical trial. This trial included patients at a single university hospital in Japan with digestive tract cancers between January 2010 and February 2018 followed up for a median (IQR) of 3.5 (2.5-5.3) years to compare the effects of vitamin D supplementation with placebo and was reported in 2019. Patients from among 417 participants in the AMATERASU trial whose residual serum samples were available were included. Data were analysed from October 20 to November 24, 2022.
Interventions
Vitamin D3 (2000 IU/d) supplementation or placebo.
Main Outcomes and Measures
The primary outcome was 5-year relapse or death. The subgroup of patients who were p53 immuno-reactive was defined by positivity for anti-p53 antibodies in serum and nuclear accumulation of p53 oncosuppressor protein in more than 99% of cancer cells, which is considered a biomarker for p53 missense mutations. Anti-p53 antibody levels were measured using chemiluminescent enzyme immune assay. Immunohistochemical staining data of p53 protein in cancer tissue in pathologic specimens were obtained from a previous study and divided into 4 grades.
Results
Among 392 patients with digestive tract cancer (mean [SD] age, 66 [10.7] years; 260 males [66.3%]), there were 37 patients with oesophageal cancer (9.4%), 170 patients with gastric cancer (43.4%), 2 patients with small bowel cancer (0.5%), and 183 patients with colorectal cancer (46.7%). Serum anti-p53 antibody was detectable in 142 patients (36.2%), and p53-immuno-histochemistry grade showed a positive association with serum anti-p53 antibody levels (coefficient = 0.19; P < .001). In the p53-immuno-reactive subgroup (80 patients), relapse or death occurred in 9 of 54 patients (16.7%) in the vitamin D group and 14 of 26 patients (53.8%) in the placebo group; 5-year relapse-free survival (RFS) was significantly higher in the vitamin D group (13 patients [80.9%]) than the placebo group (1 patient [30.6%]; hazard ratio [HR], 0.27; 95% CI, 0.11-0.61; P = .002). This was significantly different from 272 patients in the non–p53 immuno-reactive subgroup, in which vitamin D had no effect on 5-year RFS (vitamin D: 35 of 158 patients [22.2%] vs placebo: 24 of 114 patients [21.1%]; HR, 1.09; 95% CI, 0.65-1.84) (P for interaction = .005).
Conclusions and Relevance
This study found that vitamin D supplementation reduced the risk of relapse or death in the subgroup of patients with digestive tract cancer who were p53 immuno-reactive.
Medscape article – 'Game Changer' Data for Vitamin D in Digestive Tract Cancers (Open access)
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