Effect Modification by Serum Vitamin A Levels on the Association between Vitamin D and Relapse or Death in Patients with Digestive Tract Cancer.

Serum vitamin A levels positively correlated with 25-hydroxyvitamin D levels in patients with digestive tract cancer.

• Spearman correlation coefficient ρ = 0.31; P < 0.0001
• Study population: 363 patients (mean age 66 years; 67.8% male)
• Serum vitamin A ranged from 0.15 to 4.30 μmol/L with median (IQR) of 1.38 (1.05–1.74) μmol/L
• Data derived from the AMATERASU randomized clinical trial of vitamin D3 supplementation

Patients in the lowest decile of serum vitamin A had significantly higher risk of relapse or death compared to those in deciles 2–10.

• HR 2.05; 95% CI, 1.10–3.84; P = 0.03
• Serum vitamin A levels were categorized stepwise using clinical reference ranges and quantile cutoffs (halves, tertiles, quartiles, quintiles, and deciles)
• Post hoc grouping of the most coherent quantiles was used for analysis

Vitamin D supplementation significantly improved 5-year relapse-free survival in patients with middle-range serum vitamin A levels (deciles 6–8), but not in lower or higher ranges.

• In deciles 6–8: 5-year RFS was 81.4% with vitamin D versus 54.9% with placebo (HR, 0.31; 95% CI, 0.14–0.69; P = 0.004)
• No significant effect of vitamin D was observed in the lower range (deciles 1–5) or higher range (deciles 9–10)
• Interaction P-value: Pinteraction = 0.008
• Relapse-free survival was evaluated using Nelson-Aalen cumulative hazard functions and Cox proportional hazards models

Vitamin D interacts with vitamin A through receptor heterodimerization, providing a biological rationale for effect modification.

• This interaction occurs through retinoid X receptor (RXR) heterodimerization with the vitamin D receptor (VDR)
• This mechanism was cited as the basis for the hypothesis that vitamin A levels could modify vitamin D's effects on cancer outcomes
• The study is described as a post hoc analysis of the AMATERASU RCT

These findings represent the first RCT evidence that serum vitamin A levels modify the effect of vitamin D supplementation on relapse or death in patients with digestive tract cancer.

• The analysis was post hoc and exploratory in nature
• The AMATERASU trial included 363 patients with digestive tract cancer
• The primary outcome was relapse or death, assessed via relapse-free survival