Parathyroid Hormone Modifies the Effect of Vitamin D Supplementation on Risk of Relapse or Death in Patients with Digestive Tract Cancer: A Post Hoc Subgroup Analysis of the AMATERASU Randomized Clinical Trial

Background/Objectives: Parathyroid hormone (PTH), which rises compensatory with vitamin D insufficiency and has been shown to down-regulate vitamin D receptor expression, represents a biologically plausible effect modifier. We investigated whether pretreatment serum PTH modifies the effect of postoperative vitamin D supplementation on relapse-free survival, and whether adding tumor p53 status further refines subgroup identification in an exploratory analysis. Methods: This post hoc analysis utilized data from the AMATERASU trial (UMIN000001977), a single-center, randomized, double-blind, placebo-controlled trial evaluating vitamin D3 (2000 IU/day) versus placebo in patients with curatively resected stage I–III digestive tract cancers (maximum follow-up, 7.5 years). Patients were dichotomized at the cohort median PTH (41 pg/mL). The primary outcome was relapse-free survival (RFS), analyzed using multivariable Cox proportional hazards models. Results: Of 417 randomized patients, 410 had baseline PTH data. In the lower PTH subgroup (≤41 pg/mL), vitamin D significantly improved RFS compared with placebo (fully adjusted hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24–0.81; p = 0.008). Conversely, no benefit was observed in the higher PTH subgroup (>41 pg/mL; fully adjusted HR, 1.25; 95% CI, 0.64–2.44; p for interaction = 0.016). Exploratory stratification of 365 patients with p53 data showed that the supplementation benefit appeared greatest in patients with both low PTH (≤41 pg/mL) and p53-positive tumors (fully adjusted HR, 0.38; 95% CI, 0.18–0.78; p = 0.009). Conclusions: Pretreatment serum PTH is a candidate effect modifier of postoperative vitamin D supplementation in digestive tract cancers.