Vitamin D Receptor Genotype, Tumor Expression, and Outcomes After Vitamin D Supplementation in Digestive Tract Cancer: An Exploratory Post Hoc Analysis of the AMATERASU Trial
- 1Division of Molecular Epidemiology, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-Ku, Tokyo 105-8461, Japan
- 2Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-Ku, Tokyo 105-8461, Japan
- 3Department of Surgery, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara 329-2763, Tochigi, Japan
Abstract
Background/Objectives: Vitamin D supplementation effects may vary according to receptor genotype and tumor receptor abundance. We examined whether treatment effects differed according to FokI genotype and tumor nuclear vitamin D receptor (VDR) expression after surgery for digestive tract cancer. Methods: This exploratory post hoc analysis used data from the double-blind AMATERASU randomized trial (UMIN000001977), which assigned 417 patients with resected stage I–III digestive tract cancers to vitamin D3 (2000 IU/day) or placebo. FokI genotype was determined by sequencing and nuclear VDR expression by immunohistochemistry. Unadjusted Cox analyses were supplemented by pooled treatment-by-subgroup interaction models adjusted for age, sex, and pathological stage, with baseline hazards stratified by tumor site. Results: The joint analysis included 359 patients (213 vitamin D; 146 placebo). VDR expression varied across tumor sites. Among patients with the FokI CC genotype and VDR expression in quintiles 2–5 (n = 110), the unadjusted treatment hazard ratio (HR) for relapse or death was 0.30 (95% confidence interval [CI], 0.12–0.73), compared with 1.02 (95% CI, 0.61–1.71) in the complementary subgroup (n = 249; nominal interaction p = 0.02). After adjustment, the HR in the CC/VDR Q2–5 subgroup was 0.44 (95% CI, 0.18–1.10; interaction p = 0.211). For all-cause mortality, the adjusted HR was 0.46 (95% CI, 0.14–1.51; interaction p = 0.135). Conclusions: The unadjusted exploratory findings were attenuated after accounting for clinicopathological factors. Differential supplementation benefit according to the joint classification was not established. Independent validation is required before clinical use.
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BibTeX
@article{matsushima2026vitamin,
title = {{Vitamin D Receptor Genotype, Tumor Expression, and Outcomes After Vitamin D Supplementation in Digestive Tract Cancer: An Exploratory Post Hoc Analysis of the AMATERASU Trial}},
author = {Tadashi Matsushima and Akitaka Sasaki and Taisuke Akutsu and Hironori Ohdaira and Yutaka Suzuki and Mitsuyoshi Urashima},
journal = {Cancers},
year = {2026},
month = nov,
doi = {10.3390/cancers18213570},
url = {https://www.mdpi.com/2072-6694/18/21/3570},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Vitamin D Receptor Genotype, Tumor Expression, and Outcomes After Vitamin D Supplementation in Digestive Tract Cancer: An Exploratory Post Hoc Analysis of the AMATERASU Trial
AU - Tadashi Matsushima
AU - Akitaka Sasaki
AU - Taisuke Akutsu
AU - Hironori Ohdaira
AU - Yutaka Suzuki
AU - Mitsuyoshi Urashima
PY - 2026
DA - 2026/11/06
JO - Cancers
DO - 10.3390/cancers18213570
UR - https://www.mdpi.com/2072-6694/18/21/3570
AB - Background/Objectives: Vitamin D supplementation effects may vary according to receptor genotype and tumor receptor abundance. We examined whether treatment effects differed according to FokI genotype and tumor nuclear vitamin D receptor (VDR) expression after surgery for digestive tract cancer. Methods: This exploratory post hoc analysis used data from the double-blind AMATERASU randomized trial (UMIN000001977), which assigned 417 patients with resected stage I–III digestive tract cancers to vitamin D3 (2000 IU/day) or placebo. FokI genotype was determined by sequencing and nuclear VDR expression by immunohistochemistry. Unadjusted Cox analyses were supplemented by pooled treatment-by-subgroup interaction models adjusted for age, sex, and pathological stage, with baseline hazards stratified by tumor site. Results: The joint analysis included 359 patients (213 vitamin D; 146 placebo). VDR expression varied across tumor sites. Among patients with the FokI CC genotype and VDR expression in quintiles 2–5 (n = 110), the unadjusted treatment hazard ratio (HR) for relapse or death was 0.30 (95% confidence interval [CI], 0.12–0.73), compared with 1.02 (95% CI, 0.61–1.71) in the complementary subgroup (n = 249; nominal interaction p = 0.02). After adjustment, the HR in the CC/VDR Q2–5 subgroup was 0.44 (95% CI, 0.18–1.10; interaction p = 0.211). For all-cause mortality, the adjusted HR was 0.46 (95% CI, 0.14–1.51; interaction p = 0.135). Conclusions: The unadjusted exploratory findings were attenuated after accounting for clinicopathological factors. Differential supplementation benefit according to the joint classification was not established. Independent validation is required before clinical use.
SN - 2072-6694
ER -