Combined TP53 Codon 72 Genotype and p53 Expression in Association with Vitamin D Benefit in Digestive Tract Cancer: A Post-Hoc Study of the AMATERASU Trial

Published on Wednesday, 28 October 2026

Abstract

Background: Accumulating evidence suggests that vitamin D may influence cancer prognosis. We aimed to explore whether the TP53 codon 72 polymorphism (p.Pro72Arg; rs1042522) may be associated with differential effects of vitamin D supplementation on digestive tract cancer prognosis.

Methods: This post hoc analysis of the AMATERASU randomized controlled trial included patients in whom both germline TP53 codon 72 genotype and p53 immunohistochemistry (IHC) assessment were available. Patients were stratified according to TP53 codon 72 genotype and p53 IHC expression. The association between vitamin D supplementation and relapse-free survival (RFS) was evaluated using Cox proportional hazards regression models within each subgroup.

Results: A total of 333 participants (79.9%) out of 417 in the AMATERASU trial were included in the analysis. RFS was comparable between the vitamin D and placebo groups across the TP53 codon 72 genotype subgroups. The vitamin D group was significantly associated with more favorable RFS compared with the placebo group in patients with both the Arg/Arg genotype and high p53 IHC expression (HR, 0.32; 95% CI, 0.12-0.87; p = 0.03). However, with a fragility index of 2 and a non-significant three-way interaction among vitamin D supplementation, p53 IHC expression, and the Arg/Arg genotype (p for interaction = 0.09), these findings remain fragile despite reaching statistical significance, warranting careful interpretation.

Conclusions: Vitamin D supplementation was associated with more favorable RFS among patients with digestive tract cancer who had both the Arg/Arg genotype and high p53 IHC expression. These exploratory findings warrant further investigation in prospective studies.

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- The Di Bella Method (A Fixed Part - Dihydrotachysterol, Alfacalcidol, synthetic Vitamin D3 - Preferably the blood concentration value should be around the middle between 75ng/ml and 100ng/ml);

- Vitamin D (analogues and/or derivatives) and cancer - In vitro, review and in vivo publications;

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

The Di Bella's Method: Use of Vitamin D analogues and/or derivatives - together with others chemical compounds: the dosage and administration schedule must be individualised for each patient - in several Oncological Pathologies:

- A retrospective observational clinical study of triple negative breast cancer cases treated with Di Bella Method: A preliminary data;

- The Synergism of Somatostatin, Melatonin, Vitamins Prolactin and Estrogen Inhibitors Increased Survival, Objective Response and Performance Status In 297 Cases of Breast Cancer;

- Complete objective response, stable for 5 years, with the Di Bella Method, of multiple-metastatic carcinoma of the breast;

- Evaluation of the safety and efficacy of the first-line treatment with somatostatin combined with melatonin, retinoids, vitamin D3, and low doses of cyclophosphamide in 20 cases of breast cancer: a preliminary report;

- The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 122 cases of breast cancer;

- Complete objective response to biological therapy of plurifocal breast carcinoma;

- A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method: A rationale and effectiveness;

- Recurrent Glioblastoma Multiforme (grade IV – WHO 2007): a case of complete objective response achieved by means of the concomitant administration of Somatostatin and Octreotide – Retinoids – Vitamin E – Vitamin D3 – Vitamin C – Melatonin – D2 R agonists (Di Bella Method – DBM) associated with Temozolomide;

- The Di Bella Method DBM improved survival objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck;

- Chronic Lymphocytic Leukemia: Long-Lasting Remission with Combination of Cyclophosphamide, Somatostatin, Bromocriptine, Retinoids, Melatonin, and ACTH;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status;