Cancers reduced after 2 years of 2000 IU Vitamin D daily (2nd RCT) – RCT Aug

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Vitamin D Life summary

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2.5 fewer digestive tract cancers in those with the P53 mutation (Japan)

Effect of Vitamin D Supplements on Relapse or Death in a p53-Immunoreactive Subgroup With Digestive Tract Cancer
JAMA Netw Open. 2023;6(8):e2328886. doi:10.1001/jamanetworkopen.2023.28886
Post Hoc Analysis of the AMATERASU Randomized Clinical Trial
Kazuki Kanno, MD1; Taisuke Akutsu, MD, PhD1; Hironori Ohdaira, MD, PhD2; et alYutaka Suzuki, MD, PhD2; Mitsuyoshi Urashima, MD, PhD, MPH1

• Question Can vitamin D supplementation reduce the risk of relapse or death in a subgroup of patients with digestive tract cancer who were p53 immunoreactive, 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-immunoreactive 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 randomized 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 supgroup of patients with digestive tract cancer who were p53 immunoreactive.

Design, Setting, and Participants This was a post hoc subgroup analysis of the AMATERASU randomized, 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 analyzed 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 immunoreactive 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 esophageal 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-immunohistochemistry grade showed a positive association with serum anti-p53 antibody levels (coefficient = 0.19; P < .001). In the p53-immunoreactive 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 immunoreactive 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
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Note Vital trial: 25% reduction of Cancer after 2 years

Clipped from PDF

• "Vitamin D and Omega-3 Trial (VITAL) study, 2000 IU of vitamin D3 administered daily reduced all cancer mortality by 25% when the first 2 years of observation were excluded."
• The raw data in the study did not appear to support this amount of decrease

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Comment on the study – Holick Aug 2023

The Death D-Fying Vitamin D3 for Digestive Tract Cancers—The p53 Antibody Connection
JAMA Netw Open. 2023;6(8):e2328883. doi:10.1001/jamanetworkopen.2023.28883
Michael F. Holick, PhD, MD1

In 2019, Urashima et al1 reported results of a randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy of improving relapse-free survival for patients with cancers of the digestive tract who received 2000 IU vitamin D3 supplementation daily for 8 years. Based on the results from this clinical trial, the authors concluded that vitamin D3 supplementation did not improve relapse-free survival at 5 years. In this issue of JAMA Network Open, Kanno et al 2 report a post hoc subgroup analysis of this clinical trial. They evaluated the p53-immunoreactive subgroup defined by positivity for both anti-p53 antibodies in serum and nuclear accumulation of p53 by immunohistochemistry in more than 99% of cancer cells, which was considered a biomarker for p53-missense mutations. Patients who had detectable serum anti-p53 antibody and received 2000 IU daily had a significant, more than 2.5-fold improvement in relapse or death compared with the placebo group that had detectable p53 immunoreactivity. The observed 27% absolute risk reduction translates to a number needed to treat of 4. In those patients who had no p53 immunoreactivity, 2000 IU of vitamin D3 daily provided insignificant benefit for 5-year relapse-free survival.

One of the first studies to find an association of sun exposure (a surrogate for improved vitamin D status) with reduced risk of cancer was reported in 1916.3 A multitude of additional studies found that living at higher latitudes was associated with increased risk for mortality from cancer.3 In the 1990s, a strong significant negative correlation with colon cancer mortality and mean daily solar radiation in the US was observed. This was quickly followed by the observation in an 8-year prospective case-control study that the risk of getting colon cancer was 3-fold lower in people with a serum 25-hydroxyvitamin D, or 25(OH)D, level greater than 20 ng/mL.3 Several epidemiologic studies and other clinical studies, including the Women’s Health Initiative, observed that vitamin D deficiency was associated with greater risk for development of colorectal cancer.3 A quantitative meta-analysis on optimal vitamin D status for colorectal cancer prevention reported a 50% risk reduction associated with a serum 25(OH)D concentration of 34 ng/mL.3 The polymorphisms for the vitamin D receptor (VDR) also have been associated with colorectal cancer risk.3

The TP53 gene produces the protein p53, which suppresses cancer by controlling cell division, DNA repair, and apoptosis, and has been called “the guardian of the genome.”4 Vitamin D3, through its active form, 1,25-dihydroxyvitamin D3, or 1,25(OH)2D3, binds the VDR to regulate cellular proliferation, differentiation, apoptosis, and angiogenesis, all related to its potential anticancer activities.3

Approximately 50% of human cancers carry p53 mutations resulting in overproduction of mutant p53 (mutp53). These mutations not only result in loss of tumor-suppressing activities but also inactivate wild-type p53. Interestingly, mutp53 binds to the promoter region of the VDR responsive elements. This interaction is thought to elicit an antiapoptotic state and reduce the 1,25(OH)2D3-VDR’s ability to upregulate expression of proapoptotic genes.5,6

The Vitamin D and Omega-3 Trial (VITAL; NCT01169259) evaluated in a randomized double-blind placebo-controlled fashion the effect of 2000 IU of vitamin D3 and marine omega-3 fatty acids on cancer outcomes and concluded that there was no benefit of vitamin D3 supplementation for reducing risk of cancer. However, the authors acknowledged that there was a significant 25% reduction in cancer mortality. A secondary analysis of this study7 revealed that supplementation with 2000 IU vitamin D3 daily modestly reduced the incidence of metastatic and fatal cancer in the overall cohort. However, when this cohort was stratified for body mass index (BMI, calculated as weight in kilograms divided by height in meters squared), those with a BMI less than 25 had a hazard ratio of 0.62 (95% CI, 0.45-0.86), whereas for those with a BMI greater than 30, the hazard ratio was 1.05 (95% CI, 0.74-1.49), demonstrating that normal-weight participants (BMI <25) benefited the most from the vitamin D3 supplementation.7 A randomized controlled double-blind clinical trial that assessed the effect of vitamin D3 supplementation (600, 4000, or 10 000 IU daily for 6 months) on broad gene expression demonstrated a dose-dependent 25(OH)D3 alteration in broad gene expression, with 162, 320, and 1289 genes upregulated or downregulated in their white blood cells, respectively. In the group that received 10 000 IU vitamin D3 daily and raised their blood concentrations in the range of 50 to 100 ng/mL, 50% had a robust gene expression of greater than 5% of their genome, whereas the other 50% only expressed 2% to 5% of their genome. This demonstrated individual differences in gene responsiveness to the same vitamin D3 supplementation dose, with the participants attaining the same serum concentration of 25(OH)D.8 This observation may help explain why high-dose vitamin D with chemotherapy resulted in a difference in mean progression-free survival that was not statistically significant but with a significantly improved supportive hazard ratio.9

The observation by Kanno et al2 is a game changer for vitamin D and cancer. It 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. For more than 100 years, sunlight and vitamin D deficiency has been associated with the risk for many deadly cancers, including colorectal, prostate, and breast.3 However, there has been great skepticism as to whether this nutrient/hormone provides any benefit for reducing cancer risk and the morbidity and mortality associated with cancer. Several randomized clinical trials supported this skepticism.1,7 There are a variety of variables that can influence how vitamin D prevents and responds to cancer, including BMI, VDR polymorphisms, enhanced vitamin D catabolism, gene responsiveness to 1,25(OH)2D3, and the negative interaction that mutp53 has on the 1,25(OH)2D3-VDR’s ability to prevent and control cancer cell growth.3,5,6,10 It would be worthwhile to retrospectively, when possible, conduct a post hoc analysis for serum p53 antibodies and the immunohistochemistry presence for p53 in histologic cancer samples of studies that evaluated the potential benefit of vitamin D supplementation for improvement in cancer survival and found no benefit. More importantly, future studies evaluating vitamin D supplementation for the prevention of cancer and improvement of cancer outcomes should now include not only many of the variables mentioned above but also a measurement for p53 antibodies and immunohistochemical presence of p53. The results of the study by Kanno et al2 support the preponderance of association and clinical studies3,7 concluding that improvement in vitamin D status can be an effective strategy for promoting cancer remission and reducing cancer mortality. It is also important to recognize that most of the studies that have demonstrated a beneficial effect for reducing cancer risk and improving clinical outcomes have used at least 2000 IU vitamin D3 daily and raising circulating concentrations of 25(OH)D above 30 ng/mL without any significant untoward toxic effects.1-3,7 It is well documented that to achieve a circulating concentration of 25(OH)D above 30 ng/mL requires a vitamin D intake of at least 2000 IU daily, an amount that can only be obtained from a vitamin D supplement or by being a hunter-gatherer like Maasai herders and the Hadza, who maintain circulating concentrations of 25(OH)D above 30 ng/mL as a result of their daily exposure to sunlight.3

This important new observation by Kanno et al2 requires confirmation. It would be prudent, based on all available evidence, that patients with cancer consider improving their vitamin D status with 2000 IU daily to reduce morbidity and mortality associated with their cancer, except for those patients who have a hypersensitivity to vitamin D, including patients with granulomatous disorders and some lymphomas.

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10 References

• 1.Urashima M, Ohdaira H, Akutsu T, et al. Effect of vitamin D supplementation on relapse-free survival among patients with digestive tract cancers: the AMATERASU randomized clinical trial.  JAMA. 2019;321(14):1361-1369. doi:10.1001/jama.2019.2210
• 2.Kanno K, Akutsu T, Ohdaira H, Suzuki Y, Urashima M. Effect of vitamin D supplements on relapse or death in a p53-immunoreactive subgroup with digestive tract cancer: post hoc analysis of the AMATERASU randomized clinical trial.  JAMA Netw Open. 2023;6(8):e2328886. doi:10.1001/jamanetworkopen.2023.28886
• 3.Wacker M, Holick MF. Sunlight and vitamin D: a global perspective for health.  Dermatoendocrinol. 2013;5(1):51-108. doi:10.4161/derm.24494
• 4.Surget S, Khoury MP, Bourdon JC. Uncovering the role of p53 splice variants in human malignancy: a clinical perspective.  Onco Targets Ther. 2013;7:57-68. doi:10.2147/OTT.S53876
• 5.Sabapathy K, Lane DP. Understanding p53 functions through p53 antibodies.  J Mol Cell Biol. 2019;11(4):317-329. doi:10.1093/jmcb/mjz010PubMedGoogle ScholarCrossref
• 6.Stambolsky P, Tabach Y, Fontemaggi G, et al. Modulation of the vitamin D3 response by cancer-associated mutant p53.  Cancer Cell. 2010;17(3):273-285. doi:10.1016/j.ccr.2009.11.02
• 7.Chandler PD, Chen WY, Ajala ON, et al; VITAL Research Group. Effect of vitamin D3 supplements on development of advanced cancer: a secondary analysis of the VITAL randomized clinical trial.  JAMA Netw Open. 2020;3(11):e2025850. doi:10.1001/jamanetworkopen.2020.25850
• 8.Shirvani A, Kalajian TA, Song A, Holick MF. Disassociation of vitamin D’s calcemic activity and non-calcemic genomic activity and individual responsiveness: a randomized controlled double-blind clinical trial.  Sci Rep. 2019;9(1):17685. doi:10.1038/s41598-019-53864-
• 9.Ng K, Nimeiri HS, McCleary NJ, et al. Effect of high-dose vs standard-dose vitamin D3 supplementation on progression-free survival among patients with advanced or metastatic colorectal cancer: the SUNSHINE randomized clinical trial.  JAMA. 2019;321(14):1370-1379. doi:10.1001/jama.2019.2402
• 10.Jeon S-M, Shin E-A. Exploring vitamin D metabolism and function in cancer.  Exp Mol Med. 2018;50(4):1-14. doi:10.1038/s12276-018-0038-

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