Disclosures: Chandler reports no relevant financial disclosures.
March 03, 2021
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Study finds association between vitamin D, BMI and advanced cancer

Disclosures: Chandler reports no relevant financial disclosures.
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Although extensive research has explored the potential association between vitamin D and cancer, studies have produced conflicting results.

Epidemiological studies have shown that proximity to the equator, where high levels of sunlight exposure yield more vitamin D absorption, may be linked to lower incidence and death rates of certain cancers. The Vitamin D and Omega-3 Trial (VITAL) showed vitamin D did not decrease overall cancer incidence, but suggested it may reduce risk for cancer mortality.

Vitamin D Pills
Source: Shutterstock.

More recently, a secondary analysis of VITAL, published in JAMA Network Open, showed an association of vitamin D with an overall 17% reduced risk for advanced cancer. When assessing only participants with a normal BMI, the risk reduction increased to 38%.

Paulette D. Chandler, MD, MPH
Paulette D. Chandler

“For cancer prevention, we would advise individuals to continue to work on maintaining a healthy weight and make sure they’re not vitamin D deficient. Vitamin D deficiency is not always associated with symptoms, so it can go undiagnosed for years,” researcher Paulette D. Chandler, MD, MPH, a primary care physician and epidemiologist in the division of preventive medicine at Brigham and Women’s Hospital, said in an interview with Healio. “There is insufficient evidence to support universal screening for vitamin D deficiency, but some evidence suggests factors that may increase risk for vitamin D deficiency include obesity, darker pigmentation, low vitamin D intake, diseases that may contribute to malabsorption of vitamin D such as inflammatory bowel disease and little or no sun exposure.

“Vitamin D deficiency is easily corrected,” Chandler added. “Vitamin D is cheap, and it has minimal side effects.”

Chandler spoke with Healio about her findings and how adiposity might interact with vitamin D to reduce the risk for advanced cancer.

Healio: Does the finding of the original VITAL study rule out the possibility of an association between vitamin D and reduced risk for cancer?

Chandler: If you look at the original study that was published in The New England Journal of Medicine, the results hinted at a possible benefit of vitamin D supplementation, at 2,000 IU a day, for reduction in cancer death. The study reported a reduction in total cancer death of 17% that was not statistically significant but suggested a potential role in reducing fatal cancers. In a sensitivity the analysis that excluded 1 year of follow-up, the cancer death rate was 21% lower in the vitamin D group than the placebo group. In an analysis that excluded 2 years of follow-up, the cancer death rate was 25% lower in the vitamin D group than the placebo group.

Vitamin D is a fat-soluble hormone, so it is influenced by adiposity. We thought that BMI might influence the response to vitamin D supplementation based on the results from the original study, where vitamin D was significantly associated with 24% reduced risk for incident total cancer in persons with normal BMI, but in which researchers observed no risk reduction in incident total cancer among overweight or obese people. These findings suggest that vitamin D activity is greatly influenced by BMI.

Similarly, three meta-analyses of vitamin D clinical trials support our findings of a reduction in cancer mortality with vitamin D supplementation. These meta-analyses report about a 13% reduction in cancer mortality with vitamin D supplementation.

Healio: What is the mechanism of the association between vitamin D, BMI and advanced cancer?

Chandler: It’s not clear, but other studies have reported on differences in the response to vitamin D supplementation based on BMI, a crude measure of body fat. Our results suggest reduced vitamin D bioactivity in the setting of excess adipose tissue, even though obese and nonobese individuals had circulating measures of 25-hydroxyvitamin D over 30 ng/ml. We see that for those with BMI of less than 25 kg/m2, there is a reduction specifically in risk for advanced cancer.

If you look at the study by Pittas and colleagues of vitamin D and diabetes risk, The Vitamin D and Type 2 Diabetes (D2d) trial, you see that same interaction, where individuals who had a BMI of less than 25 kg/m2 seemed to have a reduction in insulin resistance with vitamin D supplementation. The Pittas study tested whether 4,000 IU daily of vitamin D3 would reduce the risk for type 2 diabetes in adults at high risk for type 2 diabetes. Researchers reported 30 % risk reduction for developing type 2 diabetes among those with BMI less than 30 kg/m2 and no reduction among those with BMI greater than or equal to 30 kg/m2. Both groups attained high 25-hydroxyvitamin D levels with treatment. Fat tissue is like a depot of hormones. The fat isn’t just sitting there; it’s active. It modulates the immune system. Unfortunately, individuals with advanced cancer are often vitamin D deficient.

Studies have suggested that obesity creates an environment where the immune system is unable to respond to and eliminate cancer cells because the T cells of the immune system are exhausted. Similarly, vitamin D supplementation may have different effects in individuals with obesity vs. individuals with normal weight based on impaired immune function in obesity. In extension, some evidence suggests that people classified as overweight or obese may have a better response to immune check point inhibitors than nonobese individuals.

Healio: Why does there seem to be a stronger association when it comes to advanced cancer?

Chandler: Once cancer starts to spread, there is more proliferation of cells and vessel development. The cells require more energy. Cells cannot continue to grow if they don’t have a good blood supply. The blood supplies energy to the cells. Vitamin D receptors are on almost every cell in the body, including cells in the immune system. Vitamin D, at least in animal studies, seems to regulate proliferation and cell death. Vitamin D may regulate the immune system and prevent blood vessel formation. Receptors are like a lock in a door that is opened with the right key. Opening the lock may start a cascade of actions that alters how a cell behaves.

Healio: Could these same benefits of vitamin D be derived through exposure to the sun?

Chandler: We know from epidemiological or ecological studies that individuals who live closer to the equator have a lower risk for developing cancers. A lot of physiological things happen when people spend time outdoors. Direct contact of sunrays on the skin allows the skin to start the production vitamin D. Sunlight helps with the production of melatonin. Sunlight influences the circadian rhythm. People often exercise outdoors, and muscle mass influences vitamin D activity.

Healio: Based on these findings, what recommendations might be made regarding vitamin D and BMI?

Chandler: The study supports the message of having a healthy body weight, which we know helps prevent cancer. A healthy weight also may be beneficial in terms of enhancing the benefits of vitamin D supplementation. Sometimes, people take a host of supplements, especially once they get a cancer diagnosis, but we also need to think about weight, because excess adipose tissue can diminish the benefits of vitamin D.

In terms of supplementation, recommendations state that individuals should have vitamin D levels over 20 ng/mL. However, in this study, participants had an average vitamin D level of around 38 ng/mL. So, if we’re thinking about cancer prevention, we probably want the vitamin D level to be over 30 ng/mL, at least. Even if we’re not thinking about cancer prevention, we want to prevent vitamin D deficiency, because it’s associated with increased risk for fractures.

Healio: What is next in terms of research into vitamin D and advanced cancer?

Chandler: The work of Kimmie Ng, MD, MPH, with her clinical trial of vitamin D among individuals with advanced colorectal cancer, will provide greater insight into potential benefits. Because there was a signal of benefit in her initial SUNSHINE trial, and it seemed to be greater among individuals with a normal BMI, this will be a good step.

References:

Chandler PD, et al. JAMA Netw Open. 2020;doi:10.1001/jamanetworkopen.2020.25850.
Haykal T, et al. J Community Hosp Intern Med Perspect. 2019;doi: 10.1080/20009666. 2019.1701839.

Keum N, et al. Ann Oncol. 2019;doi:10.1093/annonc/mdz059.

Manson JE, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1809944.

Ng, K, et al. JAMA. 2019;doi:10.1001/jama/2019.2402.

Pittas AG, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1900906.

Zhang X and Niu W. Biosci Rep. 2019;doi:10.1042/BSR20190369
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For more information:

Paulette D. Chandler, MD, can be reached at 75 Francis St., Boston, MA 02115; email: pchandler@bwh.harvard.edu.