Mounting evidence suggests that there may be an increased risk of prostate cancer among men with the highest levels of vitamin D.
At a public conference on vitamin D sponsored by the National Institutes of Health, Dr. Demetrius Albanes highlighted several studies in the medical literature, including a meta-analysis which found a 1.17-fold increased risk of prostate cancer among men in the highest categories of 25-hydroxy vitamin D [25(OH)D] status. That analysis was based on a review of 21 prospective cohorts involving 11,941 incident cases of prostate cancer ( J. Cancer Res. Clin. Oncol. 2014;140:1465-77 ). Similar findings were observed in an earlier Swedish study ( Cancer Causes Control; 2012;23:1377-85 ).
Genetic variants in four genes have been shown to predict circulating levels of vitamin D: GC, CYP24A1, CYP2R1, and DHCR7. However, a large analysis of cases and controls from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium failed to demonstrate a protective association between loci known to influence vitamin D levels and prostate cancer risk ( Cancer Epidemiol. Biomarkers Prev. 2013;22:688-96 ). In another study, Dr. Albanes and his associates found that serum vitamin D–binding protein (DBP) modified the association between serum 25-hydroxy vitamin D and prostate cancer, with higher risk for elevated 25-hydroxy vitamin D levels observed mainly among men having DBP concentrations above the median (odds ratio, 1.81 for highest vs. lowest quintile; P = .001) ( Int. J. Cancer 2013; 132:2940-7 ).
“This adds to the serologic evidence that we have seen mounting for an adverse association between higher vitamin D status and prostate cancer risk,” said Dr. Albanes, a senior investigator in the Nutritional Epidemiology Branch of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. “Many mechanisms could be put forward to be related to this. One is related to the association between a higher 25-hydroxy vitamin D status and total testosterone.” Researchers involved in an Oxford-based biomarkers project are currently analyzing vitamin D data from 12,500 cases and 15,000 controls in 32 cohorts ( http://www.ceu.ox.ac.uk/research/27/ ). Investigators from that effort “will weigh in on this topic,” he said. But for now, “there are no large trial data regarding vitamin D and prostate cancer; those would be very useful. Androgens and cell metabolism proliferation would be key targets as to how this might be coming about. I think it indicates that caution is indicated for this highly incident cancer worldwide.”
As for the impact of 25-hydroxy vitamin D on other cancers, most reports from observational studies are indicating an inverse (protective) association between 25-hydroxyvitamin D and the risk of colorectal cancer, yet data from the controlled trial component of the Women’s Health Initiative found no impact of the 400 IU dose combined with calcium after 8 years of supplementation ( N. Engl. J. Med. 2006; 354:684-96 ). Possible mechanisms of actions include the fact that 1,600 chromatin vitamin D response elements impact target genes in the colon and that vitamin D3 receptor and 1a-hydroxylase is expressed in extrarenal tissues including the colon. The anti-inflammation impact of higher vitamin D status or detoxification of secondary bile acids may also play a role.
With regard to pancreatic cancer, studies have shown an association between high concentrations of circulating levels of serum vitamin D and an elevated risk of this cancer type. A recent analysis by researchers including Dr. Albanes found that men with higher 25-hydroxy vitamin D concentrations and serum DBP below the median showed greatly elevated risk of pancreatic cancer (OR, 5.01 for highest vs. lowest quartile; P less than .0001), while risk was weakly inversely associated with serum 25-hydroxy vitamin D when DBP concentrations were higher (P = .001) ( Cancer Research 2012; 72:1190-98 ).
“The organ site differences are likely,” Dr. Albanes concluded. “Adverse associations do seem possible for prostate and pancreas, particularly strong at this point for prostate. We need additional targeted mechanistic research based on these observations. How is it that higher 25-hydroxy vitamin D status is related to a lowering of risk in colorectal cancer whereas in prostate cancer it’s elevated risk? Is it the androgen pathway? Is it cell proliferation? Consideration of cancer in the ranking of outcomes would have clinical and public health relevance, but that’s a [different] discussion.”
Dr. Albanes reported having no financial disclosures.
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