Higher Levels of Vitamin D Linked to Lower Cancer Risk, Again

Fran Lowry

April 12, 2016

Higher levels of vitamin D are associated with a reduction in cancer risk of more than a 65%, according to a study published online April 6 in PLOS ONE.

The finding comes from a pooled analysis of results from a randomized trial and a prospective cohort study, and the higher levels of vitamin D are serum levels of 25-hydroxyvitamin D (25[OH]D) above 40 ng/mL.

"Higher serum 25-hydroxyvitamin D concentrations have been associated with a lower risk of many different cancers, for example breast, colon, and lung, across a range of concentrations," said researcher Cedric Garland, DrPH, from the University of California, San Diego, School of Medicine and the Moores Cancer Center.

"We have been studying this since the 1980s, when my brother, Frank Garland, who is now deceased, and I observed that cancer was mainly due to a deficiency of vitamin D, the same way that scurvy was due to a deficiency of vitamin C," Dr Garland told Medscape Medical News.

One of his coauthors — Joan Lappe, PhD, from Creighton University in Omaha, Nebraska — was involved in a previous randomized controlled clinical that prompted this pooled analysis (Am J Clin Nutr. 2007;85:1586-1591), Dr Garland explained.

That earlier study showed that women randomly assigned to about 1000 IU of vitamin D per day had "a 77% reduction in their incidence of all cancers," he reported.

"So we knew in 2007 that we could prevent almost 80% of cancer — breast, bowel, and lung cancers — primarily in women. I was shocked because we have known this for a long time and yet nobody has done anything. We decided to get a cohort of people taking 2000 IUs, or even a bit more," he said, "and sure enough, we have found the same thing."

Dr Cedric Garland

Dr Garland's team pooled data from two cohorts: the Lappe cohort, which consisted of 1169 women with a median serum 25(OH)D concentration of 30 ng/mL; and the GrassrootsHealth cohort, which consisted of 1135 women with median of 48 ng/mL.

The median age of the 2304 women in the pooled cohort was 64 years (range, 60 to 69 years). All were non-Hispanic white women with no known cancer at study entry.

Women in the Lappe cohort came from Eastern Nebraska and were randomized to one of three groups: calcium (either 1400 mg/day of calcium citrate or 1500 mg/day of calcium carbonate) plus vitamin D placebo; calcium plus 1000 IU/day of vitamin D₃; or calcium placebo plus vitamin D placebo (control group). The women were assessed every 6 months. When a diagnosis of cancer was reported, medical records were examined to confirm the diagnosis and ascertain the diagnosis date. Serum 25(OH)D concentrations were measured at baseline and each year thereafter.

Women in the GrassrootsHealth cohort completed health questionnaires and did home blood-spot testing to determine serum 25(OH)D concentrations at 6-month intervals from January 2009 to December 2014. Cancer diagnosis dates and types were reported, as were average daily calcium supplement intake, smoking status, and height and weight for the calculation of body mass index (BMI).

The researchers noted the incidence of invasive cancer, with the exception of skin cancer, over a median of 3.9 years.

During the observation period, 58 women in the pooled cohort were diagnosed with cancer (48 from the Lappe cohort and 10 from the GrassrootsHealth cohort). The most common cancer diagnosed during the study was breast cancer, which accounted for 43% of all cancers in the pooled cohort.

After adjustment for age, BMI, smoking status, and calcium supplementation, the age-adjusted cancer incidence was 1020 cases per 100,000 person-years in the Lappe cohort and 722 per 100,000 person-years in the GrassrootsHealth cohort.

Cancer incidence declined with increased 25(OH)D. Women with 25(OH)D concentrations of at least 40 ng/mL had a 67% lower risk for cancer than women with levels of 20 ng/mL or less (hazard ratio, 0.33; 95% confidence interval, 0.12 - 0.90).

Other studies have shown similar reductions in risk for individual cancers, Dr Garland noted.

In one hospital-based case–control study, women with serum concentrations above 60 ng/mL had an 83% reduction in breast cancer risk, compared with women with concentrations below 20 ng/mL (P < .001) (Eur J Cancer. 2005;41:1164-1169).

In another study, women with 25(OH)D concentrations of at least 30 ng/mL had a 63% lower risk for breast cancer than women with concentrations below 20 ng/mL (PLoS One. 2011;6:e17251). And for postmenopausal women, the risk was 71% lower.

More recently, a nested case–control study showed that women with 25(OH)D concentrations of at least 29 ng/mL had a 55% lower risk for colorectal cancer than women with concentrations below 18 ng/mL (Cancer Prev Res [Phila]. 2015;8:675-682).

"For the people who weren't satisfied with one clinical trial, we now have a second major cohort study with almost as good results, so we had to publish it. Maybe some good souls who don't want to see so many women get breast cancer will take our findings to heart. To me, it's a scandal. Science has given us a way to protect women from breast cancer and nobody's doing anything about it. It's just a shame," Dr Garland said.

He recommends that every female 9 years and older take 4000 IU of vitamin D a day "if you want to nip cancer in the bud. There's a certain amount of cancer risk that is set in the first 15 years of life. The National Academy of Sciences has set 4000 IU as what they call the top tolerable level of intake, but they are not saying they recommend it, they are saying it is safe. The only recommended dose is 600 IU to age 70 and 800 IU at ages 71 and older, but they also say you can take 4000 IU and you will be fine, so that is what we are basing our recommendation on," he said.

Experts Cite Study Pros and Cons

The finding of an association between serum 25(OH)D concentrations of at least 40 ng/mL and an overall lower cancer risk in women 55 years and older is "exciting," said Ting-Yuan David Cheng, PhD, from the Department of Cancer Prevention and Control at the Roswell Park Cancer Institute in Buffalo, New York.

"A really unique feature of this study is that both studies attempted to, either involuntarily or voluntarily, increase the participants' vitamin D status. By repeatedly monitoring their vitamin D status, the study result is more robust than a traditional observational study, which often measures 25(OH)D only at the beginning of follow-up," Dr Cheng told Medscape Medical News.

"One issue the research team has to clarify is whether the 25(OH)D levels measured from blood spots in the GrassrootsHealth cohort are comparable to the serum level, which remains the gold standard for testing vitamin D status. A longer follow-up is also warranted to confirm the study finding, and the finding may not be applicable to women of a younger age, or to men," he said.

Dr Harvey Risch

The study has some limitations, said Harvey Risch, MD, PhD, from the Yale University School of Medicine in New Haven, Connecticut.

"The two cohorts merged in this analysis do not have comparable cancer risks, and had only slightly overlapping distributions of serum vitamin D. Even though the authors adjusted for age, BMI, and smoking in their analyses, it is not clear that these adjustments were sufficient, or that these variables were not, in themselves, responsible for a lot of the vitamin D differences between the cohorts," Dr Risch told Medscape Medical News.

"In addition, the number of cancers that were diagnosed was small, and the cancers reported in the GrassrootsHealth cohort suggest that an appreciable number of cancers were not identified. There was no significant cancer association with serum vitamin D in just the Lappe cohort, which had all but 10 of the reported cancer cases," he said.

Overall, the association between serum vitamin D or dietary vitamin D and cancer risk is not yet established.

"The authors attribute the cancer risk differences to serum vitamin D levels, but that conclusion is not well established on the basis of the data here. Further, because of long latencies between times of cancer initiation and diagnosis, and latency differences across various types of cancer, short-term studies do not really address whether vitamin D levels or intake are causally associated with cancer risk. So overall, the association between serum vitamin D or dietary vitamin D and cancer risk is not yet established," he said.

Dr Marji McCullough

Marji McCullough, ScD, RD, strategic director of nutritional epidemiology at the American Cancer Society, agrees that the numbers are small and follow-up short.

"The study is addressing an important question of identifying modifiable risk factors for cancer prevention, with a focus on vitamin D. A strength of this analysis is that they were able to look at high vitamin D levels. However, these results are based on a very small sample size, 58, and a relatively short follow-up of 3.9 years overall. One of the two studies included in this pooled analysis had only 10 cases of cancer and 1.2 years of follow-up," Dr McCullough reported.

She also noted that vitamin D levels could have been influenced by the cancer itself.

"The most common of the 58 cancers that developed was breast cancer. While there has been a lot of interest in the relation between vitamin D and breast cancer, some prospective studies with larger numbers of cases have not shown an association. The case–control studies, as noted by these authors, have shown significant reductions in risk. In case–control studies, blood levels of vitamin D are measured at or after diagnosis; therefore, it is possible that vitamin D levels in the blood are influenced by the disease itself," she said.

Dr McCullough, who is currently collaborating on pooled analyses from several cohort studies looking at blood levels of vitamin D in relation to colorectal cancer and breast cancer, cautions against taking excessive vitamin D supplementation until further research shows that doing so is safe.

"There has been much controversy about vitamin D, and the controversy has been, in part, because most of the limited number of randomized controlled trials have not shown a reduction in cancer risk, whereas observational studies have reported inverse associations, most consistently for colorectal cancer. The trials have generally provided a low dose of vitamin D or had compliance issues, but ongoing trials designed to test these relations are using higher doses," she said.

"It is important to note that some studies show increased risk for some cancers or other outcomes with vitamin D concentrations higher than 40 ng/mL in the blood, although this has been inconsistent. We need to better understand the effects of these high levels on multiple outcomes before recommending high-dose supplements," Dr McCullough said.

The study was funded by Bio-Tech Pharmacal, the Pure North S'Energy Foundation, and the Vitamin D Society. Funding for the Lappe study came from the Department of Health and Human Services. Funding for the GrassrootsHealth study was through self-sponsorship by participants and donations from the funders listed above. Dr Garland, Dr Cheng, Dr Risch, and Dr McCullough have disclosed no relevant financial relationships.

PLoS One. 2016;11:e0152441. Full text


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