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Folic Acid Linked to Elevated Prostate Cancer Risk

By Todd Neale, Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.

LOS ANGELES, March 10, 2009-- Daily folic acid supplementation may increase the risk of prostate cancer, a secondary analysis of a randomized trial revealed.

Men who took a 1 mg folic acid supplement a day had more than double the risk of developing prostate cancer as those who took a placebo (HR 2.58, 95% CI 1.14 to 5.86), Jane Figueiredo, Ph.D., of the University of Southern California here, and colleagues reported online in the Journal of the National Cancer Institute.

The findings came from a secondary analysis of the Aspirin/Folate Polyp Prevention Study, which found that aspirin had a protective effect and that folate increased the risk of having multiple or advanced colorectal adenomas.

Although adequate folate levels have been shown to play a role in the prevention of several cancers, as well as cardiovascular and neurological diseases, the vitamin's effect on prostate cancer risk remains unclear, the researchers said.

So they examined data from 643 men (mean age 57.4) who were randomized to either placebo or daily folic acid supplementation.

Through a mean follow-up of 6.6 years, 34 developed prostate cancer with a mean Gleason score of 6.4.

The estimated prostate cancer risk through 10 years was 9.7% for men taking folic acid supplements and 3.3% for men taking placebo, a difference that remained statistically significant after adjusting for age, alcohol use, aspirin treatment group, baseline multivitamin use, plasma levels of other B vitamins, and folic acid treatment group (P=0.02).

Folates may increase carcinogenesis through their role in the synthesis of nucleotides that are needed for proliferating cancer cells, the researchers said.

However, higher baseline plasma concentrations of folate in nonmultivitamin users and increased dietary folate intake -- as reported on a food frequency questionnaire -- were associated with trends toward a reduced risk of prostate cancer, although both fell short of statistical significance.

The researchers could not explain the apparent discrepancy in the results, and said that it might have something to do with the different forms of folate.

"The synthetic form of folate, folic acid, found in supplements is more bioavailable compared to folate from dietary sources and we know the amount of folate available is critical," Dr. Figueiredo said.

"The possibility of different effects from folic acid-containing supplements versus natural sources of folate definitely merits further investigation," the researchers said.

They acknowledged that the study was limited by the small number of prostate cancers, most of which were early stage, the inability to control for cancer screening, and the use of food frequency questionnaires, which could be subject to error.

In an accompanying editorial, Alan Kristal, Dr.P.H., of Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, and Scott Lippman, M.D., of M. D. Anderson Cancer Center in Houston, said the study adds to the growing literature demonstrating no benefit -- and possible harm -- from micronutrient supplementation for preventing cancer.

Because of the results of large cohort studies demonstrating positive associations between some foods and lower risk of cancer, it was not unreasonable to test micronutrient supplementation for cancer prevention, they said.

"However, in hindsight, this approach appears excessively reductionist," they said. "If food patterns do indeed affect cancer risk, this benefit is more likely related to energy intakes, relative macronutrient density, and exposure to complex mixtures of bioactive compounds that may include not only micronutrients but also non-nutrients such as glucosinolates and cathechins."

They said that future research should focus on using improved dietary assessment records in cohort studies, as well as developing "human models for cancer prevention that do not require many thousands of study participants and many years of follow-up."

The study was supported in part by grants from the National Cancer Institute and by a postdoctoral research fellowship from the National Cancer Institute of Canada. Wyeth, which markets folate supplements, provided the supplements for the study.

One of Dr. Figueiredo's co-authors is a consultant for Prozen.

The editorialists made no financial disclosures.

Primary source: Journal of the National Cancer Institute
Source reference:
Figueiredo J, et al "Folic acid and risk of prostate cancer: results from a randomized clinical trial" J Natl Cancer Inst 2009; DOI: 10.1093/jnci/djp019.

Additional source: Journal of the National Cancer Institute
Source reference:
Kristal A, Lippman S "Nutritional prevention of cancer: new directions for an increasingly complex challenge" J Natl Cancer Inst 2009; DOI: 10.1093/jnci/djp029.

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