Folic Acid and Risk of Prostate Cancer: Results From a Randomized Clinical Trial

Abstract

Data regarding the association between folate status and risk of prostate cancer are sparse and conflicting. We studied prostate cancer occurrence in the Aspirin/Folate Polyp Prevention Study, a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas conducted between July 6, 1994, and December 31, 2006. Participants were followed for up to 10.8 (median = 7.0, interquartile range = 6.0-7.8) years and asked periodically to report all illnesses and hospitalizations. Aspirin alone had no statistically significant effect on prostate cancer incidence, but there were marked differences according to folic acid treatment. Among the 643 men who were randomly assigned to placebo or supplementation with folic acid, the estimated probability of being diagnosed with prostate cancer over a 10-year period was 9.7% (95% confidence interval [CI] = 6.5% to 14.5%) in the folic acid group and 3.3% (95% CI = 1.7% to 6.4%) in the placebo group (age-adjusted hazard ratio = 2.63, 95% CI = 1.23 to 5.65, Wald test P = .01). In contrast, baseline dietary folate intake and plasma folate in nonmultivitamin users were inversely associated with risk of prostate cancer, although these associations did not attain statistical significance in adjusted analyses. These findings highlight the potential complex role of folate in prostate cancer and the possibly different effects of folic acid-containing supplements vs natural sources of folate.

The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake

“…Although folate deficiency has been linked to cancer susceptibility via increased uracil misincorporation (10), recent evidence suggests that high intake (Ն1 mg/d) of FA may exacerbate some preexisting cancers or progression of precancerous lesions, such as in the colon (11) or prostate (12). The activity of natural killer cells has been reported to be decreased in older women having higher plasma levels of unmetabolized FA (13).…”

High serum folate is associated with reduced biochemical recurrence after radical prostatectomy: Results from the SEARCH Database

“…Alternatively, folic acid supplementation may prevent malignant cell transformation on the one hand, but maintain the high cell proliferation rate that is characteristic in neoplastic cells on the other (16)(17)(18). From an epidemiological perspective, the largest randomized trial comparing folic acid supplementation versus placebo showed a higher risk of prostate cancer in men receiving folic acid supplementation, though this was a secondary outcome (4). The same results were not seen in large observational cohort studies where folate was not associated with prostate cancer (10,19).…”

“…However, the role of folate in prostate cancer carcinogenesis is very controversial (3). There is evidence suggesting dietary folate may be protective against prostate cancer while folic acid supplementation may promote cancer (4).To date, no studies have examined the role of folate in prostate cancer recurrence after primary treatment.…”

Nutritional Implications of Obesity: Before and After Bariatric Surgery

“…especially in the prostate, probably because of the increased availability of folate for the faster nucleotide synthesis of tumor cells. 17 For now, the majority of human studies indicate that dietary folate is protective against colon cancer.…”