Cancer risk with folic acid supplements: a systematic review and meta-analysis

Abstract

ObjectiveTo explore if there is an increased cancer risk associated with folic acid supplements given orally.DesignSystematic review and meta-analysis of controlled studies of folic acid supplementation in humans reporting cancer incidence and/or cancer mortality. Studies on folic acid fortification of foods were not included.Data sourcesCochrane Library, Medline, Embase and Centre of Reviews and Dissemination, clinical trial registries and hand-searching of key journals.ResultsFrom 4104 potential references, 19 studies contributed data to our meta-analyses, including 12 randomised controlled trials (RCTs). Meta-analysis of the 10 RCTs reporting overall cancer incidence (N=38 233) gave an RR of developing cancer in patients randomised to folic acid supplements of 1.07 (95% CI 1.00 to 1.14) compared to controls. Overall cancer incidence was not reported in the seven observational studies. Meta-analyses of six RCTs reporting prostate cancer incidence showed an RR of prostate cancer of 1.24 (95% CI 1.03 to 1.49) for the men receiving folic acid compared to controls. No significant difference in cancer incidence was shown between groups receiving folic acid and placebo/control group, for any other cancer type. Total cancer mortality was reported in six RCTs, and a meta-analysis of these did not show any significant difference in cancer mortality in folic acid supplemented groups compared to controls (RR 1.09, 95% CI 0.90 to 1.30). None of the observational studies addressed mortality.ConclusionsA meta-analysis of 10 RCTs showed a borderline significant increase in frequency of overall cancer in the folic acid group compared to controls. Overall cancer incidence was not reported in the seven observational studies. Prostate cancer was the only cancer type found to be increased after folic acid supplementation (meta-analyses of six RCTs). Prospective studies of cancer development in populations where food is fortified with folic acid could indicate whether fortification similar to supplementation moderately increases prostate cancer risk.

The MTHFR C677T Polymorphism and Prostate Cancer Risk: New Findings from a Meta-analysis of 7306 Cases and 8062 Controls

“…Cancers that more susceptible to folate intake are likely to be prevented at a relatively low folate level, and those cancers developing lesions at an early stage were probably more likely to be deteriorated by extra folic acid supplementation. A summary of six randomized controlled trials (Wien et al, 2012) showed folic acid intake provided a 24% increased risk of prostate cancer, and this mentioned us that prostate cancer is probably a kind of cancer with high sensitivity to folic acid. SNP C677T in MTHFR, a major enzyme in folate metabolic pathway, weakens its activity in catalyzing 5,10-methylene-THF to 5-methyl-THF, and 5-Methyl-THF is just the primary form of folate in plasma.…”

“…However, diet pattern and some variants were reported to be associated with altered risk of prostate cancer: Lin Yan (Yan et al, 2009) found consumption of soy foods could reduce prostate cancer risk and such protection may be associated with the type and quantity of soy foods; Ben Liu (Liu et al, 2012) between cruciferous vegetables intake and decreased risk of prostate cancer. As a common and major nutrient from daily vegetables, folate was believed to decrease risk of many cancer types, such as colon cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma and pancreatic cancer (Larsson et al, 2006;Kim et al, 2010), however, meta-analysis of six randomized controlled trials indicated association between a 24% increased risk of prostate cancer with folic acid intake (Wien et al, 2012).…”

Folate for therapy

“…Homocysteine elevation also occurs in people with diets deficient in folate, vitamin B 6 or B 12 . Regardless of the cause, supplementation with folate, vitamin B 6 or B 12 can lower plasma homocysteine.…”

“…Regardless of the cause, supplementation with folate, vitamin B 6 or B 12 can lower plasma homocysteine. In patients with homocystinuria, lowering homocysteine reduced the risk of cardiovascular events.…”

Folate: Essential and Beneficial, but is it Safe?

“…The association between excess folic acid and folate-sensitive cancers, such as colorectal cancer [5], has raised concerns regarding its safety with the need to find ways to minimize these risks to the public. Fortunately, a systematic review and meta-analysis of folate status and colorectal cancer risk just published by Moazzen et al [6], found no significant effect of folic acid on colorectal cancer risk.…”