Health Professionals:
Research on Folic Acid
Breast Cancer
Data from large cohort studies suggest that the increased risk for breast cancer observed at moderate to high intakes of alcohol consumption may be attenuated by adequate folate intakes (Rohan et al. 2000, Zhang et al. 1999). Folate status can be negatively impacted by chronic alcohol intake either through reduced intake of dietary folate, decreased absorption, or altered metabolism (Halsted et al. 2002). Higher folate intakes may compensate for this effect and translate into reduced risks for disease. Folate also has been associated with decreasing the risk for breast cancer in women with a family history of breast cancer (Sellers et al. 2004).
A meta-analysis of prospective and case-control studies examined dietary folate intake and blood levels in relation to risk of breast cancer. The results of this meta-analysis are consistent with previous data; there is no clear support for an overall relationship between folate intake or blood folate levels and breast cancer risk, but adequate intake may reduce the potential increased risk of breast cancer in those with moderate to high alcohol consumption (Larsson et al. 2007).
A meta-analysis of 16 prospective studies and 26 case–control studies examining the association between dietary folate intake and breast cancer risk reported that higher dietary folate intake was not significantly associated with breast cancer risk when pooling the results from prospective studies; however, there was a 21% reduced risk for breast cancer when comparing highest to lowest folate intake in pooled case-control studies (Chen et al. 2014). When stratifying by alcohol intake in prospective studies, higher folate intake conferred protection for women with higher alcohol intake, but not for those with lower intake, a finding consistent with other studies.
Lack of a significant association between folate intake and breast cancer risk among prospective cohort studies is reported by another meta-analysis that included 15 studies and over 1.8 million participants (Liu et al. 2014). This study reported no association between folate intake and breast cancer risk when stratifying by alcohol use. A meta-analysis of 36 observational studies related to dietary folate intake and breast cancer risk reported a significant 16% reduced risk for breast cancer when comparing highest to lowest dietary folate intake; however, there was no significant association with total folate intake in a pooled analysis of 15 studies (Tio et al. 2014).
A meta-analysis of 14 prospective studies reported no overall association between folate intake and breast cancer risk; however, a dose response analysis suggested a J-shaped association between folate intake and breast cancer risk (Zhang et al. 2014b). Folate intake of 200-320 micrograms/day was associated with lower breast cancer risk while daily intakes of >400 micrograms were associated with increased risk. This study also noted a reduced risk for breast cancer with higher folate intake when daily alcohol consumption exceeded 10 grams.
A meta-analysis of randomized controlled trials on the effects of folic acid supplementation and various types of cancer reported no significant effect of supplementation for an average duration of 5 years on breast cancer incidence (Vollset et al. 2013).
Two meta-analyses report no significant effect of circulating folate levels on breast cancer risk (Chen et al. 2014, Tio et al. 2014).
Although collectively, these data are conflicting, they suggest that folate may be beneficial when other risk factors for disease are present.
Cervical Cancer
Evidence of a protective effect of folate on cervical cancer or dysplasia is scant. However, associations have been reported between folate status and the presence of human Papillomavirus (HPV), an important risk factor for cervical dysplasia.
Women with low red blood cell folate concentrations and HPV were reported to have an increased risk for cervical dysplasia (Butterworth et al. 1992), and lower serum folate concentrations coexisting with HPV infection have been associated with a 7-fold increase in the risk for cervical dysplasia and carcinoma (Kwasniewska et al. 1997). Data from a cross-sectional study paralleled earlier research findings that lower folate status was associated with high-risk HPV infection and with a diagnosis of cervical intraepithelial neoplasia or invasive cervical cancer (Flatley et al. 2009). If folate is important to the onset of cervical cancer, it appears that it may be most important during the early stages of carcinogenesis.
A 2016 meta-analysis of 6 case-control studies that included 873 cases of cervical cancer reported that serum folate levels were significantly different between cases and controls, with cases having significantly lower serum folate (Zhou and Meng 2016). When stratifying by folate status, deficiency (defined differently in the studies) was associated with an increased risk for cervical cancer, particularly in studies on Asian populations or studies with smaller sample sizes (i.e., < 500). This association was not seen in studies on American populations or those with larger sample sizes.
A meta-analysis of 11 case-control studies investigating the association between the MTHFR 677 C>T polymorphism and cervical cancer risk reported an association that may be race-specific (Mei et al. 2012). Overall, there was no relationship; however, subgroup analysis reported the odds of having the TT genotype were lower in Caucasians and Europeans who had cervical cancer, but higher in Asians who had cervical cancer when compared to controls.
Other Cancers
A 2006 systematic review with meta-analysis of epidemiologic studies evaluated the association of folate intake with the risk of esophageal, gastric, and pancreatic cancer. There was no significant association between dietary folate and the risk of gastric cancer, but the findings supported the hypothesis that folate may play a role in carcinogenesis of the esophagus and pancreas. Individuals in the highest category of dietary folate intake were reported to have a significantly (34%, 50% and 51%) lower risk of esophageal squamous cell carcinoma, esophageal adenocarcinoma, and pancreatic cancer, respectively, compared with those in the lowest category (Larsson et al. 2006).
A 2010 study investigated the association between dietary folate intake and pancreatic cancer in a large cohort of over 100,000 men and women aged 55-74 years. Women in the highest quartile of food folate intake showed a statistically significant 53% reduction in risk for pancreatic cancer compared with those in the lowest quartile. Increasing quartiles of total folate revealed a significant trend for a reduction in risk for pancreatic cancer risk in women. No significant association was found between supplemental folic acid use and pancreatic cancer risk. Overall conclusions of this study infer that higher food folate and total folate intakes are associated with decreased pancreatic cancer in women, but not men (Oaks et al. 2010).
Compared with other types of cancer, there is less research available on the relationship of folate intake and lung cancer. A 2006 pooled analysis of 8 prospective studies examined the association between folate intake and lung cancer. The results indicated that folate intake was not associated with a reduction in risk for lung cancer (Cho et al. 2006).
A study using the NHANES III mortality data investigated the association between baseline serum folate concentrations and all-cancer mortality determined from death certificate data (Yang et al. 2009). After an average of 8.6 years, a non-linear association was observed between serum folate concentration and risk of all cancer mortality in which persons with low, but not classically deficient, folate status were at a statistically significant higher risk of cancer mortality compared with participants with deficient serum folate concentrations defined as less than 3.0 ng/mL (6.8 nmol/L). There was no association between folate concentrations above 4.5 ng/mL (10.2 nmol/L) and risk of all-cancer mortality. Further studies are warranted to determine whether these findings are due to chance.
A meta-analysis of randomized controlled trials on the effects of folic acid supplementation and various types of cancer reported no significant effect of supplementation for an average duration of 5 years on the incidence of cancer overall, as well as cancer of the large intestine, prostate, lung, breast, stomach, and other specific sites (Vollset et al. 2013).
Overall, the relationship between folate status and cancer remains controversial.
Folate intake has been associated with reduced risk for certain cancers, particularly colon and breast cancer. In the case of breast cancer, folate may especially be beneficial to risk reduction if other risk factors are present, including family history of breast cancer or excess alcohol consumption.
