Folate and cancer: a tale of Dr. Jekyll and Mr. Hyde?
Young-In Kim

The role of folate, a water-soluble B-vitamin, in cancer development and progression remains highly controversial. The crux of the hotly debated issue is whether folic acid (the synthetic form of folate) and/or high folate intake from dietary and supplemental sources and blood concentrations in general can increase cancer risk. Folate mediates the transfer of one-carbon units involved in nucleotide biosynthesis and biological methylations, aberrancies of which are integrally related to cancer development (1). Counterintuitive to the role of antifolates in cancer treatment that is based on the interruption of intracellular folate metabolism resulting in intracellular folate deletion and ineffective DNA synthesis (2, 3), a large body of epidemiologic studies has suggested an inverse association between intakes and blood concentrations of folate and the risk of several major human malignancies including cancer of the colorectum (4–10), pancreas (11–14), prostate (15, 16), and breast (17–23). Although the precise nature and magnitude of this purported inverse relation have been inconsistent and equivocal, general consensus from a portfolio of evidence from observational epidemiologic and animal studies is that folate deficiency increases the risk of certain cancers (24, 25).

As a corollary to this, based on the belief that folic acid is safe and may be an ideal functional food component for cancer prevention, several folic acid intervention trials in humans were undertaken and premature recommendations to take a high amount of folic acid to prevent cancers prevailed. However, seminal work performed in animal models has suggested that folate may possess dual modulatory effects on cancer development and progression depending on the stage of cell transformation at the time of intervention (26, 27). Folic acid supplementation may prevent initiation and early promotion of cancer development but it may promote the progression of established precancerous and cancer cells (26, 27).

Most randomized clinical trials have generally shown a null effect of folic acid supplementation on cancer biomarkers [e.g., colon adenomatous polyp recurrence (28) and cervical dysplasia regression (29, 30)] or a marginally protective effect [e.g., bronchial metaplasia regression (31, 32)]. Alarmingly, however, a few folic acid chemoprevention trials in humans conducted in predisposed individuals have demonstrated a potential tumor-promoting effect of folic acid supplementation. For example, in the Aspirin/Folate Polyp Prevention Study, folic acid supplementation at 1 mg/d for 6 y (n = 1021) significantly increased the risk of recurrence of advanced adenomas with a high malignant potential by 67% (RR: 1.67; 95% CI: 1.00, 2.80) and the risk of multiple adenomas 2.3-fold (RR: 2.32; 95% CI: 1.23, 4.35) (33). Furthermore, a 10-y follow-up study of this trial showed that those who received folic acid supplementation had a significantly increased risk of prostate cancer (34). A plausible mechanistic explanation proposed for these observations was that folic acid supplementation might have promoted the progression of undiagnosed preexisting (pre)neoplastic lesions in the colorectum and prostate in these highly predisposed individuals (27, 35).

Systematic reviews or meta-analyses of several large randomized clinical trials of folic acid supplementation with or without other B vitamins and cardiovascular disease outcomes as the primary endpoint reported either an increase (36) in or null effect (37–39) on cancer incidence and/or mortality as the secondary endpoint. A meta-analysis of 10 clinical trials (n = 38,233) including 3 colorectal adenoma recurrence trials and 7 trials that examined the effect of B vitamins on cardiovascular outcomes reported a marginally statistically significant 7% increase in overall cancer incidence associated with folic acid supplementation (RR: 1.07; 95% CI: 1.00, 1.14) (40). A meta-analysis of 6 clinical trials reporting prostate cancer incidence showed a 24% increase in prostate cancer incidence associated with folic acid supplementation (RR: 1.24; 95% CI: 1.03, 1.49) (40). A more recent meta-analysis of 13 clinical trials (10 trials for prevention of cardiovascular disease [n = 46,969] and 3 colorectal adenoma recurrence trials [n = 2652]) found a marginal 6% increase in overall cancer incidence (RR: 1.06; 95% CI: 0.99, 1.13) (41).

This brings us to the study by Tu et al. (42) published in this issue of the Journal. This study investigated the association between folate and folic acid intake at diagnosis and recurrence of non–muscle-invasive bladder cancer (NMIBC) in 619 patients in a prospective manner. In this study, medium to high folic acid intake was associated with a significantly increased risk of recurrence (>70%) and adverse tumor characteristics (e.g., multifocal tumors) among NMIBC patients compared with low intake, while natural folate intake was inversely, albeit non-significantly, associated with risk of tumor progression. Although NMIBC is associated with a >90% 5-y cancer-specific survival rate, >50% will recur and >10% progress to muscle invasion within 5 y, which dramatically reduces the 5-y cancer-specific survival rate (43). If confirmed, therefore, the findings from this study suggest that NMIBC patients should not be taking folic acid supplementation, while maintaining optimal folate status from natural sources of folate. In this regard, a meta-analysis of 13 epidemiologic studies that examined the association between folate intake and bladder risk reported a significant 16% reduction in the risk of bladder cancer in those with the highest total folate intake compared with those with the lowest intake (RR: 0.84; 95% CI: 0.72, 0.96); the reduction was more evident with dietary natural folate (RR: 0.82; 95% CI: 0.65, 0.99) than with folic acid (RR: 0.91; 95% CI: 0.58, 1.25) (44). Notwithstanding limitations associated with this study, the findings from this study add to a growing list of clinical trials demonstrating a tumor-promoting effect of folic acid supplementation [e.g., increased incidence of total cancer in the B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF) trial (45)] and of high dietary folate intake [e.g., increased risk of overall skin cancer, nonmelanoma skin cancer, and basal cell carcinoma in the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) trial (46)].

Folate intake and blood concentrations in North America have dramatically increased over the past decade, owing primarily to the consumption of supplemental folic acid by ≤30–40% of the North American population and partly to mandatory folic acid fortification (47–49). What is most concerning is the fact that 30–40% of newly diagnosed cancer patients initiate folic acid–containing vitamin supplementation (50, 51). In North America, the intake of folic acid can easily exceed the Tolerable Upper Intake Level of 1000 μg/d (52) by use of multivitamins (400 μg folic acid), health drinks or bars (≤400 μg folic acid), breakfast cereals (≤400 μg folic acid/serving), and fortified food products (∼100–200 μg/d) (53). Higher supplemental concentrations of folic acid (1–5 mg/d) are routinely provided to certain patients on antifolate medications to prevent adverse effects relating to folate depletion (54, 55). A recent study using the NHANES 2003–2006 data has reported that total folate and folic acid intakes are highest for those aged ≥50 y, and ∼5% of US adults aged 51–70 years exceed the Tolerable Upper Intake Level (>1000 µg) of folic acid each day (48), likely from a regular consumption of folic acid supplements (56). This age group is at risk of developing several common cancers including colorectal and prostate cancers.

Based on systematic reviews of existing literature, the expert panel convened by the US National Toxicology Program and the Office of Dietary Supplements in 2015 concluded that there was no benefit for cancer reduction from supplements among people whose baseline folate status is adequate and that there was a consistent enough suggestion in human studies of an adverse effect on cancer growth from supplemental folic acid to justify further research (25). Several important issues regarding the effect of folic acid supplementation on cancer development and progression remain to be clarified. First, the threshold level above which folic acid supplementation may exert the tumor-promoting effect on (pre)neoplastic lesions as well as dose-response of such an effect are unknown and have not been established in humans or in animals. Second, whether the potential tumor-promoting effect of high folate status is specific to synthetic folic acid or is generalizable to naturally occurring folates, such as 5-methyltetrahydrofolate, present in foods is unknown. It has been speculated that most, if not all, of the purported adverse health effects associated with high folate status, including cancer promotion, are attributable to folic acid and not natural folates. In this regard, higher concentrations of circulating unmetabolized folic acid in blood have been reported in the postfortification era, likely attributable to a high folic acid intake from both supplementation and fortification (57, 58). Whether or not high circulating unmetabolized folic acid poses a health risk, including the tumor-promoting effect, is a hotly debated topic as some of the purported adverse effects of high intakes and blood concentrations of folate and folic acid have been attributed to unmetabolized folic acid (59, 60). To date, biochemical and carcinogenic effects of folic acid have not been systematically compared with those of naturally occurring folates. Whether or not 5-methyltetrahydrofolate is a safer and effective alternative to folic acid in providing supplemental concentrations of folate is an important research question. Third, the critical stage of cell transformation at which folic acid supplementation may exert a tumor-promoting effect has not yet unequivocally been established.

Whether or not folic acid supplementation can prevent or promote the development of cancer remains a highly controversial, complex, and unresolved issue at present. The portfolio of evidence from animal and human studies collectively suggests that folic acid supplementation may prevent neoplastic initiation but it may promote the progression of established precancerous lesions. Notwithstanding the lack of compelling supportive evidence, folic acid supplementation should be avoided in cancer patients and survivors and in highly predisposed and susceptible individuals at risk of developing cancer. Furthermore, folic acid supplementation should not be routinely recommended to those ≥50 y of age, an age group with a high intake of folic acid (48) and with a high prevalence of precursor lesions (61). Given the inverse association between dietary folate intake and cancer risk as well as a more consistent protective effect associated with natural folates compared with synthetic folic acid observed in epidemiologic studies, folate should be obtained from natural dietary sources for optimal folate status and for a possible cancer-preventive effect. The public health ramifications of the potential cancer-promoting effect of folic acid supplementation are quite serious. Although recent population-based epidemiologic studies have provided some reassurance that the drastically increased folate and folic acid intake postfortification have not resulted in an increased incidence of colorectal cancer in the United States and, in fact, that there has been a decreasing trend of colorectal cancer incidence postfortification, these studies are associated with significant limitations (62, 63). As such, safety and adverse effects, with a particular attention to cancer incidence and mortality, of the dramatically increased folate status in North America resulting from prevalent folic acid supplemental use require continued careful monitoring.