Folate and Cancer—Timing Is Everything

Abstract

ALARGE NUMBER OF EPIDEMIOLOGICAL STUDIES HAVE shown that a higher intake of folate, as well as higher intakes of vegetables and fruit, is associated with a decreased risk of colorectal polyps and cancer. These results have been corroborated by animal experiments, and biological mechanisms underlying these associations have been proposed: folate functions as a source of carbon moieties in the synthesis of nucleotides that are essential for DNA replication and repair. Folate deficiency leads to mutations and chromosomal damage—effects that are also central to the efficacy of antifolate chemotherapeutic agents (eg, methotrexate). In addition, folate status is important for the provision of S-adenosylmethionine, the universal methyl donor, involved in normal and pathological methylation of DNA. Disturbances in DNA methylation are relevant in carcinogenesis; however, the role of folate in these epigenetic changes is not yet understood. Despite its central function in maintaining DNA integrity, the role of folate in cancer prevention may not be as straightforward as initially conceived. Recent experiments have suggested that the timing of folate administration during cancer progression can modify outcomes. Folate administration prior to the existence of preneoplastic lesions can prevent tumor development, whereas provision of folate once early lesions are established appears to increase tumorigenesis. This initially counterintuitive observation may be explained by the function of folate in nucleotide synthesis. Rapidly proliferating tissues, including tumors, have an increased requirement for nucleotides; thus many cancers up-regulate folate receptors, and antifolate drugs are efficacious in cancer treatment. The overall chemopreventive effectiveness and potentially deleterious consequences of folate supplementation in humans can be established only through randomized controlled trials. In this issue of JAMA, Cole and colleagues present results of the first large chemoprevention trial investigating the effects of folate supplementation (at 1 mg/d folic acid, the synthetic form of folate) on the development of colorectal adenomas, established colorectal cancer precursors. Follow-up was performed with 2 colonoscopic surveillance cycles, at 3 years and approximately 3 to 5 years later. An important eligibility criterion for entry in the Aspirin/ Folate Polyp Prevention Study was history of an adenoma. This choice was made because the risk of a metachronous adenoma is high in this group compared with the appearance of new adenomas in previously unaffected individuals, and this criterion allowed a shorter trial and reduced sample size. The study therefore addressed secondary rather than primary prevention of adenoma. Overall, there was no effect of 1-mg/d supplementation on the development of adenoma, with risk ratios (RRs) of 1.04 (95% confidence interval [CI], 0.90-1.20) at 3 years and 1.13 (95% CI, 0.93-1.37) at the second follow-up. However, at the second follow-up, there was a 67% increased risk of advanced lesions (RR, 1.67; 95% CI, 1.00-2.80), along with a more than 2-fold increased risk of having at least 3 adenomas (RR, 2.32; 95% CI, 1.23-4.35). Of concern, the risk of cancers other than colorectal cancer was significantly increased in the intervention group (P=.02), an observation largely attributable to prostate cancer. Moreover, the study showed no evidence that folate supplementation reduced cardiovascular outcomes, an expected benefit because of the homocysteine-lowering effects of folate. How should the unexpected results of this study be interpreted? The most likely explanation for the increased risk of advanced and multiple adenomas in the intervention group is that undetected early precursor lesions were present in the mucosa of these patients (who are at increased adenoma risk), and that folic acid promoted growth of these lesions. This hypothesis is consistent with experimental studies showing increased colorectal neoplasia when folic acid is administered after lesions are present. Nonetheless, by the nature of the design, the results do not provide information on primary prevention by folic acid (the potential for folic acid to reduce the incidence of first adenomas). The question of efficacy of folate in cancer prevention is not resolved, and animal experiments showing chemopreventive effects of folate, as well as the strong observational epidemiological evidence, speak to the potential of folate as