Folate in Cancer Treatment and Prognosis: A Multi-"Omic" Approach
Authors: Cornelia Ulrich
Journal: Clinical Cancer Research (2007)

ED04-01  Multiple facets of folate status can impact outcomes among cancer patients. Accordingly, one can best evaluate the role of folate in cancer treatment and prognosis by adopting the paradigm of “integrated prognostics”, which encompasses pharmacogenetic and pharmacogenomic relationships, in addition to health behaviors. Central components of folate status include (1) folate intakes from diet and supplements; (2) folate-related tumor characteristics, including folate-related gene expression, DNA methylation, and possibly microsatellite instability; (3) polymorphisms in folate metabolism; and (4) use of chemotherapeutic agents, including thymidylate synthase inhibitors (e.g. 5-fluorouracil) or antifolates (e.g., methotrexate). This presentation will illustrate emerging knowledge on all of these interrelated factors in relation to colorectal cancer outcomes.  Folate is a critical nutrient for one-carbon transfer reactions, including the methylation of DNA and other molecules, as well as the de novo synthesis of thymidine and purines. These nucleotides are needed for DNA synthesis and repair, as well as for cellular growth. Accordingly, folate deficiency - or inhibition of folate-related enzymes - compromises DNA synthesis, induces DNA damage, and reduces overall genomic DNA methylation (1). To date it is not well defined whether folate deficiency impacts promoter DNA methylation and thus affects gene silencing.  Several chemotherapeutic agents, including 5-fluorouracil and antifolates (e.g., methotrexate), target enzymes in the folate pathway. Their efficacy is largely linked to the induction of DNA damage by causing DNA strand breaks. Genetic polymorphisms in folate-metabolizing enzymes are common and can alter the efficacy and toxicity associated of drugs targeting folate metabolism (2, 3). Similarly, expression levels of genes in folate metabolism appear to have both prognostic and predictive value. Most investigations to date have focused on thymidylate synthase expression (4), although more recent research points to a role of other genes in folate metabolism and nucleotide synthesis (5). The successful use of antifolate drugs and thymidylate synthase inhibitors in cancer treatment illustrates the utility of folate depletion in tumors. However, it is unclear whether a patients’ folate intake, either from dietary sources or supplements, will affect treatment efficacy or outcomes. This question is complex, because leucovorin, a form of folate, can enhance the binding of 5-FU and enhances its efficacy, yet other research suggests that higher folate status over the longer-term may abrogate 5-FU efficacy.  Recent data suggest that the timing of folate administration during carcinogenesis may result in opposing effects (6). A higher folate status is expected to protect against mutations and, thus, may reduce early on the progression to pre-malignant lesions. Yet, subsequently a higher folate status may enhance the growth of those lesions or any existing tumors, due to the importance of folate in nucleotide synthesis (7, 8). A recent randomized controlled trial among patients with a history colorectal polyps showed an elevated risk of recurring advanced and multiple adenoma in the intervention arm (1 mg folic acid/day) (9). These results are consistent with a role of folate in the promotion of existing pre-malignant lesions (6). The findings from this trial raise concern about the common use of folate-containing supplements in cancer patients in that they are also likely to harbor pre-malignant or malignant lesions. To date it is unknown whether folate use will adversely affect cancer progression, recurrence, and metastasis (6). Use of folate-containing supplements among cancer patients is high and commonly increases after diagnosis (10).  In summary, there is evidence that multiple components of folate status, including genetics, genomics, treatment, and health behaviors, can affect cancer outcomes. Together, these findings call for an integrated approach to investigating folate status and prognosis among cancer patients, taking into account the tumor’s and patient’s biologic characteristics, treatment modalities, as well as dietary and supplemental folate intakes.  References:  1. Choi SW, Mason JB. Folate status: effects on pathways of colorectal carcinogenesis. J Nutr 2002;132:2413S-2418S.  2. 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A randomized trial of folic acid for the prevention of colorectal adenomas. JAMA 2007;297:2351-9.  10. Velicer CM, Ulrich CM. Vitamin and mineral supplement use among U.S. adults after cancer diagnosis: a systematic review. Submitted.