Dietary folate consumption and breast cancer risk.

Deficient dietary folate intake may predispose individuals to cancer as a consequence of disruption of DNA synthesis, repair, and methylation (1,2); diets deficient in methyl groups may result in the activation of oncogenes and inactivation of tumor suppressor genes (3). Relatively low intake of methionine and relatively high intake of alcohol may increase folate requirements, the former by reducing the availability of methyl groups (4) and the latter by interfering with folate metabolism (5). Epidemiologic evidence linking dietary folate, methionine, and alcohol intake with cancer risk is limited. Two prospective studies (6,7) showed that diets low in folate and methionine and high in alcohol were associated with increased risk of colorectal adenomas and of colon cancer, respectively. Another prospective study (8) showed an increased risk of recurrence of colorectal adenoma in association with a high-alcohol, lowfolate diet, and a case–control study (9) showed an increased risk of rectal cancer in association with a low-folate, high-alcohol dietary combination. A recent prospective study (10) showed some evidence for an inverse association between folate intake and breast cancer risk in women with relatively high alcohol intake; alcohol consumption by itself has been associated with an increased breast cancer risk (11). Given the paucity of currently available prospective data, we examined the association between dietary folate intake and breast cancer risk and its modification by methionine and alcohol intake in a cohort study in Canada. A case–cohort analysis was undertaken within the cohort of 56 837 women in the Canadian National Breast Screening Study (NBSS) (12–14) who completed a self-administered, quantitative food-frequency questionnaire developed for the NBSS (15,16). The NBSS was approved by the University of Toronto Human Subjects Review Committee. The dietary questionnaire ascertained the frequency of consumption and usual portion size of 86 food items (including alcoholic beverages) and was used to estimate daily intake of alcohol (standard servings of beer [350 mL], wine [120 mL], and spirits [45 mL] were estimated to contain 12.6 g, 13.8 g, and 17.1 g of ethanol, respectively) and calories with the use of a nutrient database developed by modifying the U.S. Department of Agriculture’s food-composition tables to include typically Canadian foods (17). Data on intake of folate, methionine, and specific carotenoids were obtained from previously published values (18– 20). The values for folate intake presented here are for intake from dietary sources alone, since data on the folate content of vitamin supplements were not available. Major sources of dietary folate were liver, green leafy vegetables, and whole-grain cereals. Case patients were the 1469 women diagnosed with incident invasive carcinoma of the breast during follow-up from recruitment (which occurred from 1980 through 1985) to December 31, 1993, and ascertained by record linkage to the Canadian Cancer Database. For the analysis, a subcohort was constructed by the selection of a random sample of 5681 women from the dietary cohort. After exclusions, the main analyses were based on 1336 case patients (1469 case patients minus 128 with no diet questionnaire available minus five with extreme values for energy intake [i.e., those subjects for whom natural log-transformed total energy intake was more than three standard deviations from the mean natural logtransformed total energy]) and 5382 women (including 144 of the case patients) in the subcohort (5681 minus 256 with no diet questionnaire available minus 43 with extreme energy values). Incidence rate ratios (IRRs) and robust standard errors (21) for the association between folate intake and breast cancer risk were estimated with the use of Poisson regression. Case patients contributed person-time to the study from their date of enrollment until the date of diagnosis of their breast cancer, and non-case subjects contributed person-time from their date of enrollment until December 31, 1993, or death (whichever came first). The IRRs were adjusted for energy intake (22) and for the variables listed in the footnotes to the tables. Tests for trend (on 1 df) in the association between folate and breast cancer risk were performed by fitting categorized variables as continuous variables, and tests for interaction were based on likelihood ratio tests comparing models with and without product terms representing the variables of interest. All statistical tests were two-sided, and P values less than .05 were considered to be statistically significant. Overall, as well as in postmenopausal women alone, there was no association between dietary folate intake and breast cancer risk (Table 1). There was some suggestion of an increased risk at the uppermost quintile level of folate intake in premenopausal women, but the associated 95% confidence interval (CI) included unity. Risk varied little in association with folate intake among women in the lowest 80% of the distribution of alcohol consumption (intakes of ø14 g of alcohol/day) (Table 2, A), but there were marked reductions in risk associated with folate intake among those consuming more than 14 g of alcohol/day, and the associated test for trend was statistically significant (P 4 .004) [the adjusted IRR associated with an intake of >14 g of alcohol/day versus that associated with an intake of ø14 g of alcohol/ day was 1.12 (95% CI 4 0.94–1.34); risk was greater at higher levels of intake (16)]. This pattern, while evident in both menopausal strata, was more pronounced in postmenopausal women. However, on formal testing, there was no evidence for an interaction between folate and alcohol [e.g., in the total study population, x(1) 4 1.380; P 4 .24]. There was little evidence for variations