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A Prospective Study of Folate Intake and the Risk of Breast Cancer
Shumin Zhang, MD, ScD, David J. Hunter, MBBS, ScD, Susan E. Hankinson, ScD, Edward L. Giovannucci, MD, ScD, Bernard A. Rosner, PhD, Graham A. Colditz, MD, DrPH, Frank E. Speizer, MD, Walter C. Willett, MD, DrPH
LOW FOLATE INTAKE has increased tumor occurrence in animal models' and has been associated with higher risk of colon cancer in epidemiologic studies, particularly in the presence of alcohol consumption. Deficient folate status can reduce the availability of S-adenosylmethionine for DNA methylation and may thereby influence gene expression. Diminished folate status may also result in abnormal DNA synthesis due to misincorporation of uracil into DNA leading to chromosome breaks and disruption of DNA repair. Alcohol is a known folate antagonist and thus could plausibly increase the requirement for folate intake.
We hypothesized that higher folate intake might reduce risk of
breast cancer, particularly among women with greater alcohol consumption, which itself
moderately increases breast cancer risk. Because no prospective data are available,
we examined these hypotheses in the Nurses' Health Study, a large cohort study among US
women.
Study Cohort - In 1976, 121700 female registered
nurses aged 30 to 55 years living in
11 states completed a mailed questionnaire about their medical history and lifestyle.
Biennially, a mailed questionnaire has been sent to update information on potential risk
factors and to ascertain newly diagnosed diseases. In 1980, a 61-item food frequency questionnaire was included to obtain dietary
information. In 1984, the dietary questionnaire was expanded to 126 items. Similar questionnaires were used to update diet in 1986 and 1990. Through May 31, 1996, the follow-up rate was 95% complete
as percentage of potential person-years.
Context: Folate is involved in DNA synthesis and methylation and may reduce breast cancer risk, particularly among women with greater alcohol consumption.
Objectives: To assess the association between folate intake and risk of breast cancer and whether higher folate intake may reduce excess risk among women who consume alcohol.
Design: Prospective cohort study performed in 1980, with 16 years of follow-up.
Setting and Participants: A total of 88,818 women who completed the dietary questionnaire section of the Nurses' Health Study in 1980.
Main Outcome Measure: Incidence of invasive breast cancer by levels of folate and alcohol intake.
Results: A total of 3483 cases of breast cancer were documented. Total folate intake was not associated with overall risk of breast cancer. However, among women who consumed at least 15 g/d of alcohol, the risk of breast cancer was highest among those with low folate intake. For total folate intake of at least 600 pg/d compared with 150 to 299 ug/d, the multivariate relative risk (RR) was 0.55 (95% confidence interval [CII, 0.39-0.76; P for trend =.001). This association was only slightly attenuated after additional adjustment for intake of beta carotene, lutein/zeaxanthin, preformed vitamin A, and total vitamins C and E. The risk of breast cancer associated with alcohol intake was strongest among women with total folate intake of less than 300 ug/d (for alcohol intake ~l5 g/d vs <1 5 g/d, multivariate RR, 1.32; 95% Cl, 1.15-1.50). For women who consumed at least 300 pg/d of total folate, the multivariate RR for intake of at least 15 g/d of alcohol vs less than 15 g/d was 1.05 (95% Cl, 0.92-1.20). Current use of multivitamin supplements, the major source of folate, was associated with lower breast cancer risk among women who consumed at least 15 g/d of alcohol (for current users of supplements vs never users, RR, 0.74; 95% Cl, 0.59-0.93).
Conclusions: Our findings suggest that the excess risk of breast cancer associated with alcohol consumption may be reduced by adequate folate intake.
JAMA. 1999,281:1632-1637