Short Communication Interaction of Dietary Folate Intake, Alcohol, and Risk of Hormone Receptor-defined Breast Cancer in a Prospective Study of Postmenopausal Women 1 Thomas A. Sellers, 2 Robert A. Vierkant, James R. Cerhan, Susan M. Gapstur, Celine M. Vachon, Janet E. Olson, V. Shane Pankratz, Lawrence H. Kushi, and Aaron R. Folsom Department of Health Sciences Research, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota 55905 [T. A. S., R. A. V., J. R. C., C. M. V., J. E. O., V. S. P.]; Department of Preventive Medicine, Northwestern University Medical School, Chicago, Illinois 60611 [S. M. G.]; Division of Research, Kaiser Permanente, Oakland, California 94611 [L. H. K.]; and Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55454 [A. R. F.] Abstract Alcohol intake is an established risk factor for breast cancer, but the underlying mechanism remains unknown. Four recent studies have described interactions of alcohol and low folate intake. We examined this interaction on the risk of postmenopausal breast cancer stratified by tumor receptor status for estrogen (ER) and progesterone (PR). The Iowa Women’s Health Study is a prospective cohort study of 34,393 at-risk women. Alcohol use and folate intake from diet and supplements were estimated at baseline in 1986 through a semiquantitative food frequency questionnaire. Through 1999, 1,875 cases of breast cancer were identified through linkage to the Iowa Surveillance, Epidemiology, and End Results registry. Compared with nondrinkers with folate intakes above the 50 th percentile, women with low folate and high alcohol were at 1.43-fold greater risk (1.02–2.02). When stratified by tumor receptor status for ER or PR, the risks for low folate/high alcohol were 2.1 (1.18 –3.85), 1.0 (0.76 –1.42), 1.2 (0.88 –1.70), and 1.2 (0.69 –2.02) for ER, ER, PR, and PR tumors, respectively. Because the results were limited primarily to ER tumors, one plausible interpretation of these data is that alcohol influences breast cancer through its metabolite, acetaldehyde, rather than through effects on ER levels and receptor-mediated pathways. Introduction There is consistent evidence that alcohol intake increases risk of breast cancer (1). A recent pooled analysis of 300,000 women and 4,335 cases suggests that intake of 2–5 drinks/day increases risk by roughly 40% (2). The underlying mechanisms through which this occurs are not firmly established (3) but may include an influence on circulating levels of estrogens (4), immune function, enhanced permeability of chemical carcinogens, de- creased absorption of essential nutrients (5), or through metab- olism of alcohol to acetaldehyde, a known carcinogen (6). There are now four large epidemiological studies that suggest that risks associated with intake of alcohol may be greater in women with low intakes of dietary folate. The orig- inal report, from the Nurses Health Study (7), was quickly replicated with analyses of the Canadian National Breast Can- cer Screening Trial (8), a case-control study from Italy (9), and the Iowa Women’s Health Study (10). The consistency of this interaction lends credence to the possibility that the results are real and not merely a chance observation. The current report describes an updated analysis of the Iowa Women’s Health Study. We reported previously that alcohol is a risk factor for breast cancer (11), primarily for tumors lacking receptors for ER 3 and PR (12), and corroborated the interaction between low folate intake and alcohol consump- tion (10). The current analyses bring together these previous observations to examine the interaction within strata defined by tumor receptors for ER and PR. Materials and Methods Definition of Cohort. Detailed methods of the Iowa Women’s Health Study have been published elsewhere (13). Briefly, the cohort represents 41,836 licensed drivers ages 55– 69 years who responded to a mailed survey. Diet and Risk Factor Assessment. The questionnaire solic- ited information on factors known or suspected to be relevant to breast cancer risk, including alcohol use, and a 127-item semi- quantitative food frequency questionnaire that included use of multivitamins and supplements. Average daily alcohol intake over the previous year was assessed by summing the products of frequency of use of specific beverages by their ethanol content. The reliability and accuracy of the instrument is good (14). Exclusion Criteria. We excluded women at baseline if they were not postmenopausal (n = 569), had a total or partial mastectomy (n = 1,870), or had any cancer other than skin cancer (n = 2,293). We also excluded women if 30 items on the food frequency questionnaire were left blank or if their responses resulted in extreme energy intake values (600 or 5,000 kcal/day; n = 2,712). These exclusions left a total of 34,393 women eligible for follow-up. Received 9/14/01; revised 5/21/02; accepted 6/7/02. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 The Iowa Women’s Health Study was supported by a grant from the National Cancer Institute (R01 CA39741; to A. R. F., J. R. C. was supported in part by a National Cancer Institute Preventive Oncology Award (K07 CA64220). 2 To whom requests for reprints should be addressed, at Department of Health Sciences Research, Mayo Clinic, 200 1 st Street SW, Rochester, MN 55905. Phone: (507) 284-5535; Fax: (507) 266-2478; E-mail: sellers@mayo.edu. 3 The abbreviations used are: ER, estrogen; PR, progesterone; RR, risk ratio; CI, confidence interval. 1104 Vol. 11, 1104 –1107, October 2002 Cancer Epidemiology, Biomarkers & Prevention