- breast cancer
- alcohol
- BRCA1/2 mutation carriers
- case-control study
Introduction
Epidemiologic studies have reported positive associations between alcohol consumption and risk of invasive breast cancer. Combined analyses suggest that breast cancer risk increases ∼9% for every 10-gram increment (less than one drink) in daily alcohol consumption (1-3). A recent analysis of pooled data from 53 studies concluded that ∼4% of breast cancers in developed countries may be attributable to alcohol consumption (4).
There have been some inconsistencies in both direction and strength of the observed associations, particularly in studies showing an inverse relation (see ref. 5 for example), which could reflect interstudy variability in the prevalence of factors that modify the relation between alcohol and breast cancer risk. No meaningful risk differences have been seen by menopausal status (1, 2, 6, 7) or family history (3, 8, 9). Carrying a deleterious germ-line mutation in the BRCA1 or BRCA2 genes could be a modifying factor. The effects of alcohol intake on breast cancer risk in women with these mutations are unknown, and we examined this issue in BRCA1 and BRCA2 mutation carriers ages <50 years at diagnosis or interview.
Materials and Methods
A detailed description of the study design and analytic methods is provided elsewhere.16 Briefly, six research institutions in the United States, Canada, and Australia who were members of the Breast Cancer Family Registry (10) and from two additional sources, the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer in Australia (www.kconfab.org; ref. 11) and the Ontario Cancer Genetics Network in Canada, recruited female subjects. Study subjects were non-Hispanic white women with and without invasive breast cancer (hereafter called cases and controls, respectively) who completed the same risk factor questionnaire and who were determined to carry a deleterious mutation of BRCA1 or BRCA2.
We assigned to each subject a reference date, defined for cases as the date of first diagnosis of invasive breast cancer and for controls as the date of the earliest of the following events: interview, bilateral mastectomy, bilateral oophorectomy, or diagnosis of in situ breast cancer. All sites collected biological samples and gathered risk factor data using epidemiologic questionnaires containing identical information. DNA was tested for BRCA1 and BRCA2 mutations either by full sequencing by Myriad Genetics or by one of several other methods that had been validated against full sequencing (12). We analyzed the data using unconditional logistic regression, stratified on family history of breast or ovarian cancer in first-degree relatives, restricted to women with reference age of <50 years, and who had been interviewed no later than 5 years after their reference dates. We computed the 95% confidence intervals (95% CI) for odds ratios (OR) using a robust variance estimator (13) to account for possible correlation in covariates among family members. To reduce the effects of outliers in trend tests for continuous variables, the variables were first categorized and then the reported values in each category were replaced by the median for that category. This study involved 195 cases and 302 controls with BRCA1 mutations and 128 cases and 179 controls with BRCA2 mutations. The institutional review boards at each site approved the study protocol.
Results
Table 1 shows selected characteristics for carriers of BRCA1 or BRCA2 mutations. Cases were older than controls, were more likely to be ascertained through clinic-based study centers, and were less likely than controls to have a family history for breast or ovarian cancer.
Characteristics of non-Hispanic white BRCA mutation carriers with and without invasive breast cancer by mutation status
Table 2 shows ORs relating breast cancer risk to alcohol consumption, adjusted for age, study site, family history, smoking, and number of full-term pregnancies. Compared with never users of alcohol, ever users were not at increased risk for breast cancer regardless of whether they were BRCA1 carriers (OR, 1.06; 95% CI, 0.73-1.52) or BRCA2 carriers (OR, 0.66; 95% CI, 0.45-0.97). There was no evidence for a linear trend in risk with drink-years among BRCA1 carriers (P = 0.5) or BRCA2 carriers (P = 0.4). Similarly, there was no evidence for a linear trend in risk with increasing rates of alcohol consumption, measured as grams daily (P = 0.4 and 0.9 for BRCA1 and BRCA2 carriers, respectively), although modest alcohol intake (<4 grams daily) was associated with a nominally significant decrease in breast cancer risk for BRCA2 mutation carriers (OR, 0.41; 95% CI, 0.22-0.77). We observed no significant differences in risks by type of alcohol (beer, wine, or spirits; data not shown).
Risk of invasive breast cancer among white non-Hispanic BRCA1 and BRCA2 mutation carriers according to alcohol consumption for women under 50 years of age by gene
Discussion
The present data do not support a positive association between alcohol intake and breast cancer risk for women who carry a germ-line mutation of BRCA1 or BRCA2 but suggest a possible reduction in risk in BRCA2 mutation carriers for modest alcohol intake. Several study limitations warrant consideration in interpreting these findings. We included only data from living affected carriers because of the difficulty of obtaining accurate histories of alcohol consumption from relatives of deceased patients. To minimize the potential for survival and recall bias, we restricted the analysis to carrier cases who were interviewed within 5 years of their breast cancer diagnosis (∼85% of these women were interviewed within 3 years of diagnosis). We also duplicated major analyses for a subset of more recent cases and did not find substantial differences in the magnitudes of ORs. The study subjects were not a random sample of all mutation carriers specific for disease status but were recruited mainly from members of families with multiple cases of breast cancer and, in some instances, ovarian cancer. The association between alcohol and breast cancer risk in these carriers may not be the same as that among carriers in the general population.
These potential limitations must be balanced against the strengths of this study. These include the large numbers of premenopausal carriers available, the uniform way, in which lifestyle characteristics were ascertained using a common questionnaire, and the inclusion only of young women who carried deleterious mutations. These findings should be further investigated to clarify the relation, if any, between breast cancer risk and alcohol intake among genetically susceptible women.
Acknowledgments
We thank Heather Thorne and Eveline Niedermayer Davis for the supply of data for this project and Dr. M. McCredie (Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand) for the important contribution to this study.
Footnotes
↵16 R.W. Haile, et al. BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer risk before age 50, submitted for publication.
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Grant support: National Cancer Institute NIH grant RFA CA-95-003 and through cooperative agreements with The University of Melbourne, Northern California Cancer Center, and Cancer Care Ontario as part of the Breast Cancer Family Registry; National Health and Medical Research Council of Australia, Cancer Council of New South Wales, Victorian Health Promotion Foundation, and Victorian Breast Cancer Research Consortium (Australian Breast Cancer Family Study); NIH grant U01CA 71966 (recruitment of controls by the Northern California Cancer Center); and Kathleen Cuningham Foundation, National Breast Cancer Foundation, National Health and Medical Research Council, Cancer Council of Victoria, Cancer Council of South Australia, Queensland Cancer Fund, Cancer Council of New South Wales, Cancer Foundation of Western Australian, and Cancer Council of Tasmania (kConFaB).
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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.
- Accepted May 31, 2006.
- Received April 19, 2006.
References
Volume 15, Issue 8
