Effect of Reproductive Factors and Oral Contraceptives on Breast Cancer Risk in BRCA1/2 Mutation Carriers and Noncarriers: Results from a Population-Based Study Eunjung Lee, 1 Huiyan Ma, 2 Roberta McKean-Cowdin, 1 David Van Den Berg, 1 Leslie Bernstein, 2 Brian E. Henderson, 1 and Giske Ursin 1,3 1 Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California; 2 City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, California; and 3 Department of Nutrition, University of Oslo, Oslo, Norway Abstract Background: Multiparity and breast-feeding reduce breast cancer risk, whereas oral contraceptive use may slightly increase breast cancer risk in the general population. However, the effects of these factors in BRCA1 and BRCA2 mutation carriers are less clear. Methods: Case patients were 1,469 women from Los Angeles County ages 20 to 49 years with newly diagnosed breast cancer. Control subjects were 444 women without breast cancer, individually matched to a subset of cases on race, age, and neighborhood. BRCA1/2 genes were sequenced in the cases, and odds ratios of breast cancer associated with various repro- ductive and hormonal factors in BRCA1/2 mutation carriers and noncarriers were estimated using multi- variable logistic regression. Results: Ninety-four women had a deleterious BRCA1 or BRCA2 mutation. Number of full-term pregnancies was inversely associated with breast cancer risk regardless of BRCA1/2 mutation status. Longer breast- feeding duration was protective among noncarriers but not among mutation carriers; however, this apparent effect modification was not statistically significant (P = 0.23). Neither oral contraceptive use overall nor the use of low-dose oral contraceptives was associated with an increased risk of breast cancer in any subgroup. Conclusions: Our results suggest that parity protects against breast cancer in BRCA1/2 mutation carriers, whereas breast-feeding does not. Our data suggest no association between oral contraceptive use and breast cancer risk in BRCA1/2 mutation carriers. Further confirmation that currently available low-dose oral contraceptives do not increase breast cancer risk in carriers is important from a public health perspective given the high prevalence of oral contraceptive use in the United States. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3170–8) Introduction Women with mutations in BRCA1/2 have a high risk of developing cancers of the breast and ovaries (1-3). The exact mechanisms that account for why BRCA1/2 mutation carriers predominantly develop cancers of these hormonally regulated organs are not clear, but it is possible that BRCA1/2 may interact with estrogen in breast carcinogenesis. Estrogen is involved in breast carcinogenesisbypromotingcellproliferationand/orby acting as a genotoxic agent, through its metabolites, generating mutagenic DNA damage (4, 5). BRCA1 and BRCA2 are involved in several cellular functions important in carcinogenesis including DNA damage repair as well as cell cycle checkpoint (6). Therefore, it seems plausible that the cancer-promoting effects of estrogen would be even stronger in the absence of functioning BRCA1/2. Further, BRCA1 has been shown torepressestrogen-dependentandestrogen-independent transactivation activity of estrogen receptor-a (7-10). Reproductive factors such as multiparity, early age at first full-term pregnancy, breast-feeding, and late age at menarchehavebeenconsistentlyfoundtoprotectagainst breast cancer (11, 12). Parity and early age at first birth predominantly protect against estrogen receptor-positive and progesterone receptor-positive tumors, whereas breast-feeding and possibly late age at menarche may protect against both receptor-positive and receptor- negative disease (13, 14). Thus, it is possible that these reproductive factors act through different hormonal mechanisms, some of which may involve estrogen, progesterone, or sex hormone binding globulin (15, 16). Oral contraceptive use has also been associated with a slightly increased risk of breast cancer (17), although the effect is modest, possibly restricted to current use, and not observed in all studies. Although the overall effects of these reproductive and hormonal risk factors are well established, the extent to whichtheseriskfactorscontributetobreastcancerriskin Cancer Epidemiol Biomarkers Prev 2008;17(11). November 2008 Received 5/14/08; revised 7/7/08; accepted 8/5/08. Grant support: CA17054 and CA74847 from the National Cancer Institute, National Institutes of Health, 4PB-0092 from the California Breast Cancer Research Program of the University of California, and in part through contract no. N01-PC-35139, and T32 ES-013678 from the National Institute of Environmental Health Sciences, National Institute of Health. The collection of cancer incidence data used in this publication was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. The ideas and opinions expressed herein are those of the authors, and no endorsement by the State of California, Department of Health Services is intended or should be inferred. Requests for reprints: Giske Ursin, Department of Preventive Medicine, Keck School ofMedicine,UniversityofSouthernCalifornia/NorrisComprehensiveCancerCenter, Room 4407, 1441 Eastlake Avenue, Los Angeles, CA 90089. Phone: 323-865-0423; Fax: 323-865-0142. E-mail: gursin@usc.edu Copyright D 2008 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-08-0396 3170 on June 16, 2017. © 2008 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from