Research Article Family History, Mammographic Density, and Risk of Breast Cancer Lisa J. Martin 1 , Olga Melnichouk 1 , Helen Guo 1 , Anna M. Chiarelli 2 , T. Gregory Hislop 4 , Martin J. Yaffe 3 , Salomon Minkin 1 , John L. Hopper 5 , and Norman F. Boyd 1 Abstract Purpose: Mammographic density is a strong and highly heritable risk factor for breast cancer. The purpose of this study was to examine the extent to which mammographic density explains the association of family history of breast cancer with risk of the disease. Subjects and Methods: We carried out three nested case-control studies in screening programs that included in total 2,322 subjects (1,164 cases and 1,158 controls). We estimated the independent and combined associations of family history and percent mammographic density at baseline with subsequent breast cancer risk. Results: After adjustment for age and other risk factors, compared with women with no affected first- degree relatives, percent mammographic density was 3.1% greater for women with one affected first-degree relative, and 7.0% greater for women with two or more affected relatives (P = 0.001 for linear trend across family history categories). The odds ratios for breast cancer risk were 1.37 [95% confidence interval (95% CI), 1.10-1.72] for having one affected relative, and 2.45 (95% CI, 1.30-4.62) for having two or more affected re- latives (P for trend = 0.0002). Adjustment for percent mammographic density reduced these odds ratios by 16% and 14%, respectively. Percent mammographic density explained 14% (95% CI, 4-39%) of the association of family history (at least one affected first-degree relative) with breast cancer risk. Conclusions: Percent mammographic density has features of an intermediate marker for breast cancer, and some of the genes that explain variation in percent mammographic density might be associated with familial risk of breast cancer. Cancer Epidemiol Biomarkers Prev; 19(2); 456–63. ©2010 AACR. Introduction The tendency of breast cancer to cluster in families is widely recognized, and most of this familial aggregation is thought to reflect inherited susceptibility (1). However, it is estimated that only 20% to 25% of the excess risk of breast cancer in the first-degree relatives of women affect- ed by the disease can be attributed to mutations in known genes, including the high-penetrance susceptibil- ity genes BRCA1 and BRCA2, as well as the moderate and low-penetrance genes identified to date (2-4). Much remains to be learned about why having a family history of the disease is a risk factor for breast cancer. We consider here the association of family history of breast cancer with mammographic density, a strong risk factor for the disease that is highly heritable (5). Mammo- graphic density refers to the extent of radiologically dense breast tissue, which varies greatly across women of the same age, reflecting differences in breast tissue composition (6). Stroma and epithelium attenuate X-rays more than fat and appear light in a mammogram, where- as fat appears dark (7). The extent of mammographic density is expressed as a percentage by determining the proportion of the total projected area in the breast that is occupied by dense tissue. Women with density in ≥75% of the breast have a risk of breast cancer four to six times that of women of the same age and body mass index with little or no density (8, 9). Percent mammographic density (PMD) is associated with several factors that are also associated with risk of breast cancer. PMD is lower in women who are parous or postmenopausal (10, 11), is increased by the use of hor- mone therapy (12), and is reduced by the use of tamoxi- fen (13). Body weight and age, however, are inversely associated with PMD (14, 15). These factors account for only about 20% to 30% of the variance of PMD. Twin studies have shown that >60% of the residual variance after adjustment for age and other covariates can be ex- plained by inherited factors (5). As PMD is a risk factor for breast cancer, and is highly heritable, it might account for some of the association of family history with risk of breast cancer. Some previous studies, using qualitative methods of classifying mammographic features, have shown that women with a family history of the disease Authors' Affiliations: 1 Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, 2 Population Studies and Surveillance, Cancer Care Ontario, and 3 Imaging Research, Sunnybrook Health Sciences Centre, Toronto, Canada; 4 BC Cancer Agency, Vancouver, Canada; and 5 Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Australia Corresponding Author: Lisa J. Martin, Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, 610 University Ave., Toronto, Ontario, Canada, M5G 2M9. Phone: 416-936-2339; Fax: 416- 946-2024. E-mail: lmartin@uhnres.utoronto.ca doi: 10.1158/1055-9965.EPI-09-0881 ©2010 American Association for Cancer Research. 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