Abstract MS2-1: Genetics and Epidemiology of Mammographic Breast Density
Authors: Vachon CMM 
Published: August 2014

Abstract
Differences in the relative amounts of fat, connective and epithelial tissues in the breast lead to variations in mammographic appearance. Breast density is a measure that reflects this variation in tissue composition and is most commonly assessed as the absolute amount or proportion of the mammogram comprised of fibroglandular or non-fatty tissue. Breast density has been characterized using both qualitative and quantitative estimates. The most widely used clinical density measure is the American College of Radiology's Breast Imaging Reporting and Data System (BI-RADS) four-category tissue composition measure. Quantitative estimates include user-assisted thresholding methods, and more recently, automated area and volumetric density measures. Increased breast density is common, with 26–32% of women in the general population having dense tissue occupying over half of their breast. Breast density has been shown to be a strong risk factor for breast cancer at any age of mammography, in both Caucasian and non-Caucasian populations, and years prior to the breast cancer. Women with over 50% of their breast comprised of dense tissue have a 3–5 fold increased risk of breast cancer relative to those with low or no density. Further, up to one third of all breast cancers are found in women with density over 50%.
Breast density decreases with age, with the greatest declines seen between ages 45–55. This decline has been hypothesized to reflect the reduction of hormones and involution of the breast tissue with onset of menopause. Several risk factors demonstrate associations with percentage breast density that are consistent with their breast cancer associations, suggesting these factors may potentially affect breast cancer risk through their influence on breast density. Positive associations are seen between breast density and nulliparity, late age at first birth, never having breast fed, postmenopausal hormone use (particularly combination therapy), and alcohol intake. Inverse associations are seen with tamoxifen use as well as body mass index (BMI), but BMI and breast density have been shown to be independent risk factors for breast cancer, and likely act through different pathways on risk. Taken together, the epidemiologic risk factors account for only 20–30% of the variation in breast density in the population.
Genetics also contribute to the variability in breast density. Twin and family studies have shown that percentage breast density is highly heritable, and that inherited factors explain between 30–60% of the variance. Some of these genetic factors are shared between breast density and breast cancer. Of the established breast cancer loci, single nucleotide polymorphisms in LSP1, ZNF365, ESR1 and RAD51L1, are also associated with breast density. Additional genetic loci for breast density (including a variant at 12q24) have been validated in large consortia. However, the loci identified to date together account for less than 5% of the variance in breast density. Identifying additional genetic loci for breast density will not only help inform the biology of breast density but also contribute to understanding breast cancer and risk prediction efforts.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr MS2-1.