Background: Mammographic breast density (MBD) and family history are consistently associated with breast cancer risk, and breast density may account for a proportion of susceptibility to this disease. MBD has been shown to correlate in small cohort studies of twins and siblings. However, MBD has not been studied on a large scale in multi-generation families. We investigated the familial relative risk of MBD in the Utah population, as clustering of breast density in extended relatives may provide evidence for the role of genetics in breast density and inform screening recommendations.

Methods: Using the Utah Population Database (UPDB), an extensive genealogical database linked to medical records) we identified 189,812 women ages 35-85 with pedigree information, who underwent digital mammography between 2005-2012, with no history of breast/ovarian cancer and no indication of tamoxifen/aromatase inhibitor use. Individuals with unusually frequent screening (>1/yr) or with inconsistent MBD assessments were not included. Subjects were categorized according to Breast Imaging-Reporting and Data System (BI-RADS®) composition classification at index mammogram available in radiology records of Intermountain Healthcare and University of Utah Healthcare systems, representing the majority of mammograms in Utah, as: (I) 0-25% fibroglandular densities (mostly fat); (II) 26-50% fibroglandular (scattered densities); (III) 51-75% fibroglandular (heterogeneously dense); or, (IV) >75% fibroglandular densities (extremely dense). Familial recurrence risks of MBD classification and breast cancer were estimated using Cox regression models in relatives (mothers, daughters, and sisters or 1st-degree; aunts, nieces, grandmothers, and granddaughters or 2nd-degree; first- and second-cousins) of probands classified as BI-RADS I (N=18,170) or BI-RADS IV (N=11,787), compared to those in the most common classifications, BI-RADS II (N=79,825) and III (N=80,030) combined. Women in the comparison group were randomly selected and matched 5:1 to probands on birth year.

Results: Relatives of women with a history of extremely dense breasts (BI-RADS IV) were at increased relative risk (RR) of extremely dense breasts compared to women in BI-RADS II/III: 1st-degree, RR=2.3 (95%CI 2.0-2.7, P<10-15); 2nd-degree, RR=1.8 (95%CI 1.5-2.2, P<10-9); first cousins, RR=1.2 (95%CI 1.1-1.4, P<10-5); and second cousins, RR=1.1 (95%CI 1.06-1.2, P<10-5). Conversely, relatives of women in BI-RADS I (mostly fat) were at decreased risk of BI-RADS IV: 1st-degree, RR=0.5 (95%CI 0.4-0.5, P<10-15); 2nd-degree, RR=0.7 (95%CI 0.6-0.8, P<10-6); first cousins, RR=0.85 (95%CI 0.8-0.9, P<10-4); and second cousins, RR=0.9 (95%CI 0.9-<1.0, P<10-8). First-degree relatives of women in BI-RADS IV were at slightly greater risk of breast cancer compared to women in BI-RADS II/III (RR=1.2, 95%CI 1.1-1.4; P=0.004), while women in category I showed no increased cancer risk.

Conclusions: BI-RADS composition categories available from radiology records in the UPDB appear to be useful in assessing familial risk of MBD at the population level. Our results may inform screening guidelines in more distant as well as close relatives of women with a history of extremely dense breasts, whose families may be more susceptible to breast cancer.

Citation Format: Karen Curtin, Leigh Neumayer, Matthew B Morgan, Matthew A Stein, Nicola J Camp, Geraldine P Mineau, Kerry G Rowe, Saundra S Buys. Familial risk of breast density in extended Utah pedigrees [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-07-07.