ABSTRACT: BACKGROUND:Well-tolerated and commonly used medications are increasingly assessed for reducing breast cancer risk. These include metformin and statins, both linked to reduced hormone availability and cell proliferation or growth and sometimes prescribed concurrently. We investigated independent and joint associations of these medications with mammographic breast density (MBD), a useful biomarker for the effect of chemopreventive agents on breast cancer risk. METHODS:Using data from a cross-sectional study of 770 women (78% Hispanic, aged 40-61?years, in a mammography cohort with high cardiometabolic burden), we examined the association of self-reported "ever" use of statins and metformin with MBD measured via clinical Breast Imaging Reporting and Data System (BI-RADS) density classifications (relative risk regression) and continuous semi-automated percent and size of dense area (Cumulus) (linear regression), adjusted for age, body mass index, education, race, menopausal status, age at first birth, and insulin use. RESULTS:We observed high statin (27%), metformin (13%), and combination (9%) use, and most participants were overweight/obese (83%) and parous (87%). Statin use was associated with a lower likelihood of high density BI-RADS (RR?=?0.60, 95% CI?=?0.45 to 0.80), percent dense area (PD) (??=?-?6.56, 95% CI?=?-?9.05 to -?4.06), and dense area (DA) (??=?-?9.05, 95% CI?=?-?14.89 to -?3.22). Metformin use was associated with lower PD and higher non-dense area (NDA), but associations were attenuated by co-medication with statins. Compared to non-use of either medication, statin use alone or with metformin were associated with lower PD and DA (e.g., ??=?-?6.86, 95% CI: -?9.67, -?4.05 and ??=?-?7.07, 95% CI: -?10.97, -?3.17, respectively, for PD) and higher NDA (??=?25.05, 95% CI: 14.06, 36.03; ??=?29.76, 95% CI: 14.55, 44.96, respectively). CONCLUSIONS:Statin use was consistently associated with lower MBD, measured both through clinical radiologist assessment and continuous relative and absolute measures, including dense area. Metformin use was associated with lower PD and higher NDA, but this may be driven by co-medication with statins. These results support that statins may lower MBD but need confirmation with prospective and clinical data to distinguish the results of medication use from that of disease.
