The Contributions of Breast Density and Common Genetic Variation to Breast Cancer Risk

Abstract

We evaluated whether a 76-locus polygenic risk score (PRS) and Breast Imaging Reporting and Data System (BI-RADS) breast density were independent risk factors within three studies (1643 case patients, 2397 control patients) using logistic regression models. We incorporated the PRS odds ratio (OR) into the Breast Cancer Surveillance Consortium (BCSC) risk-prediction model while accounting for its attributable risk and compared five-year absolute risk predictions between models using area under the curve (AUC) statistics. All statistical tests were two-sided. BI-RADS density and PRS were independent risk factors across all three studies (P interaction = .23). Relative to those with scattered fibroglandular densities and average PRS (2(nd) quartile), women with extreme density and highest quartile PRS had 2.7-fold (95% confidence interval [CI] = 1.74 to 4.12) increased risk, while those with low density and PRS had reduced risk (OR = 0.30, 95% CI = 0.18 to 0.51). PRS added independent information (P < .001) to the BCSC model and improved discriminatory accuracy from AUC = 0.66 to AUC = 0.69. Although the BCSC-PRS model was well calibrated in case-control data, independent cohort data are needed to test calibration in the general population.

A polygenic risk score for breast cancer in women receiving tamoxifen or raloxifene on NSABP P-1 and P-2

“…However, comparison with the few studies to date on the PRS and breast cancer association [21, 22] suggests that there is some attenuation of the association in the SERM-treated population. Although the PRS distributions are not directly comparable across these studies, a one-unit increase in PRS was associated with a 1.4-fold increased risk of breast cancer in this NSABP population, but associated with a 1.8-fold increase (95 % CI 1.6–2.1) in a general population [21]. Because of the known risk reduction associated with these SERMs, the SNPs (PRS) may not be as strong a risk factor in moderate to high-risk women on tamoxifen and raloxifene.…”

“…Taken together, these validated loci are estimated to explain up to 14 % of familial breast cancer risk [5]. Two recent studies showed that a polygenic risk score (PRS) composed of 76–77 of these genetic loci can identify individuals at increased breast cancer risk in the general population [21, 22]. Specifically, those at highest risk by the PRS had a 1.8-fold increased risk for breast cancer relative to the second quartile of PRS, and those in the lowest quartile had a reduced risk (0.6 fold) of breast cancer [21].…”

“…Two recent studies showed that a polygenic risk score (PRS) composed of 76–77 of these genetic loci can identify individuals at increased breast cancer risk in the general population [21, 22]. Specifically, those at highest risk by the PRS had a 1.8-fold increased risk for breast cancer relative to the second quartile of PRS, and those in the lowest quartile had a reduced risk (0.6 fold) of breast cancer [21]. The PRS association with breast cancer was stronger among those with ER-positive compared to ER-negative disease and effectively stratified breast cancer risk in women both with and without a family history of breast cancer [22].…”

Risk assessment for peri- and post-menopausal women taking food supplements containing isolated isoflavones

“…Boyd (2013) described 10 epidemiological studies in which breast density was demonstrated to be related to the risk of breast cancer, the results of which demonstrate the usefulness of this method. Two recent studies have confirmed that per cent mammographic density is the strongest risk factor for breast cancer besides genetic variants and family history (Vachon et al, 2015;Maskarinec et al, 2015). In several interventional studies increased mammographic density has been shown to be related to the intervention if the intervention was a combined hormonal replacement therapy in postmenopausal women (reviewed in Ursin and Qureshi, 2009).…”

Diagnostic Accuracy of Breast Medical Tactile Examiners (MTEs): A Prospective Pilot Study

“…Breast cancer screening and early cancer detection programs include breast self-examination [7,8,9], clinical breast examination (CBE) [10,11,12,13,14,15,16,17,18,19], mammography [14,15,16,19,20,21,22,23,24], ultrasonography [14,23,24,25,26], and magnetic resonance imaging [23,27]. Although there has been constant progress in the understanding of risk factors and genetic dispositions for breast cancer [28,29,30,31,32,33,34,35,36], the majority of breast cancer cases still occur without known predictors. This study is concerned with the introduction of vision-impaired medical tactile examiners (MTEs) for performing CBE in a diagnostic breast unit in order to assess the feasibility, acceptance, and diagnostic value of this approach.…”