Purpose Benign breast disease (BBD) is a strong breast cancer risk factor but identifying patients that might develop invasive breast cancer remains a challenge. Methods By applying machine-learning to digitized H&E-stained biopsies and computer-assisted thresholding to mammograms obtained circa BBD diagnosis, we generated quantitative tissue composition metrics and determined their association with future invasive breast cancer diagnosis. Archival breast biopsies and mammograms were obtained for women (18-86 years) in a case-control study, nested within a cohort of 15,395 BBD patients from Kaiser Permanente Northwest (1970-2012), followed through mid-2015. Cases (n=514) who developed incident invasive breast cancer and controls (n=514) were matched on BBD diagnosis age and plan membership duration. Results Increasing epithelial area on the BBD biopsy was associated with increasing breast cancer risk [Odds ratio(OR) 95% confidence interval(CI) Q4 vs Q1=1.85(1.13-3.04);Ptrend=0.02]. Conversely, increasing stroma was associated with decreased risk in non-proliferative, but not proliferative, BBD (Pheterogeneity=0.002). Increasing epithelium-to-stroma proportion [OR(95%CI)Q4 vs Q1=2.06(1.28-3.33);Ptrend=0.002] and percent mammographic density (MBD) [OR(95%CI)Q4 vs Q1=2.20(1.20-4.03);Ptrend=0.01] were independently and strongly predictive of increased breast cancer risk. In combination, women with high epithelium-to-stroma proportion/high MBD had substantially higher risk than those with low epithelium-to-stroma proportion/low MBD [OR(95%CI)=2.27(1.27-4.06);Ptrend=0.005], particularly among women with non-proliferative [Ptrend=0.01] versus proliferative [Ptrend=0.33] BBD. Conclusion Among BBD patients, increasing epithelium-to-stroma proportion on BBD biopsies and percent MBD at BBD diagnosis were independently and jointly associated with increasing breast cancer risk. These findings were particularly striking for women with non-proliferative disease (comprising ~70% of all BBD patients), for whom relevant predictive biomarkers are lacking.
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