Abstract BACKGROUND The association between histological subtypes of benign breast disease (BBD) and risk of subsequent breast cancer in the post-mammography era of increased BBD detection, requires continued study to inform clinical management of high-risk women. METHODS We identified a cohort of 8,915 women diagnosed with histologically-confirmed benign lesions between 2010 and 2023 from the Joanne Knight Breast Health Center in St. Louis. Risk of subsequent breast events after a benign biopsy was assessed with Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs). RESULTS Within a median follow-up of 6.5 years, 363 women developed breast cancer. The cohort was 63.7% White, 32.4% Black, and 3.9% Asian. Breast cancer risk increased across subtypes of BBD, from proliferative disease without hyperplasia (PDWA) to atypical hyperplasia (AH), with AH risk modified by time since biopsy and menopause. Compared with women with nonproliferative disease, age-adjusted risk for breast cancer was 1.69 for PDWA (HR = 95%CI 1.40, 2.30) and 2.78 for AH (HR = 2.78, 95%CI 2.01, 3.85, p trend 0.0001). Risk estimates attenuated but remained similar in fully adjusted models. Risks associated with BBD subtypes were similar for Black and White women, but Black women with AH had greater risk of breast cancer since recent biopsy (≤4 years) and during the premenopausal period (p het = 0.033). CONCLUSION Breast cancer risk increases with the degree of epithelial proliferation, highest in AH, amplified by recent biopsy and premenopause, particularly in Black women, consistent with the excess risk seen after ductal carcinoma in situ in this group.
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