Advancing Evidence of the Associations between specific Benign Breast Diagnoses and Future Breast Cancer Risk

Abstract Background: Benign breast disease (BBD) increases breast cancer risk; however, associations between specific BBD diagnoses and breast cancer risk are insufficiently studied. Methods: We analyzed 131,075 benign breast biopsy episodes from 1994–2022 identified from eight Breast Cancer Surveillance Consortium registries. Pathological diagnoses were classified into 38 BBDs within 4 categories. For comparison, women with no prior breast biopsy and a negative screening mammogram (N=1,599,694) were identified. Associations of BBDs with invasive breast carcinoma and ductal carcinoma in situ (DCIS) were estimated using Fine-Gray competing risk models. Results: Over a median follow-up of 7.5 years, 35,251 invasive breast cancers and 9,743 DCIS cases occurred. Lobular carcinoma in situ was associated with a 5.61-fold (95% confidence interval [CI]: 4.10–7.68) increased risk of invasive carcinoma and an 8.82-fold (95% CI: 5.39–14.4) increased risk of DCIS. Among proliferative changes with atypia BBDs, invasive cancer hazard ratios (HRs) ranged from 2.76–4.85; DCIS HRs, 5.07–8.51. Among proliferative changes without atypia BBDs, invasive HRs ranged from near-null (papillomatosis) to moderate and strong associations (e.g., HR=1.55 for usual ductal hyperplasia and 2.84 for multiple papillomas); DCIS HRs=1.37–5.04. Nonproliferative BBDs were associated with low-to-moderate risk (invasive HRs=0.63 for atrophy to 2.16 for benign breast parenchyma; DCIS HRs=0.66–4.29). Most associations declined with increasing time since biopsy. Conclusions: Associations between BBDs and breast cancer varied widely within commonly used histologic categories. Impact: Advancing knowledge of specific BBD diagnoses may improve breast cancer risk prediction and support targeted screening and prevention strategies.