The association between mammographic density and breast cancer molecular subtypes: a systematic review and meta-analysis

Abstract

To conduct a systematic review and meta-analysis to evaluate the whether high mammographic density (MD) is differentially associated with all subtypes of breast cancer. The PubMed, Cochrane Library, and Embase databases were searched systematically in October 2022 to include all studies that investigated the association between MD and breast cancer subtype. Aggregate data of 17,193 breast cancer cases from 23 studies were selected, including five cohort/case-control and 18 case-only studies. The relative risk (RR) of MD were combined using random/fixed effects models for case-control studies, and for case-only studies, relative risk ratios (RRRs) were a combination of luminal A, luminal B, and HER2-positive versus triple-negative tumours. Women in the highest density category in case-control/cohort studies had a 2.24-fold (95% confidence interval [CI] 1.53, 3.28), 1.81-fold (95% CI 1.15, 2.85), 1.44-fold (95% CI 1.14, 1.81), and 1.59-fold (95% CI 0.89, 2.85) higher risk of triple-negative, HER-2 (human epidermal growth factor receptor 2) positive, luminal A, and luminal B breast cancer compared to women in the lowest density category. RRRs for breast tumours being luminal A, luminal B, and HER-2 positive versus triple-negative in case-only studies were 1.62 (95% CI 1.14, 2.31), 1.81 (95% CI 1.22, 2.71) and 2.58 (95% CI 1.63, 4.08), respectively, for BIRADS 4 versus BIRADS 1. The evidence indicates MD is a potent risk factor for the majority of breast cancer subtypes to different degrees. Increased MD is more strongly linked to HER-2-positive cancers compared to other breast cancer subtypes. The application of MD as a subtype-specific risk marker may facilitate the creation of personalised risk prediction models and screening procedures.