Global mammographic asymmetry and short-term breast cancer risk by breast density: a nationwide screening cohort of 5.5 million women.

Global mammographic asymmetry (GA) is generally considered benign, and its association with subsequent breast cancer risk is unclear. We examined whether GA on screening mammography predicts short-term and long-term breast cancer and whether this varies by Breast Imaging Reporting and Data System (BI-RADS) breast density. In this retrospective cohort study using the Korean National Health Insurance Service screening programme, we included women aged ≥40 years who underwent screening mammography in 2009-2010 and had no prior breast cancer. GA and BI-RADS density were recorded on baseline mammograms; incident invasive breast cancer through December 31, 2019 was ascertained from insurance claims. Cox proportional hazards models estimated adjusted hazard ratios (aHRs) for breast cancer associated with GA overall and by BI-RADS density and follow-up interval (<1, 1-2 and ≥2 years), adjusting for demographic, reproductive and lifestyle factors. Among 5,475,113 women, GA was present in 4.0 %. Overall, GA was associated with a modestly increased breast cancer risk (aHR 1.15; 95 % CI 1.11-1.19), strongest within 1 year of screening (aHR 1.90; 95 % CI 1.70-2.12). In women with BI-RADS 1 breasts, GA doubled overall risk (aHR 2.03) and quadrupled short-term risk (<1 year: aHR 4.14), whereas in BI-RADS 4 breasts GA did not increase overall risk (aHR 0.94). GA is uncommon but identifies women at substantially elevated short-term breast cancer risk, particularly those with non-dense breasts, and has limited long-term prognostic value in extremely dense breasts. These findings support consideration of short-interval follow-up or supplemental imaging when GA is reported in non-dense breasts.