The Role of Adiposity and Lipid Biomarkers in Postmenopausal Breast Cancer Risk: A Causal Mediation Analysis Based on a Nationwide Cohort Study

Abstract

Background: Obesity is a known risk factor for breast cancer; however, its biological pathways remain to be fully understood. Lipid metabolism may play a role, yet its contribution has not been clearly quantified in large-scale population studies. Methods: We analyzed data from 2,088,751 postmenopausal Korean women who underwent national health screenings between 2009 and 2010, with follow-up through 2021. General adiposity and central adiposity were assessed using body mass index (BMI) and waist circumference (WC). Lipid biomarkers, including total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides, were measured during follow-up. Breast cancer incidence was identified via International Classification of Diseases, 10th Revision and catastrophic illness codes. Adjusted hazard ratios (HR) were estimated using Cox regression, and causal mediation was examined using two-way and four-way decomposition methods. Results: During follow-up, 18,364 breast cancer cases were diagnosed. Compared with BMI <23 kg/m(2), HR was 1.84 [95% confidence interval (CI), 1.72-1.97] for BMI >= 30 kg/m(2). Compared with WC < 80 cm, HR was 1.45 (95% CI, 1.39-1.51) for those with WC >= 88 cm. Mediation analyses showed that HDL and LDL cholesterol contributed modestly (<5.5%), and most of the association was explained by direct effects. Conclusions: This study confirmed that obesity, particularly central adiposity, is a strong independent risk factor for postmenopausal breast cancer, with minimal mediation by lipid biomarkers. Impact: This large-scale cohort study underscores obesity as a key target for breast cancer prevention, independent of lipid profile status.