Independent associations between obesity, glucose metabolism, and breast cancer risk through unrelated pathways.

BACKGROUND We examined whether fasting blood glucose (FBG) mediates the associations between body mass index (BMI), waist circumference (WC), and breast cancer (BC) risk among postmenopausal women, while considering the temporal order of exposure, mediator, and disease onset. METHODS Data from 2,093,578 postmenopausal women in the Korean National Breast Cancer Screening Program (2009-2010) were analyzed. Participants underwent at least one repeat screening (2011-2014) and were followed until 2021. Baseline BMI and WC served as exposures, and FBG levels, measured during 2011-2014, were examined as potential mediators. Associations among BMI, WC, FBG, and BC risk were evaluated using Cox proportional hazards regression and mediation analyses. RESULTS Over a median follow-up of 11.9 years, 17,120 women (0.82%) developed BC. Compared to lower values higher BMI (≥30 kg/m2) and WC (≥88 cm) were significantly associated with increased BC risk, with hazard ratios (HRs) of 1.82 (95% confidence interval [CI]=1.69-1.96) and 1.43 (95% CI = 1.37-1.49), respectively. Two-way decomposition mediation analysis indicated that FBG minimally mediated these associations, with natural indirect effect odds ratios near 1.00 and mediated effects ranged up to 2.23%. A four-way decomposition further confirmed that over 95% of the associations were attributable to the controlled direct effects of BMI and WC, while the pure indirect effect via FBG comprised approximately 5% of the total association. CONCLUSION Although BMI and WC are robustly linked to BC risk, FBG plays a negligible mediating role. These findings suggest that obesity and glucose metabolism independently influence breast cancer risk.