Early-adulthood body mass index, mammographic density and post-menopausal breast cancer risk: a mediation analysis.

BACKGROUND: To explore potential mechanistic pathways and inform prevention strategies, this study examined whether mammographic density (MD) mediates the inverse association between higher early-adulthood body mass index (BMI) and lower post-menopausal breast cancer risk. METHODS: We analysed data from 33,816 post-menopausal women in the UK PROCAS cohort, with self-reported BMI at age 20. MD was measured using full-field digital mammography and assessed using the visual analogue scale (VAS) percentage density and Volpara®-derived fibroglandular volume (FGV). Counterfactual mediation modelling estimated natural direct and indirect effects. RESULTS: Over a median follow-up of 10.44 years, there were 1261 new post-menopausal breast cancers. Higher VAS and FGV were associated with increased breast cancer risk. BMI at age 20 was associated with lower VAS density and reduced breast cancer risk [Hazard Ratio per 5 kg/m²: 0.849 (0.771-0.938)]. The calculated proportion mediated by VAS density was 59.9% (32.6-150), after accounting for intermediate confounding by BMI in later adulthood. FGV was positively associated with higher BMI at cohort entry but not at age 20. CONCLUSIONS: Lower VAS density may partially explain the inverse association between early-adulthood BMI and post-menopausal breast cancer risk. The link between FGV and breast cancer risk may represent a different biological pathway.