Cancer
Mechanisms underlying the effect of adiposity on risk of postmenopausal estrogen receptor-positive breast cancer: an interventional mediation analysis in the Melbourne Collaborative Cohort Study Frances Albers* Frances Albers Makayla Lou Ghazaleh Dashti Christopher Swain Sabina Rinaldi Vivian Viallon Amalia Karahalios Kristy Brown Marc Gunter Roger Milne Dallas English Brigid Lynch
Background: Adiposity increases the risk of postmenopausal estrogen receptor (ER)-positive breast cancer. Inflammation, insulin and insulin-like growth factors, and sex-steroid hormones may explain this effect. We performed interventional mediation analysis to estimate the effects of hypothetical interventions targeting these pathways in postmenopausal women with obesity on reducing their excess risk of ER-positive breast cancer relative to postmenopausal women with normal weight.
Methods: The mediation analysis included 1,260 postmenopausal women (352 ER-positive breast cancers) from a case-cohort within the Melbourne Collaborative Cohort Study. A Monte Carlo g-computation approach with non-parametric bootstrapping was used to estimate risk differences (RDs) and 95% confidence intervals (CIs) for interventional direct and indirect effects of hypothetical interventions that would shift the joint distribution of inflammation, insulin and sex-steroid hormone biomarkers in postmenopausal women with obesity to that observed in postmenopausal women with normal weight.
Results: The RD for the total effect of obesity versus normal weight on postmenopausal ER-positive breast cancer was 16.1 (95% CI: 3.3, 30.4) additional cases per 1,000 women. RDs for interventional indirect effects through inflammation, insulin and sex-steroid hormones were 16.4 (95% CI: 4.3, 27.2), -8.4 (95% CI: -23.4, 1.2) and 13.0 (95% CI: 3.3, 23.7) additional cases per 1,000 women, respectively. The RD for the interventional direct effect not via any pathway was -5.3 (95% CI: -17.4, 10.6) additional cases per 1,000 women.
Conclusion: Inflammation and sex-steroid hormones, but not insulin, may contribute to the detrimental effect of adiposity on risk of postmenopausal ER-positive breast cancer and may be targets for intervention.