Association between menopausal hormone therapy, mammographic density and breast cancer risk: results from the E3N cohort study

Abstract

BACKGROUND: Menopausal hormone therapy (MHT) is a risk factor for breast cancer (BC). Evidence suggests that its effect on BC risk could be partly mediated by mammographic density. The aim of this study is to investigate the relationship between MHT, mammographic density and BC risk using data from a prospective study.METHODS: The data analyzed refer to a case-control study nested into the French cohort E3N and include 453 cases and 453 matched controls. A quantitative measure of mammographic density, a detailed history of MHT use during follow-up and information on potential confounders were available for all women. The association of mammographic density with MHT duration and time since last use was evaluated by linear regression models. Mediation modelling techniques were applied to estimate under the hypothesis of a causal model the proportion of the effect of MHT on BC risk mediated by percent mammographic density for BC overall and by ER/PR status.RESULTS: Mammographic density was higher in current (mean percent mammographic density 33%; 95% CI: 31–35%) than in former (29%; 95% CI 27% to 31) and never users (24%; 95% CI, 22–26%). Mammographic density increased with the duration of MHT within one year of therapy and reached a steady state thereafter. After discontinuation of the therapy, mammographic density decreased with time since last use and reached values similar to those of never users after 8 years. The OR of BC for current versus never MHT users, adjusted for age, year of birth, menopausal status at baseline and BMI, was 1.67 (95% CI, 1.04 to 2.68). The proportion of effect mediated by percent mammographic density was 34% on the log scale for any BC and became 48% when the correlation between BMI and percent mammographic density was accounted for. These results are limited to hormone receptor positive BCs.CONCLUSIONS: Our results suggest that under a causal model the effect of MHT on BC risk was partially mediated by MD that appeared to be modified by MHT for up to 8 years after MHT termination.