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 was to investigate the relationship between MHT, mammographic density and BC risk using data from a prospective study. METHODS We used data from a case-control study nested within the French cohort E3N including 453 cases and 453 matched controls. Measures of mammographic density, history of MHT use during follow-up and information on potential confounders were available for all women. The association of mammographic density with MHT 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 hormonal receptor status. RESULTS Among MHT users, only 4.2% used exclusively estrogens compared with 68.3% who used exclusively estrogens plus progestogens. Mammographic density was higher in current users (mean percent mammographic density for a 60 year old woman 33%; 95% CI: 31% to 35%) than in past (29%; 27% to 31%) and never users (24%; 22% to 26%). Mammographic density increased with the duration of MHT within one year of therapy and reached a steady state thereafter. After MHT discontinuation, 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% for any BC and became 48% when the correlation between BMI and percent mammographic density was accounted for. These effects were limited to hormone receptor positive BC. CONCLUSIONS Our results suggest that under a causal model nearly half of the effect of MHT on hormone receptor positive BC risk is mediated by mammographic density, which appears to be modified by MHT for up to 8 years after MHT termination.