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. 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 between MHT and mammographic density was evaluated by linear regression models. We applied mediation modelling techniques to estimate, under the hypothesis of a causal model, the proportion of the effect of MHT on BC risk mediated by percent mammographic density (PMD) for BC overall and by hormone receptor status. Among MHT users, 4.2% used exclusively oestrogen alone compared with 68.3% who used exclusively oestrogens plus progestogens. Mammographic density was higher in current users (for a 60-year-old woman, mean PMD 33%; 95% CI 31 to 35%) than in past (29%; 27 to 31%) and never users (24%; 22 to 26%). No statistically significant association was observed between duration of MHT and mammographic density. In past MHT users, mammographic density was negatively associated with time since last use; values similar to those of never users were observed in women who had stopped MHT at least 8 years earlier. The odds ratio 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 PMD was 34% for any BC and became 48% when the correlation between BMI and PMD was accounted for. These effects were limited to hormone receptor-positive BC. 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.

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更年期激素治疗、乳房 X 光密度和乳腺癌风险之间的关联：E3N 队列研究的结果

更年期激素治疗（MHT）是乳腺癌（BC）的危险因素。有证据表明，其对 BC 风险的影响可能部分是由乳房 X 线摄影密度介导的。本研究的目的是利用前瞻性研究的数据来调查 MHT、乳房 X 光密度和 BC 风险之间的关系。我们使用了法国 E3N 队列中一项病例对照研究的数据，其中包括 453 例病例和 453 例匹配对照。所有女性均可获得乳房X线密度测量、随访期间MHT使用史以及潜在混杂因素的信息。通过线性回归模型评估 MHT 和乳房 X 光密度之间的关联。我们应用中介建模技术来估计，在因果模型的假设下，MHT 对 BC 风险的影响比例是由 BC 的乳房 X 光密度百分比 (PMD) 和激素受体状态介导的。在 MHT 使用者中，4.2% 的人仅单独使用雌激素，而仅使用雌激素加孕激素的比例为 68.3%。当前使用者（对于 60 岁女性，平均 PMD 33%；95% CI 31 至 35%）的乳房 X 光密度高于过去（29%；27 至 31%）和从未使用者（24%；22至 26%）。MHT 持续时间和乳房 X 光密度之间没有观察到统计学上显着的关联。在过去的 MHT 用户中，乳腺 X 光密度与上次使用后的时间呈负相关；在至少 8 年前停止 MHT 的女性中观察到与从未使用者相似的数值。根据年龄、出生年份、基线绝经状态和 BMI 进行调整后，目前使用 MHT 者与从未使用过 MHT 者的 BC 比值比为 1.67（95% CI，1.04 至 2.68）。对于任何 BC，由 PMD 介导的影响比例为 34%，当考虑到 BMI 和 PMD 之间的相关性时，这一比例变为 48%。这些影响仅限于激素受体阳性 BC。我们的结果表明，在因果模型下，MHT 对激素受体阳性 BC 风险的影响近一半是由乳房 X 光密度介导的，在 MHT 终止后长达 8 年内，乳房 X 光密度似乎会被 MHT 改变。