Postmenopausal hormone replacement therapy (HRT) was found to be associated with lower risk of colorectal cancer (CRC). However, little is known regarding associations with molecular subtypes of CRC. The current study includes female participants of a large German population‐based case–control study (922 CRC cases and 1,183 controls). Tumor tissue samples were analyzed for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), BRAF and KRAS mutation status. Multivariable logistic regression models were used to assess the association of HRT use with molecular subtypes and pathways. Postmenopausal HRT use was overall associated with reduced risk of CRC (adjusted odds ratio (aOR) 0.62, 95% confidence interval (CI) 0.50–0.76) and no major differences were observed for molecular subtypes or for tumor marker combinations representing molecular pathways. When stratified by median age (≤/>71 years) potentially stronger risk reductions were observed in the older group for subtypes showing MSI (OR = 0.36, 95% CI 0.17–0.76), BRAF mutation (OR = 0.40, 95% CI 0.30–0.83) and CIMP‐high (OR = 0.40, 95% CI 0.21–0.73) and for CRC suggestive of the sessile serrated pathway (OR = 0.45, 95% CI 0.20–1.01). In conclusion, postmenopausal use of HRT was similarly associated with risk reduction of major molecular tumor subtypes and pathways of CRC. Potentially stronger risk reductions with CRC subtypes diagnosed at higher ages require confirmation and clarification from other studies. The current study extends the limited understanding of the mechanisms of HRT in CRC prevention.

中文翻译：

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绝经后激素替代疗法和大肠癌的风险由分子亚型和途径决定。

发现绝经后激素替代疗法（HRT）与降低结直肠癌（CRC）的风险有关。然而，关于与CRC的分子亚型的关联知之甚少。当前的研究包括一项大型的德国人口病例对照研究（922例CRC病例和1,183例对照）的女性参与者。分析肿瘤组织样品的微卫星不稳定性（MSI），CpG岛甲基化子表型（CIMP），BRAF和KRAS突变状态。多变量logistic回归模型用于评估HRT使用与分子亚型和途径的关联。绝经后HRT的使用总体上与CRC风险降低有关（校正比值比（aOR）为0.62，95％置信区间（CI）为0.50-0。76），没有观察到分子亚型或代表分子途径的肿瘤标志物组合的主要差异。如果按中位年龄（≤/> 71岁）进行分层，则较老的组在显示MSI（OR = 0.36，95％CI 0.17-0.76），BRAF突变（OR = 0.40，95％CI 0.30 –0.83）和CIMP高（OR = 0.40，95％CI 0.21–0.73），对于CRC提示无柄锯齿状途径（OR = 0.45，95％CI 0.20–1.01）。总之，绝经后使用HRT与减少主要分子肿瘤亚型和CRC通路的风险相似。在更高年龄诊断出的CRC亚型，降低风险的潜力可能更大，这需要其他研究的确认和澄清。当前的研究扩展了对HRT预防CRC的机制的有限理解。