350 Menopausal Hormone Therapy and Risk of Foregut Cancers: A Series of Nested Case-Control Studies in the Clinical Practice Research Datalink

Abstract Background Menopausal hormone therapy (MHT) has been investigated for its potential influence on risks of oesophageal, gastric, and primary liver cancers, but evidence remains inconclusive. This study aimed to evaluate associations between MHT use and these cancers using a large, nested case-control design. Method Using the UK Clinical Practice Research Datalink (CPRD) linked with National Cancer Registration and Analysis Service data, we conducted nested case-control studies assessing MHT exposure and risks of oesophageal, gastric, and primary liver cancers in female patients. Users were defined in a hierarchial fashion as oestrogen-only, oestrogen-and-progesterone, or tibolone (an oestrogen analogue) users. Multivariable logistic regression models adjusted for confounders including smoking, alcohol, comorbidities, and viral hepatitis status. Sensitivity analyses included extended lag periods and multiple imputation for missing data. Results A total of 5,225 cases matched to 50,599 controls across the three cancer sites were evaluated. MHT use was associated with a 15% decreased risk of oesophageal cancer (adjusted OR=0.85, 95% CI 0.72, 1.00, p=0.048,) and a 33% decreased risk of primary liver cancer (adjusted OR=0.67, 95% CI 0.49, 0.92, p=0.01). A dose-response relationship was suggested for primary liver cancer in a test for trend but was not statistically significant. Oestrogen-only MHT users showed a stronger protective association for primary liver cancer. No protective effect was found for gastric cancer. Histological subtype analyses showed no significant associations. Sensitivity analyses supported the robustness of findings. Conclusions These findings support a protective effect of systemic MHT, particularly oestrogen-only formulations, on oesophageal and primary liver cancer risk, but not gastric cancer.