Menopausal hormone therapy and risk of biliary tract cancers

Background Gallbladder cancer (GBC) has a female predominance, while the other biliary tract cancers (BTC) have a male predominance, suggesting sex hormones may be involved in carcinogenesis. We sought to evaluate the association between menopausal hormone therapy (MHT) and the risk of BTC in women. Methods This nested case-control study was conducted in the UK Clinical Practice Research Datalink. Cases diagnosed between 1990-2017 with incident primary cancers of the gallbladder (GBC), cholangiocarcinoma, ampulla of Vater (AVC), and mixed type were matched to five controls on birth year, diagnosis year, and years in the general practice using incidence density sampling. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between MHT use and BTC type. Results The sample consisted of 1,682 BTC cases (483 GBC, 870 cholangiocarcinoma, 105 AVC, and 224 mixed) and 8,419 matched controls with a mean age of 73 (standard deviation: 11) years. Combined formulations (estrogen-progesterone) were associated with an increased GBC risk (OR: 1.97; 95% CI: 1.08, 3.59). Orally administered MHT was associated with an increased GBC risk (OR: 2.28, 95% CI: 1.24, 4.17). Estrogen-only formulations (OR: 0.59; 95% CI: 0.34, 0.93) and cream or suppository administrations (OR: 0.57; 95% CI: 0.34, 0.95) were associated with decreased cholangiocarcinoma risk. The number of prescriptions, dose, duration of use, and time since last use were not associated with GBC or cholangiocarcinoma risk. MHT use was not associated with risk of AVC or mixed cancer. Conclusion Combination MHT formulations and oral administrations are associated with increased GBC risk, while estrogen-only formulations were associated with a lower cholangiocarcinoma risk. MHT formulation and administration should be carefully considered when prescribing.