Menopausal hormone therapy and incidence, mortality, and survival of breast cancer subtypes: A prospective cohort study

Abstract Background: Menopausal hormone therapy (MHT) is associated with an increased risk of postmenopausal breast cancer, predominantly the luminal A-like subtype. Little is known about the impact of MHT on deaths from breast cancer subtypes. This study aimed to explore associations between MHT use and the incidence, mortality, and survival of intrinsic-like breast cancer subtypes. Methods: Data from 160,881 participants with self-reported MHT use from the prospective Norwegian Women and Cancer Study were analyzed. Among them, 7,844 were incident breast cancer cases, and 721 were breast cancer-specific deaths. Cox proportional hazard regression was performed to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between MHT use and the incidence, mortality, and survival of breast cancer subtypes. Results: MHT use was associated with increased incidence of overall, luminal A-like, and luminal B-like breast cancer, with respective HRs of 1.44 (95% CI: 1.36–1.52), 1.41 (95% CI: 1.31–1.52), and 1.23 (95% CI: 1.09–1.40) among current estrogen-progestin therapy (EPT) users compared with never users. The risk increased by 4%, 4%, and 2% per year of EPT use for overall, luminal A-like, and luminal B-like breast cancers, respectively. Increased risk of overall and luminal A-like breast cancer mortality was also associated with MHT use, with 61% (95% CI: 1.36–1.91) and 115% (95% CI: 1.51–3.05) increased risk among current EPT users compared with non-users. Among patients with breast cancer, pre-diagnostic MHT use was not associated with overall breast cancer survival but was inversely associated with survival from triple-negative breast cancer (TNBC; HR, 0.41; 95% CI: 0.24–0.73 among current users). Results varied significantly according to tumor subtype (pheterogeneity = 0.02). Conclusions: Our study suggests that MHT use increases the risk of incident and fatal overall, luminal A-like, and incident luminal B-like breast cancer but does not decrease overall survival among patients with breast cancer. Further research is needed to elucidate the mechanisms underlying the differential associations between MHT use and breast cancer mortality and survival, and to explore whether MHT use among patients with TNBC is indeed free from harm.