Menopausal Hormone Therapy use and breast cancer risk by receptor subtypes: results from the New South Wales Cancer Lifestyle and EvaluAtion of Risk (CLEAR) study

Breast cancer risk is increased with current Menopausal Hormone Therapy (MHT) use, with higher risks reported for ER+ (Estrogen Receptor positive), and ER+/PR+ (Estrogen and Progesterone Receptor positive) breast cancers than those of ER- and ER-/PR- status, respectively. There is limited evidence to suggest MHT use is associated with the specific subtype characterised as ER+/PR+/HER2- (Estrogen and Progesterone Receptor positive and Human Epidermal growth factor Receptor2 negative) status. This study aims to investigate the MHT-breast cancer relationship for breast cancer tumor receptor subtypes defined by ER expression alone, by ER and PR expression only and by joint expression of ER, PR, and HER2. Analyses compared 399 cancer registry-verified breast cancer cases with receptor status information and 324 cancer-free controls. We used multinomial logistic regression to estimate adjusted odds ratios (aORs) and 95% Confidence Intervals (CI) for current and past versus never MHT use, for subgroups defined by tumor receptor expression. Current, but not past, use of MHT was associated with an elevated risk of ER+ breast cancer (aOR = 2.04, 95%CI: 1.28-3.24) and ER+/PR+ breast cancer (aOR = 2.29, 1.41-3.72). Current MHT use was also associated with an elevated risk of the ER+/PR+/HER2- subtype (aOR = 2.30, 1.42-3.73). None of the other subtypes based on ER, ER/PR or ER/PR/HER2 expression were significantly associated with current MHT use in this analysis. Current, but not past, use of MHT increases the risk of breast cancer, with consistently higher risks reported for ER+ and ER+/PR+ subtypes and mounting evidence regarding the specific ER+/PR+/HER2- subtype. Our findings contribute to quantification of the effects of MHT, and support efforts to articulate the receptor-mediated mechanisms by which MHT increases the risk of breast cancer.