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

Abstract

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.

Fig 1. Available and eligible cases and controls for the analysis of MHT and breast cancer risk by receptor subtype.

Fig 2. MHT use and invasive breast cancer risk by breast cancer hormone receptor (ER/PR) status.

Legend: p* = p-value is for the test of global null hypothesis that the OR estimates are equal to one (i.e their reference group OR). Breast cancers with ER-/PR+ status (n = 6) were excluded from the analyses. All odds ratios were adjusted for age at index date, BMI, parity cross-classified by age at first birth, time since menopause, family history of breast cancer, place of residence, socioeconomic disadvantage quintile, oral contraceptive use, history of breast screening and alcohol consumption.

Fig 3. MHT use and invasive breast cancer risk for subtypes based on ER, PR, and HER2 status.

P* = p-value is for the test of global null hypothesis that the OR estimates are equal to one (i.e their reference group OR). All odds ratios were adjusted for age at index date, BMI, parity cross-classified by age at first birth, time since menopause, family history of breast cancer, place of residence, socioeconomic disadvantage quintile, oral contraceptive use, breast screening history and alcohol consumption.