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.

Usha Salagame,Dianne L O’Connell,Sam Egger,Karen Canfell,Emily Banks,Anna Sapino

doi:10.1371/journal.pone.0205034

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.

Highlights

It is estimated that 1.67 million new cases of breast cancer were diagnosed in 2012, making breast cancer the second most common cancer globally and the most frequent cancer among women [1]
The Estrogen Receptor (ER)+/Progesterone Receptor (PR)+/Human Epidermal growth factor Receptor2 (HER2)- phenotype is a surrogate for so-called luminal A intrinsic subtype and for the luminal B intrinsic subtype, the ER+/PR+ /HER2+ phenotype is a surrogate for the luminal B subtype
Information on the method of HER2 detection was not extracted; it is not known if cases with equivocal results for HER2 were tested by Immunohistochemistry or Fluorescence In-Situ Hybridisation

Summary

Introduction

It is estimated that 1.67 million new cases of breast cancer were diagnosed in 2012, making breast cancer the second most common cancer globally and the most frequent cancer among women [1]. Differences between breast cancers by ER/PR status have been shown in the aetiology [3,4,5,6,7,8,9,10,11], disease progression and prognosis [12], epidemiology [8,13,14,15] and response to available treatments [2,16,17]. The ER-/ PR-/HER2+ is a surrogate for the HER2 subtype and the triple negative phenotype (ER-/PR-/ HER2-) is a surrogate for the basal subtype of breast cancers [19]. As per the widely accepted 13th St Gallen International Breast Cancer Conference (2013) Expert Panel recommendations, these are referred to as luminal A-like, luminal B-like, HER2 type and triple negative-basal-like subtypes respectively, to indicate that they are proxies of the molecular subtypes [20]. In Australia, the three tumor markers—ER, PR and HER2 are routinely used in the diagnostic workup of breast cancer because of their utility in prognosis and guiding treatment [21], given some analytical problems with Ki67 measurement and standardisation

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