Breast-related effects of selective estrogen receptor modulators and tissue-selective estrogen complexes.

Carolyn L Smith,Richard J Santen,Sebastian Mirkin,Barry Komm

doi:10.1186/bcr3677

Abstract

A number of available treatments provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis. However, as breast safety is a major concern, new options are needed, particularly agents with an improved mammary safety profile. Results from several large randomized and observational studies have shown an association between hormone therapy, particularly combined estrogen-progestin therapy, and a small increased risk of breast cancer and breast pain or tenderness. In addition, progestin-containing hormone therapy has been shown to increase mammographic breast density, which is an important risk factor for breast cancer. Selective estrogen receptor modulators (SERMs) provide bone protection, are generally well tolerated, and have demonstrated reductions in breast cancer risk, but do not relieve menopausal symptoms (that is, vasomotor symptoms). Tissue-selective estrogen complexes (TSECs) pair a SERM with one or more estrogens and aim to blend the positive effects of the components to provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis without stimulating the breast or endometrium. One TSEC combination pairing conjugated estrogens (CEs) with the SERM bazedoxifene (BZA) has completed clinical development and is now available as an alternative option for menopausal therapy. Preclinical evidence suggests that CE/BZA induces inhibitory effects on breast tissue, and phase 3 clinical studies suggest breast neutrality, with no increases seen in breast tenderness, breast density, or cancer. In non-hysterectomized postmenopausal women, CE/BZA was associated with increased bone mineral density and relief of menopausal symptoms, along with endometrial safety. Taken together, these results support the potential of CE/BZA for the relief of menopausal symptoms and prevention of postmenopausal osteoporosis combined with breast and endometrial safety.

Highlights

Vasomotor symptoms (VMSs) occur in up to 88% of women during the early years of menopause [1], and vulvar-vaginal atrophy (VVA) symptoms are reported by up to 50% of postmenopausal women [2]
This review summarizes the breast-related effects of Hormone therapy (HT), selective estrogen receptor modulator (SERM), and Tissue-selective estrogen complex (TSEC) in postmenopausal women
In the randomized, double-blind, Multiple Outcomes of Raloxifene Evaluation (MORE) trial of postmenopausal women with osteoporosis (n = 7,705), RLX decreased the risk of invasive breast cancer by 72% over 4 years compared with placebo (PBO) (relative risk (RR) 0.28, 95% CI 0.17 to 0.46) [65]

Summary

Introduction

Vasomotor symptoms (VMSs) occur in up to 88% of women during the early years of menopause [1], and vulvar-vaginal atrophy (VVA) symptoms (for example, vaginal dryness, irritation, soreness, and dyspareunia) are reported by up to 50% of postmenopausal women [2]. Preclinical comparisons of different tissue-selective estrogen complexes The breast-related effects of different TSECs, combining RLX, LAS, or BZA with one or more estrogens, have been evaluated in preclinical studies (Table 1) [30,62,64,97,98,99]. Results from microarray studies comparing gene expression profiles of BZA, RLX, and LAS alone and in combination with CE in MCF-7 human breast cancer cells supported a broad range of differences in gene expression patterns across the different SERM and TSEC combinations [62,96]. In an MCF-7 cell proliferation study, RLX, LAS, and BZA all significantly antagonized CE-stimulated proliferation of breast cancer cells; BZA exhibited similar or better efficacy at inhibiting MCF-7 cell growth than the other SERMs evaluated [62]. In a separate study of the effects of BZA, RLX, and LAS alone and in combination with CE on mammary gland morphology in OVX sexually immature

Key results

Study design

Conclusions

Findings

35. Brisken C