Elsevier

Cancer Treatment Reviews

Volume 30, Issue 8, December 2004, Pages 695-706
Cancer Treatment Reviews

NEW DRUGS
Selective oestrogen receptor modulators/new antioestrogens: a clinical perspective

https://doi.org/10.1016/j.ctrv.2004.04.003Get rights and content

Abstract

Following tamoxifen, the first selective oestrogen receptor modulator (SERM), a number of other antioestrogens have been developed. The first-generation SERMs exhibit cross-resistance with tamoxifen and have agonist effects on the uterus. Toremifene has equal efficacy to tamoxifen and may be useful as a tamoxifen alternative. Efficacy results for droloxifene and idoxifene were disappointing and their clinical development ceased. Response rates for second-generation SERMs such as raloxifene and arzoxifene are also not high, although raloxifene shows promise in the chemoprevention of breast cancer. Paradoxically, high-dose oestrogens are proving to be effective breast cancer treatment with similar responses to tamoxifen in postmenopausal women with advanced disease, although these drugs are not well tolerated. Fulvestrant is a new type of oestrogen receptor (ER) antagonist with no agonist effects, which binds, blocks and degrades the ER. Fulvestrant produces high response rates compared with the SERMs, is not cross-resistant with SERMs or aromatase inhibitors (AIs) and is equally as effective as the AI anastrozole in the treatment of postmenopausal women with advanced breast cancer who have progressed after prior antioestrogen therapy. Pure antioestrogens such as the ER antagonist fulvestrant provide opportunities for therapeutic sequencing with tamoxifen and AIs and offer exciting possibilities for the future treatment of breast cancer.

Introduction

Oestrogen has a number of important physiological effects on hormone-dependent reproductive tissues. It controls the growth of breast epithelial tissue, regulates the menstrual cycle by promoting endometrial proliferation in the uterus, and regulates circulating cholesterol levels, thereby providing a protective effect on the cardiovascular system.1 Oestrogen also protects against the loss of bone mineral density (BMD) and cognitive function in elderly women.[1], [2], [3] The biological role of oestrogen is mediated through high-affinity binding to the oestrogen receptor (ER).4 Breast tumours that express the ER are stimulated by oestrogen5 and antioestrogen therapy has thus become an established treatment for ER-positive breast cancer.

Treatment decisions for breast cancer can be complicated due to the varied clinical course of the disease and the many different treatments available. Patients with ER-positive tumours in whom hormonal therapy may be indicated include patients with metastatic breast cancer that is not immediately life threatening. In patients with early disease, hormonal therapy may also be used as adjuvant treatment.6

Section snippets

Evolution of antioestrogen therapy

At the end of the 19th century, Beatson7 first reported that the growth of human breast carcinomas may be associated with ovarian function (i.e. hormones) and antihormonal therapy has been evolving ever since. Pharmacological doses of oestrogens began to be used as treatment for breast cancer in pre- and postmenopausal women in the early 1940s and, second to ovarian ablation, oestrogen therapy is probably the oldest form of hormonal treatment for breast cancer.8 A schematic depicting the

First-generation SERMs (triphenylethylenes)

A number of triphenylethylene derivatives have been developed. For each of these antioestrogens, pre-clinical data suggested improved efficacy and safety profiles when compared with tamoxifen.[13], [14], [15]

Toremifene

Toremifene is structurally related to tamoxifen and, due to the high probability of cross-resistance between these two antioestrogens, was developed as an alternative to tamoxifen in the hope that it would produce fewer uterotrophic effects.[16], [17], [18]

High-dose oestrogens

Triphenylchlorethylene, triphenylmethylethylene, and stilboestrol were the first synthetic oestrogens to be used to treat carcinoma of the breast, with favourable results.8 It is only relatively recently, however, that high-dose estrogens have been included in the category of SERMs, as it is now apparent that these agents have antioestrogenic effects on breast tumours. It may seem rather paradoxical that both the reduction of oestrogen levels and the administration of high-dose oestrogen can

Fulvestrant: an oestrogen receptor antagonist

Fulvestrant is the first of a new type of ER antagonist with no known agonist effects, which binds, blocks and degrades the ER. The lack of oestrogen agonist activity was first demonstrated preclinically54 and confirmed in a study in healthy volunteers.55 The latter study evaluated the effects of fulvestrant 125 and 250 mg with or without ethinyloestradiol on the endometrium in 30 healthy, postmenopausal volunteers. In addition to blocking the oestrogenic effects of oestradiol, fulvestrant had

Optimising treatment: where are we now?

Clinical data for the SERMs have been somewhat disappointing in the advanced disease setting, as the efficacy advantages over tamoxifen seen in preclinical studies have not materialised in patients. However, greater potential may exist in the adjuvant or chemoprevention setting, where beneficial effects on bone, lipid and the endometrium will be of maximum benefit. At present, third-generation AIs such as anastrozole and letrozole are the only hormonal therapies that have been demonstrated in

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