Endocrinology and hormone therapy in breast cancer: Selective oestrogen receptor modulators and downregulators for breast cancer – have they lost their way?

Oestrogen has important physiological effects on the growth and function of hormone-dependent tissues, including breast epithelium, uterus, vagina and ovaries. In addition, oestrogen preserves bone mineral density and reduces the risk for osteoporosis, protects the cardiovascular system by reducing cholesterol levels, and modulates cognitive function and behaviour. Tamoxifen is a nonsteroidal anti-oestrogen that antagonizes the action of oestrogen and is effective in both the treatment [1,2] and prevention of breast cancer [3]. Although concerns were raised regarding the potential anti-oestrogenic effects on normal tissues, paradoxically tamoxifen acts as an oestrogen on bone, blood lipids and the endometrium [4]. In the adjuvant and prevention settings, this may increase the risk for endometrial cancer in women taking tamoxifen, although the risk has been perceived to be small in relation to the substantial benefit from reduction in breast cancer related events [5]. Likewise, breast epithelial cells and established carcinomas adapt to chronic anti-oestrogen exposure and develop resistance to tamoxifen, which may also result from the drug's partial agonistic activity stimulating tumour regrowth [6].The term 'selective oestrogen receptor modulator' (SERM) refers to the capacity of separate anti-oestrogens to exert alternative effects on various oestrogen regulated targets. Over the past 10–15 years several strategies were employed to improve or alter the agonist/antagonist profile of tamoxifen. An understanding of structure–function relationships led to chemical modifications of tamoxifen, either by altering the side chains to produce new tamoxifen analogues such as toremifene, idoxifene, droloxifene, lasofoxifene and TAT-59; or by altering the nonsteroidal triphenylethylene ring structure of tamoxifen to produce a nonsteroidal 'fixed ring' structure such as the benzothiophene derivatives raloxifene and arzoxifene, the benzopyran derivative acolbifene, or the indole