Optimisation of antioestrogen therapy: laboratory and clinical concepts

Abstract

SynopsisTamoxifen, a non-steroidal antioestrogen, is the first line endocrine therapy for breast cancer. Laboratory studies during the past decade have provided valuable clues to understand the mode of action of tamoxifen so that the drug can be used to its best advantage in the clinic. Animal models (carcinogen-induced rat mammary carcinoma models, spontaneous mouse mammary tumours, and athymic mice inoculated with hormone-dependent human breast cancer cell lines) all demonstrate that tamoxifen is a tumouristatic agent and long-term or indefinite therapy is required to prevent the appearance of tumours. However, when treatment is stopped, tumours appear spontaneously or can be encouraged to re-appear with oestrogen therapy. These data clearly support the view that adjuvant clinical trials with tamoxifen should employ an indefinite treatment policy or at least until the time of treatment failure. Several clinical trials organisations in Great Britain (CRC and Scottish trial) have recruited a significant number of premenopausal patients. However, unlike postmenopausal patients, long-term tamoxifen therapy of premenopausal women often causes an increase in circulating oestrogen. Since tamoxifen has been shown to be a competitive inhibitor of oestrogen action, strategies to reduce ovarian steroidogenesis (oophorectomy or Zodalex®) may provide an optimal environment to sustain the long-term effectiveness of adjuvant tamoxifen therapy.