Aromatase inhibition in the treatment of advanced breast cancer: is there a relationship between potency and clinical efficacy?
Two-thirds of breast tumours are oestrogen-receptor positive and 60-70% of these tumours respond to interventions that reduce the effects of oestrogen. Until recently, tamoxifen was the drug of choice for the treatment of hormone-responsive early and advanced breast cancer. However, tamoxifen is associated with increased incidences of endometrial cancer and thromboembolic disease, and many tumours eventually become resistant to treatment with tamoxifen. Thus, there is a need for alternative therapies with different mechanisms of action. In postmenopausal women, aromatase inhibitors (AIs) suppress oestrogen levels by inhibiting oestrogen synthesis via the aromatase enzyme pathway. The third-generation AIs (anastrozole, letrozole and exemestane) are more potent than the earlier AIs (aminoglutethimide, formestane and fadrozole) with respect to both aromatase inhibition and oestrogen suppression. While the earlier AIs were unable to show any benefit over megestrol acetate or tamoxifen as second- and first-line therapy, respectively, in postmenopausal women with advanced breast cancer, third-generation AIs have shown significant benefits in both settings. Comparison of aromatase inhibition and oestrogen suppression between the third-generation AIs anastrozole and letrozole showed a small but significantly greater difference in the degree of suppression of oestrone and oestrone sulphate (but not oestradiol), with letrozole. In an open-label trial, there were no significant differences between letrozole and anastrozole for the clinical end points of time to progression (primary end point), time to treatment failure, overall survival, clinical benefit, duration of clinical benefit, time to response, duration of response or objective response rate in patients with confirmed hormone receptor-positive tumours. Together these data suggest that once a certain threshold of aromatase inhibition is reached, small differences in oestrogen suppression between the third-generation AIs do not lead to clinically significant differences in overall efficacy.
Sainsbury
R
R
Department of Surgery, Royal Free and University College Medical School, Charles Bell House, 67-73 Riding House Street, London W1W 7EJ, UK. r.sainsbury@ucl.ac.uk
D000077384:Anastrozole; D000730:Androstadienes / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001141:Aromatase / Q000187:drug effects; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D013629:Tamoxifen / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use
D000730:Androstadienes; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077384:Anastrozole; D000077289:Letrozole; D001141:Aromatase; C056516:exemestane