Aromatase inhibitors: a dose-response effect?

Aminoglutethimide, the first aromatase inhibitor, was established in the 1970s as an active treatment for patients with advanced breast cancer, but its lack of specificity was associated with side effects. Since that time, a series of much more specific non-steroidal aromatase inhibitors has been developed which are up to 10 000 times as potent as aminoglutethimide in vivo with no evidence of inhibition of other steroid pathways at doses required to inhibit oestrogen. Two of these inhibitors, letrozole (Femara; Novartis) and anastrozole (Arimidex; Zeneca) are now well established in the treatment of advanced breast cancer and are under investigation as adjuvant therapy. These agents achieve 98-99% aromatase inhibition in patients, and reduce serum concentrations of oestrone and oestradiol beyond the limit of detection in many patients (Iveson et al. 1993). Until recently, it had been assumed that no clinical dose-response effect could exist beyond the achievement of maximum serum oestrogen suppression, but recent data have suggested this may not be the case. If a dose-response effect does indeed exist for modern aromatase inhibitors, then it has important implications for their future development.