Aromatase inhibitors and their use in the sequential setting.

Abstract

Over the past decade several novel aromatase inhibitors have been introduced into clinical practice. The discovery of these drugs followed on from the observation that the main mechanism of action of aminogluthemide was via inhibition of the enzyme aromatase thereby reducing peripheral levels of oestradiol in postmenopausal patients.The second-generation drug, 4-hydroxyandrostenedione (formestane), was introduced in 1990 and although its use was limited by its need to be given parenterally it was found to be a well-tolerated form of endocrine therapy.Third-generation inhibitors include vorozole, letrozole, anastrozole and exemestane, the former three being non-steroidal inhibitors, the latter being a steroidal inhibitor. All are capable of inhibiting aromatase action by >95% compared with 80% in the case of 4-hydroxyandrostenedione.The sequential use of different generations of aromatase inhibitors in the same patients is discussed. Studies suggest that an optimal sequence of these compounds may well result in longer Endocrine-Related Cancer (1999) 6 259-263 remission in patients with hormone receptor positive tumours.

The implications of genetic variation for the pharmacokinetics and pharmacodynamics of aromatase inhibitors

“…Trials of each of these agents have shown excellent clinical activity and a low incidence of serious short-term adverse events that reflects greater specificity of action [16][17][18][19][20][21][22][23]. After initial licensing in the 1990s for the treatment of postmenopausal women with metastatic breast cancer, the use of third-generation AIs in the adjuvant and neoadjuvant setting is now standard of care [24][25][26][27][28][29][30].…”