Are Differences in the Available Aromatase Inhibitors and Inactivators Significant?

Aromatase inhibitors are endocrine agents with a different mode of action than tamoxifen against breast tumors. In postmenopausal women, estrogen concentrations are maintained primarily via aromatase, a cytochrome P-450 enzyme that acts at the final step in the estrogen synthesis pathway. The first clinically available aromatase inhibitor, aminoglutethimide, was introduced for the second-line treatment of advanced breast cancer in the late 1970s. Despite proven efficacy in this setting, its widespread use was limited by its overall toxicity and its lack of selectivity for the aromatase enzyme. This led to the search for novel, more effective, and less toxic aromatase inhibitors. As a result, several aromatase inhibitors with a high degree of selectivity for aromatase and improved tolerability have become clinically available for the treatment of postmenopausal women with advanced breast cancer: (a) anastrozole; (b) letrozole; (c) fadrozole; (d) formestane; and (e) exemestane. Of these, formestane and exemestane are steroidal nonreversible aromatase inhibitors, also known as aromatase inactivators, whereas fadrozole, anastrozole, and letrozole are nonsteroidal reversible aromatase inhibitors. These agents differ in pharmacokinetics, selectivity, and potency, although all are more selective than aminoglutethimide. Some differences in adverse effect profile are also noticeable between and within these two classes of agents. The clinical significance of these differences is not yet evident but may well prove to be relevant in the long-term adjunctive setting. I n t r o d u c t i o n It has long been established that estrogen is the major hormone involved in the biology of breast cancer (1). Endocrine agents have therefore been designed to affect the supply of estrogens to the breast tumor, primarily by blockade of estrogen activity at the receptor level or by inhibition of estrogen production. However, drug resistance remains a significant problem in breast cancer treatment, and this has led to the development of a variety of endocrine agents to 1 Presented at the First International Conference on Recent Advances and Future Directions in Endocrine Therapy for Breast Cancer, June 21-23, 2001, Cambridge, MA. 2 To whom requests for reprints should be addressed, at Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 424, Houston, TX 77030. Phone: (713) 792-2817; Fax: (713) 794-4385; E-mail: abuzdar@ notes.mdacc.tmc.edu. extend the treatment options for breast cancer patients with hormone-sensitive disease. Aromatase inhibitors are endocrine agents that have a different mode of action than tamoxifen against breast tumors in postmenopausal women. Several aromatase inhibitors with a high degree of selectivity for aromatase and improved tolerability have become clinically available for the treatment of postmenopausal women with advanced breast cancer (2-6). P h a r m a c o l o g y of A r o m a t a s e Inhibi tors In postmenopausal women, ovarian estrogen production diminishes with age. In these women, estrogen concentrations are maintained primarily via aromatase, a cytochrome P-450 enzyme complex that acts at the final step in the estrogen synthesis pathway and catalyzes the production of estrogens estrone and estradiol by extraglandular conversion from androgens androstenedione and testosterone, respectively. These drugs act by suppression of aromatase activity in fat, liver, and muscle cells and in breast tumor tissue itself. They can be divided into two classes: (a) steroidal drugs; and (b) nonsteroidal drugs (Ref. 7; see Table 1). The steroidal class (type I) comprises primarily formestane and exemestane, and the nonsteroidal class (type II) comprises primarily the imide aminoglutethimide, the imidazole fadrozole, and the triazoles anastrozole and letrozole. A third nonsteroidal triazole, vorozole, has recently been withdrawn from clinical development. M e t h o d of Admin i s t ra t ion Anastrozole and letrozole are well absorbed following oral dosing, with long terminal half-lives, allowing for once-daily dosing [anastrozole, 1 mg; letrozole, 2.5 mg (3, 4)]. In contrast, formestane is subject to high first-pass metabolism when given p.o., has a relatively short terminal half-life (approximately 2 h), and has to be administered by i.m. injection (250 mg) every 2 weeks (8). Exemestane is p.o. bioavailable and has a terminal half-life of about 24 h during chronic treatment, allowing oncedaily therapy (25 mg) (9). M e c h a n i s m of Ac t ion Steroidal and nonsteroidal aromatase inhibitors differ in their modes of interaction with and inhibition of the aromatase enzyme. Steroidal inhibitors compete with the endogenous substrates androstenedione and testosterone for the active site of the enzyme, where they act as false substrates and are processed to intermediates that bind irreversibly to the active site, causing irreversible enzyme inhibition. Hence, they are sometimes termed aromatase inactivators. Nonsteroidal inhibitors also compete with the endogenous substrates for access to the active site, where they then form a coordinate bond to the heine iron atom. They effectively exclude, therefore, both the natural substrate and oxygen from the enzyme. The coordinate bonding is Research. on October 24, 2017. © 2001 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Clinical Cancer Research 4361s Table 1. Structure of aromatase inhibitors, pharmacology, and the selectivity data Chemistry Arimidex Letrozole Exemestane Nonsteroidal Nonsteroidal Steroidal