This Article Full Text Full Text (PDF) All Versions of this Article: theoncologist.2008-0055v1 13/8/829    most recent eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Google Scholar Articles by Miller, W. R. Articles by Goss, P. E. PubMed PubMed Citation Articles by Miller, W. R. Articles by Goss, P. E.

Breast Cancer

Aromatase Inhibitors: Are There Differences Between Steroidal and Nonsteroidal Aromatase Inhibitors and Do They Matter?

^aUniversity of Edinburgh, Edinburgh, UK; ^bUniversity of Maryland School of Medicine, Baltimore, Maryland, USA; ^cThe Ohio State University, Columbus, Ohio, USA; ^dPfizer Italia s.r.l., Milan, Italy; ^eSection of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway; ^fHospital Universitari Arnau de Vilanova, Lleida, Spain; ^gUniversity of Kiel, Kiel, Germany; ^hUniversity Montpellier 1, Centre Hospitalier Universitaire, Montpellier, France; ⁱTohoku University School of Medicine, Sendai, Miyagi, Japan; ^jHarvard Medical School, Boston, Massachusetts, USA

Key Words. Aromatase inhibitor • Exemestane • Letrozole • Anastrozole • Mechanism of action

Correspondence: William R. Miller, D.Sc., Ph.D., Breast Unit, Paderewski Building, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. Telephone: 0131-537-2501/5; Fax: 0131-537-2449; e-mail: wmiller{at}staffmail.ed.ac.uk

Received March 6, 2008; accepted for publication June 13, 2008; first published online in THE ONCOLOGIST Express on August 11, 2008.

Disclosure: W.R.M. discloses that this article discusses letrozole (Novartis), anastrozole (AstraZeneca), and exemestane (Pfizer) for validation of mechanism of action. He has also been on the advisory board for Pfizer and received speaker's honoraria. J.B. has received honoraria and research funding from Pfizer (exemestane). A.M.H.B. has received honoraria and research support from AstraZeneca (anastrozole research). R.W.B. discloses that this article discusses exemestane (Pfizer), anastrozole (AstraZeneca), and letrozole (Novartis) for use in breast cancer therapy. He also received an honorarium for participating in an expert panel meeting from Pfizer/CC Ford Healthcare. E.d.S. is an employee and has stock options in Pfizer (exemestane). P.E.L. has received speaker's honoraria from Novartis, AstraZeneca, and Pfizer. A.L. discloses no conflict of interest. N.M. discloses that the article discusses exemestane (Pfizer), anastrozole (AstraZeneca), and letrozole (Novartis) for breast cancer treatment, and he has been on an advisory board and received honoraria from Pfizer (exemestane). T.M. has research funding from Novartis (letrozole) and has received a consulting fee from Pfizer (exemestane). H.S. has research funding and has received an honorarium from Pfizer (exemestane). P.E.G. discloses that this article discusses letrozole (Novartis), anastrozole (AstraZeneca), and exemestane (Pfizer) for validation of mechanism of action. He also discloses that the article discusses aromatase inhibitors for prevention (Novartis, AstraZeneca, Pfizer), and that he has received speaker's honoraria from Novartis, AstraZeneca, and Pfizer. The content of this manuscript has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from any commercial bias; they have disclosed no financial relationships relevant to this content.

Aromatase inhibitors (AIs) are approved for use in both early- and advanced-stage breast cancer in postmenopausal women. Although the currently approved "third-generation" AIs all powerfully inhibit estrogen synthesis, they may be subdivided into steroidal and nonsteroidal inhibitors, which interact with the aromatase enzyme differently. Nonsteroidal AIs bind noncovalently and reversibly to the aromatase protein, whereas steroidal AIs may bind covalently and irreversibly to the aromatase enzyme. The steroidal AI exemestane may exert androgenic effects, but the clinical relevance of this has yet to be determined. Switching between steroidal and nonsteroidal AIs produces modest additional clinical benefits, suggesting partial noncrossresistance between the classes of inhibitor. In these circumstances, the response rates to the second AI have generally been low; additional research is needed regarding the optimal sequence of AIs. To date, clinical studies suggest that combining an estrogen-receptor blocker with a nonsteroidal AI does not improve efficacy, while combination with a steroidal AI has not been evaluated. Results from head-to-head trials comparing steroidal and nonsteroidal AIs will determine whether meaningful clinical differences in efficacy or adverse events exist between the classes of AI. This review summarizes the available evidence regarding known differences and evaluates their potential clinical impact.