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Exemestane

A Review of its Use as Adjuvant Treatment for Early Breast Cancer in Postmenopausal Women

  • Adis Drug Evaluation
  • Published:
American Journal of Cancer

Summary

Abstract

Exemestane (Aromasin®) is an irreversible steroidal aromatase inactivator that suppresses estrogen levels, leading to regression of hormone-dependent breast cancers in postmenopausal women. It is indicated for the adjuvant treatment of estrogen receptor-positive early breast cancer in postmenopausal women who have already received 2–3 years of adjuvant tamoxifen, to complete a total of 5 years’ endocrine therapy.

In the IES (Intergroup Exemestane Study) in postmenopausal women with early estrogen receptor-positive breast cancer, switching to exemestane 25 mg/day for 2–3 years after receiving tamoxifen for 2–3 years (to a total of 5 years) improved disease-free survival and reduced the risk of contralateral breast cancer compared with continued tamoxifen. Overall survival was also significantly improved in the estrogen receptor-positive/ unknown population of exemestane recipients when adjusted for nodal status and prior chemotherapy and hormone replacement therapy (HRT) use. Exemestane appears to have a favorable tolerability profile compared with tamoxifen, although possible detrimental effects of estrogen suppression on bone mineral density (BMD) and cardiovascular (CV) risk require further investigation.

Because of a lack of comparative trials with aromatase inhibitors, the optimal combination choices and duration of aromatase inhibitor/inactivator and tamoxifen treatment have yet to be determined; however, postmenopausal women who have already received 2–3 years of adjuvant tamoxifen for early breast cancer should be considered for switching to exemestane to complete 5 years’ endocrine therapy.

Pharmacological Properties

Exemestane is an orally active irreversible steroidal aromatase inactivator. It inactivates the aromatase enzyme by binding irreversibly to the active site. This suppresses aromatase activity in postmenopausal women and thereby the peripheral formation of estrogens from adrenal androgens. This leads to regression of hormone-dependent breast tumors.

The administration of exemestane does not affect plasma levels of testosterone, androstenedione, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, cortisol, aldosterone, luteinizing hormone or follicle-stimulating hormone; however, it did result in a dose-dependent decrease in sex hormone binding globulin. The effects of exemestane on the lipid profile are not yet clear.

Following oral administration, exemestane is rapidly absorbed and peak plasma concentrations are reached within 1–2 hours. Exemestane is distributed extensively into tissues and is metabolized mainly by cytochrome P450 3A4 to metabolites that are inactive or less potent than the parent drug. The mean terminal half-life of exemestane is 27 hours.

The pharmacokinetics of exemestane are affected by hepatic and renal impairment; however, dosage adjustments are not required in these patients as the changes are not thought to be clinically significant.

Therapeutic Efficacy

One well designed trial (IES) has investigated the efficacy of orally administered adjuvant exemestane 25 mg/ day for 2–3 years following 2–3 years of initial tamoxifen compared with continuing tamoxifen for a total of 5 years in postmenopausal women with early breast cancer. An interim analysis of the IES study (at a median follow-up of 30.6 months), and the first IES mature analysis (at a median follow-up of 55.7 months) showed that the primary endpoint of disease-free survival was significantly higher in patients who changed to exemestane treatment than in those who continued tamoxifen treatment. The risk of contralateral breast cancer was significantly lower in exemestane recipients, and the subsidiary endpoint of breast cancer-free survival was also significantly higher in the exemestane group.

Furthermore, a significant improvement in overall survival in the exemestane group was demonstrated at 55.7 months’ follow-up in patients with estrogen receptor-positive disease or unknown estrogen receptor status when adjusted for nodal status, chemotherapy use, and HRT use.

There were no between-group differences in health-related quality of life in a subgroup of patients from the IES study.

Tolerability

Exemestane is generally well tolerated. In postmenopausal women in the IES study, exemestane recipients had a significantly higher incidence of diarrhea and arthralgia than tamoxifen recipients, and a significantly lower incidence of gynecologic symptoms and muscle cramps than those who received tamoxifen. Thromboembolic events occurred significantly more in tamoxifen recipients at 30.6 months’ follow-up; however, the between-group difference was not significant in a updated analysis at 55.7 months’ follow-up.

The incidences of the most frequent adverse events at the first analysis, CV disease (not including myocardial infarction), hot flashes, and pain or aches, were not significantly different between groups. Exemestane appears to cause moderate BMD loss in postmenopausal women and also affects bone metabolism, although some of these effects may be reversed after treatment ends. At the 55.7-month follow-up of IES, the incidence of fractures was significantly higher in exemestane compared with tamoxifen recipients. Exemestane may reverse the detrimental effects of tamoxifen on endometrial thickening.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Adis International Inc., 770 Township Line Road, Suite 300, Yardley, PA, 19067, USA

    Marit D. Moen & Antona J. Wagstaff

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  1. Marit D. Moen
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Correspondence to Marit D. Moen.

Additional information

Various sections of the manuscript reviewed by: G. Bertelli, South West Wales Cancer Institute, Swansea, UK; A.U. Buzdar, Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; A. Howell, Christie Hospital NHS Trust, Manchester, UK; P.E. Lønning, Department of Oncology, Haukeland University Hospital, Bergen, Norway; C. Markopoulos, Athens University Medical School, Athens, Greece; H. Mouridsen, Department of Oncology, Rigshospitalet, Copenhagen, Denmark; R.M. O’Regan, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘exemestane’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE, and AdisBase search terms were ‘exemestane’ and ‘early breast cancer’ and ‘adjuvant’ and ‘postmenopausal’. Searches were last updated 8 August 2006.

Selection: Studies in postmenopausal women with early breast cancer who received exemestane. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Exemestane, early breast cancer, postmenopausal, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Moen, M.D., Wagstaff, A.J. Exemestane. Am J Cancer 5, 259–272 (2006). https://doi.org/10.2165/00024669-200605040-00005

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