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posted Nov 24, 2009, 12:57 AM by DERC 藥物教育資源中心

(Originally posted on 2004-11-11)

Exemestane - the Preferred Adjuvant Hormonal Therapy in Metastatic Breast Cancer after Tamoxifen?


Exemestane (EXE) is a steroidal irreversible aromatase inhibitor blocking the conversion of androgens to estrogens in peripheral tissues. It is currently indicated in the treatment of oestrogen-receptor positive advanced breast cancer in women with natural or induced post-menopausal status whose disease has progressed following anti-oestrogen therapy.

In contrast to nonsteroidal aromatase inhibitors (NS-AI), especially the 3rd generation aromatase inhibitors (such as anastrozole and letrozole) which bind reversibly to the cytochrome P450 (heme) moiety of the aromatase enzyme, EXE acts as false substrate that binds irreversibly to the substrate binding site of the enzyme. Both groups are well tolerated and exert similar efficacy with an over 90% reduction in circulating levels of estrogen.[1] However, the difference is EXE causes profound and prolonged reduction in aromatase levels, while NS-AI leads to aromatase up-regulation, thus possibly resulting in an earlier emergence of a resistant cell population [2]. In addition, EXE should theoretically exert a more effective global or some intra-tumoral aromatase inhibition because its metabolite, 17-hydroxyEXE has weak androgenic activity.

Clinical Trial Review: Exemestane vs Tamoxifen

Coombes et al. [3] conducted a double-blinded, randomized international trial to test whether switching to EXE after 2-3 years of tamoxifen therapy was more effective than continuing tamoxifen therapy for up to 5 years as recommended in the standard treatment. The study involved over 4500 patients and they were followed up for a median of 30.6 months. The EXE group showed a 32% statistically significant reduction in risk which corresponded to an absolute benefit in terms of disease-free survival of 4.7% at three years of randomization. The survival free of distant disease was better in the EXE group but the overall survival was not significantly different.

EXE was associated with a higher incidence of arthralgia and diarrhea than tamoxifen, but gynecologic symptoms (such as vaginal bleeding) and thromboembolic events were recorded more frequently in the tamoxifen group.

The trial panel recommended switching after 2-3 years after the start of tamoxifen treatment to EXE because of the following reasons. First of all, breast cancer frequently becomes resistant to tamoxifen within 5 years of continued treatment. Laboratory studies indicate the change in drug-receptor interaction of tamoxifen is caused by the up-regulation of tyrosine kinase receptors (especially the HER2 & epidermal growth-factor receptors) and downstream protein kinase. This change not only increases the expression of agonistic activity of tamoxifen but also increases the sensitivity of breast cancers to estradiol. Secondly, the serious side effects of tamoxifen, including thromboembolism and uterine carcinoma, can occur after prolonged use. Thirdly, tamoxifen can decrease bone resorption and thus, pretreatment with tamoxifen might lessen the effect of osteopenia caused by EXE.

Paridaens et al. [4] conducted an open-label and randomized trial to compare EXE versus tamoxifen as first-line hormonal therapy for postmenopausal women with metastatic breast cancer. This study involved over 380 patients and the median progression-free survival for patients taking EXE was 10.9 months while those taking tamoxifen was 6.7 months. Both complete and partial response rate were also higher in the EXE group (complete response: 7.4% vs 2.6%; partial response 36.8% vs 26.6%).

Clinical Trial Review: Exemestane vs other NS-AIs

Lonning et al. [1] conducted an open-label trial to evaluate the efficacy and toxicity of EXE in postmenopausal women with metastatic breast cancer who has progressive disease after 8 or more weeks of treatment with a NS-AI (including aminoglutethimide, anastrozole, letrozole and vorozole). The patient was first receiving 25mg of EXE once daily and would be given 100mg upon development of progressive disease. The study sample size was over 240 patients with a median duration of treatment of 37 weeks and 58 patients received a dose escalation to 100mg daily.

EXE produced objective responses in 6.6% of treated patients, including 8.1% and 4.8% of patients after failure of treatment with aminoglutethimide and other NS-AIs. No additional clinical benefit was observed in patients with an increasing dose of EXE to 100mg. Furthermore, both doses of EXE are well tolerated by patients with nausea, fatigue and hot flushes as the three most frequently complained side effects.

Fernie et al. [5] also had similar findings in a study to investigate the efficacy of EXE in postmenopausal women with metastatic breast cancer after failure of multiple hormonal therapies, including NS-AI. The study involved 96 patients and 4.2% had objective response and 34.4% had stable disease for at least 24 weeks.


The current standard treatment for hormone-receptor positive breast cancer as recommended by the American Society of Clinical Oncology is tamoxifen for up to 5 years [6]. In patients failing tamoxifen therapy, a high dose progestogen therapy such as megestrol acetate used to be the second-line option for these patients until the arrival of the aromatase inhibitors.

Considerable evidence now demonstrates that aromatase inhibition [7, 8] is superior, in terms of both efficacy and tolerability to megestrol acetate in postmenopausal women with tamoxifen-resistant advanced breast cancer and metastatic breast cancer. There is additionally some early evidence that EXE is superior to the NS-AI [1]. The long-term consequence of estrogen deprivation in postmenopausal women presently remains unclear. Particular concern should be paid on bone and cardiovascular health. Nevertheless, EXE appears a promising preferred option in treating advanced, metastatic breast cancer in natural- or induced-postmenopausal women failing tamoxifen treatment [9].


  1. Lonning PE Bajetta E, Murray R, et al. Activity of EXE in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial. Journal of Clinical Oncology 2000, Vol 18, No.11:2234-2244
  2. Paridaens R, Dirix L, Lohrisch C, et al. Mature results of a randomized phase II multicenter study of EXE versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Annuals of Oncology 2003. 14:1391-1398
  3. Coombes RC, Hall E, Gibson L, et al. A randomized trial of EXE after 2-3 years of tamoxifen therapy in postmenopausal women with primary breast cancer. The New England Journal of Medicine 2004. Vol 350, No. 11:1081-1092
  4. Paridaens R, Therasse P, Dirix L, et al. First results of a randomized phase III trial comparing EXE versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. European Journal of Cancer Supplement 2003:Vol 2, No 3:126
  5. Fernie NL, Zekri JM, Leonard RCF, et al. EXE in metastatic breast cancer; effective therapy after 3rd generation aromatase inhibitor failure. Poster Session IV of San Antonio 2003
  6. Winer EP, et al. American Society of Clinical Oncology Technology Assessment Working Group Update: Use of aromatase inhibitors in the adjuvant setting. J. Clin. Oncol. 2003:21:2597-2599
  7. Buzdar AU, Jonat W, Howell A, et al. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from tow mature phase III trials. Cancer1998;83:1142-1152
  8. Dombernowsky P, Smith I, Falkson G, et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer; double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 1998;16:453-461
  9. Piccart-Gebhart MJ. New stars in the sky of treatment for early breast cancer. Editorial in the New England Journal of Medicine 2004. Vol 350, No. 11:1140-1142