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      Exemestane in early breast cancer: a review

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          Abstract

          The adjuvant treatment of women with endocrine-sensitive early breast cancer has been dominated for the last 40 years by tamoxifen. However, the side-effects associated with this therapy have prompted a search for safer and biochemically more selective endocrine agents and led to the development of the third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane. Promising results in advanced disease have paved the way for treating early breast cancer, and AIs are increasingly replacing tamoxifen in the adjuvant setting. Several large, randomized trials with AIs have been completed or are ongoing in women with early-stage breast cancer, documenting the significant impact that these drugs are making on the risk for recurrence of breast cancer. As a result, there is increasing and widespread use of AI therapy for the treatment of early-stage endocrine-responsive breast cancer. This review summarizes the data for exemestane in the adjuvant setting, showing that a switch to exemestane after 2 to 3 years of tamoxifen therapy is associated with a statistically significant survival benefit and is regarded as being sensitive by international and national experts.

          Most cited references32

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          Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials

          The Lancet, 365(9472), 1687-1717
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            Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer.

            AIB1 (SRC-3) is an estrogen receptor (ER) coactivator that, when overexpressed in cultured cells, can reduce the antagonist activity of tamoxifen-bound ERs. Signaling through the HER-2 receptor pathway activates AIB1 by phosphorylation. To determine whether high AIB1 expression alone or together with HER-2 reduces the effectiveness of tamoxifen in breast cancer patients, we quantified expression of AIB1 and HER-2 in tumors from breast cancer patients with long-term clinical follow-up who received either no adjuvant therapy or adjuvant tamoxifen therapy after breast cancer surgery. AIB1 and HER-2 protein levels in tumors from 316 breast cancer patients were determined using western blot analysis. Molecular variables (e.g., expression of AIB1, ER, progesterone receptor, p53, Bcl-2), tumor characteristics, and patient outcome were assessed using Spearman rank correlation. Disease-free survival (DFS) curves were derived from Kaplan-Meier estimates, and the curves were compared by log-rank tests. The effect of AIB1 on DFS adjusted for other prognostic factors was assessed by multivariable analysis using the Cox proportional hazards model. All statistical tests were two-sided. High AIB1 expression in patients not receiving adjuvant tamoxifen therapy was associated with better prognosis and longer DFS (P =.018, log-rank test). In contrast, for patients who did receive tamoxifen therapy, high AIB1 expression was associated with worse DFS (P =.049, log-rank test), which is indicative of tamoxifen resistance. The test for interaction between AIB1 expression and tamoxifen therapy was statistically significant (P =.004). When expression of AIB1 and HER-2 were considered together, patients whose tumors expressed high levels of both AIB1 and HER-2 had worse outcomes with tamoxifen therapy than all other patients combined (P =.002, log-rank test). The antitumor activity of tamoxifen in patients with breast cancer may be determined, in part, by tumor levels of AIB1 and HER-2. Thus, AIB1 may be an important diagnostic and therapeutic target.
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              Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial.

              Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2-3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. After a median follow-up of 55.7 months (range 0-89.7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0.76 (95% CI 0.66-0.88, p=0.0001) in favour of exemestane, absolute benefit 3.3% (95% CI 1.6-4.9) by end of treatment (ie, 2.5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0.85 (95% CI 0.71-1.02, p=0.08), 0.83 (0.69-1.00, p=0.05) when 122 patients with oestrogen-receptor-negative disease were excluded. Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2-3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                December 2008
                December 2008
                : 4
                : 6
                : 1295-1304
                Affiliations
                [1 ]Interdisciplinary Breast Centre, Helios Klinikum Berlin-Buch, University Charité, Berlin, Germany;
                [2 ]Department of Gynecology/Obstetrics, Klinikum Offenbach GmbH, Offenbach, Germany
                Author notes
                Correspondence: Prof Dr med. Michael Untch, Head of Department of Gynecology/Gynecologic Oncology, Head of the Interdisciplinary Breast Center, Helios Klinikum Berlin-Buch, Academic Hospital of the University Charité, Schwanebecker Chaussee 50, 13125 Berlin, Germany, Tel +49 030 9401/53300, Fax +49 030 9401/53309, Email muntch@ 123456berlin.helios-kliniken.de
                Article
                tcrm-4-1295
                2643110
                19337436
                974cb95f-b81c-4ce2-887f-658de276a9b9
                © 2008 Dove Medical Press Limited. All rights reserved
                History
                Categories
                Review

                Medicine
                early breast cancer,adjuvant setting,endocrine-sensitive,tamoxifen,aromatase inhibitor,exemestane,switch,ies 31,nsabp b-33,team

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