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Clinical Utility of Exemestane in the Treatment of Breast Cancer

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Clinical Utility of Exemestane in the Treatment of Breast Cancer Journal name: International Journal of Women’s Health Article Designation: Review Year: 2015 Volume: 7 International Journal of Women’s Health Dovepress Running head verso: Zucchini et al Running head recto: Exemestane for the treatment of breast cancer open access to scientific and medical research DOI: http://dx.doi.org/10.2147/IJWH.S69475 Open Access Full Text Article REVIEW Clinical utility of exemestane in the treatment of breast cancer Giorgia Zucchini1 Abstract: Breast cancer is the most prevalent cancer in women, causing a significant mortality Elena Geuna1 worldwide. Different endocrine strategies are available for the treatment of hormone-sensitive Andrea Milani1 breast cancer, including antiestrogen tamoxifen and fulvestrant, as well as third-generation Caterina Aversa2 aromatase inhibitors (AIs), such as letrozole, anastrozole, and exemestane. In this review, we Rossella Martinello2 will focus on exemestane, its clinical use, and its side effects. Exemestane is a steroidal third- Filippo Montemurro1 generation AI now used in all treatment settings for breast cancer. In the metastatic disease, it has been extensively investigated as the first-, second-, and further-line treatment and it is 1 Investigative Clinical Oncology, now registered for the treatment of postmenopausal women with advanced estrogen-receptor- Fondazione del Piemonte per l’Oncologia-Candiolo Cancer Institute positive breast cancer whose disease has progressed following antiestrogen therapy. A potential (IRCCs), Candiolo, 2University of Turin lack of cross-resistance with nonsteroidal AIs has been described, giving additional therapeutic Medical School, Turin, Italy opportunities in sequences of endocrine agents. Exemestane is also approved for the adjuvant For personal use only. treatment of postmenopausal early breast cancer, either as upfront monotherapy for 5 years, as a switch following 2–3 years of tamoxifen, or as extended therapy beyond 5 years of adjuvant treatment. New promising data also showed a beneficial effect in young premenopausal early breast cancer patients, when administered together with ovarian suppression. Interesting results have also emerged when exemestane has been investigated as neodjuvant treatment as well as preventive agent in healthy women at high risk for breast cancer. Exemestane is generally well tolerated, with a side effect profile similar to that of other AIs, including menopausal symptoms, arthralgia, and bone loss. In conclusion, exemestane can be considered an effective and well- tolerated endocrine treatment option for all stages of breast cancer. Keywords: breast cancer, endocrine therapy, aromatase inhibitors, exemestane Introduction Breast cancer is one of the most frequently diagnosed cancers among women, with International Journal of Women's Health downloaded from https://www.dovepress.com/ by 54.191.40.80 on 06-Jun-2017 approximately 232,340 new cases and 39,620 deaths estimated among US women in 2013.1 Corresponding figures in the European Union are 358,967 and 90,800, respectively.2,3 Estrogen hormones have been implicated in promoting breast cancer develop- ment and progression in the majority of women. Endocrine manipulation has been exploited therapeutically for more than a century, starting from empirical observations of regression of locally advanced breast cancers after oophorectomy in premenopausal patients.4 Correspondence: Giorgia Zucchini While ovaries represent the main source of estrogens in premenopausal women, Investigative Clinical Oncology, the principal source of circulating estrogens in the postmenopausal stage is the aro- Fondazione del Piemonte per matization of the adrenal and ovarian androgens androstenedione and testosterone l’Oncologia–Candiolo Cancer Institute (IRCCs), Strada Provinciale 142, Km 3.95, to estrogens. Aromatase, a member of the cytochrome P-450 (CYP) family located CAP 10060, Candiolo, Turin, Italy predominantly in the liver, adrenal glands, and fat tissue, is responsible for this Tel +39 011 993 3958 Email [email protected] reaction.5 submit your manuscript | www.dovepress.com International Journal of Women’s Health 2015:7 551–563 551 Dovepress © 2015 Zucchini et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/IJWH.S69475 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Powered by TCPDF (www.tcpdf.org) 1 / 1 Zucchini et al Dovepress Different endocrine strategies have been developed for 7,12-dimethylbenzanthracene (DMBA)-induced mammary the treatment of hormone-sensitive breast cancer, depending tumors. These experiments revealed that exemestane was on the patient’s menopausal status: 1) blockade/downregu- highly effective when administered by both subcutaneous lation of estrogen receptor (ER) obtained with the selective and oral routes,20 with a greater efficacy than that observed ER modulator (SERM) tamoxifen and the selective ER for the steroidal AIs formestane, atamestane, and plomestane downregulator (SERD) fulvestrant, 2) inhibition of estradiol in similar models.21,22 biosynthesis by blocking the production of gonadotropins An oral dose of exemestane is rapidly absorbed, with (follicle-stimulating hormone/luteinizing hormone) with peak plasma concentrations reached within 2 hours of gonadotropin-releasing hormone (GnRH) agonists in pre- administration. After 4 hours, plasma concentrations fall to menopausal women and, finally 3) inhibition of peripheral undetectable levels, although inhibitory activity persists for at tissue production of estrogen using aromatase inhibitors (AIs) least 5 days despite a plasma half-life of only 27 hours. This in postmenopause. long-lasting effect may be due to the irreversible aromatase AIs can be subdivided into two major groups: steroidal inhibition; thus a new enzyme biosynthesis is required to AIs (SAIs) and nonsteroidal AIs (NSAIs) and, according to renew estrogen production, leading to a persistent inhibitory the chronologic order of their clinical development, they are effect even after clearance.23 classified as first-, second-, and third-generation inhibitors. Metabolism occurs through CYP3A4; however, inhibi- Early first-generation inhibitors, such as aminoglutethim- tion of the activity of the major CYP enzymes experienced in ide, showed reasonable efficacy against metastatic breast healthy volounteers does not seem to influence exemestane cancer.6 However, they lacked specificity, antagonizing the disposition.24 production of mineralocorticoids and glucocorticoids in addi- The main exemestane metabolite identified in the plasma tion to sex steroids, resulting in excessive toxicity.7 is 17-hydroxyexemestane, showing concentrations nearly Second-generation agents, namely, formestane and ten times less than that of the parental compound. Other fadrozole, had fewer side effects compared with aminoglu- metabolites are inactive or inhibit aromatase with decreased For personal use only. tethimide, but they showed limited efficacy.8–12 potency.23 Subsequently, more specific antagonists of aromatase Because exemestane and its metabolites are excreted have been developed and, at the present time, the three third- in both urine and feces, impaired renal as well as hepatic generation compounds available are anastrozole, letrozole, function both lead to reduced metabolism, with consequent and exemestane. The first two are categorized as reversible elevated plasma levels.25 NSAIs, whereas exemestane is an irreversible SAI.13,14 Exemestane induces maximal estradiol suppression after This review will address the steroidal irreversible antago- 3–7 days, reaching steady-state levels within 7 days with nist exemestane, with a major focus on its developmental daily dosing.23,26 steps and clinical applications in the treatment of hormone- The initial Phase I clinical trials identified a daily exemes- sensitive breast cancer. tane oral dose of 25 mg as the minimum effective dose pro- ducing the highest degree of estrogen suppression.23,27,28 This International Journal of Women's Health downloaded from https://www.dovepress.com/ by 54.191.40.80 on 06-Jun-2017 Pharmacology and preclinical dosage was found to inactivate 98% of the total aromatase development activity, resulting in a 85%–95% reduction of plasma estrone, Exemestane (6-methylenandrosta-1,4-diene-3,17-dione) is an estradiol, and estrone sulfate levels, compared to pretreatment irreversible SAI. Due to its androstenedione-like structure, levels.29 This level of inhibition appears in the range of that exemestane competes with the natural substrates androstene- described for the other third-generation AIs and compares dione and testosterone. By forming covalent bonds with the favorably with the ,90% inhibition described for first- and substrate-binding site of the enzyme, it finally leads to irre- second-generation inhibitors.30 versible aromatase inactivation, a mechanism that has been Comparative studies revealed exemestane administered defined “suicidal inhibition.”15–17 at 25 mg/day to inhibit aromatization as efficiently as anas- Preliminary in vitro
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