Exemestane in the Adjuvant Treatment of Breast Cancer in Postmenopausal Women

Kittaneh, Muaiad; Glück, Stefan

doi:10.4137/bcbcr.s6234

Cited by 12 publications

(18 citation statements)

References 103 publications

(291 reference statements)

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“…The incidence of common AEs reported in this trial, including hot flush, arthralgia, and musculoskeletal stiffness, was consistent with previous comparisons of exemestane and anastrozole that found few differences between these agents in the adjuvant setting [19, 29]. …”

Section: Discussionsupporting

confidence: 90%

“…Musculoskeletal symptoms and decreased bone mineral density are anticipated effects of hormonal therapies, such as AIs, that produce menopause-like effects [32]. In study MA.27, arthralgia, muscle pain, and fractures were reported in both the exemestane and anastrozole treatment groups; however, exemestane was associated with a significantly lower incidence of self-reported new-onset osteoporosis compared with anastrozole ( P = 0.001) [20, 29]. Treatment algorithms for musculoskeletal AEs related to AI therapy have been developed, and discontinuation of AI therapy is rarely required [33–35].…”

Section: Discussionmentioning

confidence: 99%

“…Although results from two meta-analyses reported a higher risk of cardiovascular AEs associated with AIs compared with tamoxifen, these data have not been confirmed in a placebo-controlled trial, and available data do not support a substantial risk of ischemic cardiovascular events associated with AI treatment or differences in the risk of cardiovascular events for the different AIs [29, 30, 36–39]. Studies with longer follow-up time are needed to further define the cardiovascular safety profile of AI therapy.…”

Section: Discussionmentioning

confidence: 99%

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A randomized, double-blind, controlled study of exemestane versus anastrozole for the first-line treatment of postmenopausal Japanese women with hormone-receptor-positive advanced breast cancer

Iwata

Masuda

Ohno

et al. 2013

Breast Cancer Res Treat

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The aromatase inhibitors exemestane and anastrozole are approved in Japan for first-line treatment of postmenopausal patients with advanced, hormone-receptor-positive breast cancer. This phase 3, randomized, double-blind study directly compared time to progression (TTP) for exemestane and anastrozole therapy in this patient population. Eligible patients were randomized to receive exemestane 25 mg or anastrozole 1 mg, each once daily. The primary endpoint was TTP based on assessment by an expert radiologic images review committee (ERIRC). Secondary endpoints included investigator-assessed TTP, time to treatment failure, overall survival, objective response rate, clinical benefit rate, and safety. A total 298 patients were randomized to receive exemestane (n = 149; mean age 63.4 years) or anastrozole (n = 149; mean age 64.0 years). Median ERIRC-assessed TTP was 13.8 and 11.1 months (hazard ratio = 1.007; 95 % confidence interval [CI]: 0.771, 1.317) and median investigator-assessed TTP was 13.8 and 13.7 months (hazard ratio = 1.059; 95 % CI: 0.816, 1.374) in the exemestane and anastrozole arms, respectively. Median overall survival was 60.1 months in the anastrozole arm and was not reached in the exemestane arm at data cutoff. The objective response rate was 43.9 % (95 % CI: 35.3, 52.8) and 39.1 % (95 % CI: 30.6, 48.1) in the exemestane and anastrozole arms, respectively. Treatment-related adverse events grade ≥3 occurred in 9.4 and 6.0 % of patients, and treatment-related serious adverse events occurred in 4.0 and 3.4 % of patients in the exemestane and anastrozole arms, respectively. In this study, the efficacy and safety profiles of exemestane were similar to those of anastrozole in Japanese patients with advanced, hormone-receptor-positive breast cancer; however, TTP non-inferiority of exemestane versus anastrozole was not confirmed.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A randomized, double-blind, controlled study of exemestane versus anastrozole for the first-line treatment of postmenopausal Japanese women with hormone-receptor-positive advanced breast cancer

Iwata

Masuda

Ohno

et al. 2013

Breast Cancer Res Treat

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“…[ 7 ] Exe is the first steroidal aromatase inhibitor (AI) which inhibits in vivo formation of oestrogens (estrone and estradiol), thereby reducing stimulation for breast cancer cell proliferation. [ 8 ] Variability in response and side effect profile has been observed in patients in many AI clinical trials and the underlying mechanism remains undefined. [ 9 – 13 ] Recently, the major metabolic pathway of Exe has been delineated; as a reduction of double bond in 17 keto group via aldo-keto reductase (AKR) to form 17β-dihydroexemestane (17DhExe) is a major pathway for exemestane phase I metabolism.…”

Section: Introductionmentioning

confidence: 99%

Validation of a Rapid and Sensitive LC-MS/MS Method for Determination of Exemestane and Its Metabolites, 17β-Hydroxyexemestane and 17β-Hydroxyexemestane-17-O-β-D-Glucuronide: Application to Human Pharmacokinetics Study

et al. 2015

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A novel, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the evaluation of exemestane pharmacokinetics and its metabolites, 17β-dihydroexemestane (active metabolite) and 17β-dihydroexemestane-17-O-β-D-glucuronide (inactive metabolite) in human plasma. Their respective D3 isotopes were used as internal standards. Chromatographic separation of analytes was achieved using Thermo Fisher BDS Hypersil C18 analytic HPLC column (100 × 2.1 mm, 5 μm). The mobile phase was delivered at a rate of 0.5 mL/min by gradient elution with 0.1 % aqueous formic acid and acetonitrile. The column effluents were detected by API 4000 triple quadrupole mass spectrometer using electrospray ionisation (ESI) and monitored by multiple reaction monitoring (MRM) in positive mode. Mass transitions 297 > 121 m/z, 300 > 121 m/z, 299 > 135 m/z, 302 > 135 m/z, 475 > 281 m/z, and 478 > 284 m/z were monitored for exemestane, exemestane-d3, 17β-dihydroexemestane, 17β-dihydroexemestane-d3, 17β-dihydroexemestane-17-O-β-D-glucuronide, and 17β-dihydroexemestane-17-O-β-D-glucuronide-d3 respectively. The assay demonstrated linear ranges of 0.4 – 40.0 ng/mL, for exemestane; and 0.2 – 15.0 ng/mL, for 17β-dihydroexemestane and 17β-dihydroexemestane-17-O-β-D-glucuronide, with coefficient of determination (r2) of > 0.998. The precision (coefficient of variation) were ≤10.7%, 7.7% and 9.5% and the accuracies ranged from 88.8 to 103.1% for exemestane, 98.5 to 106.1% for 17β-dihydroexemestane and 92.0 to 103.2% for 17β-dihydroexemestane-17-O-β-D-glucuronide. The method was successfully applied to a pharmacokinetics/dynamics study in breast cancer patients receiving exemestane 25mg daily orally. For a representative patient, 20.7% of exemestane in plasma was converted into 17β-dihydroexemestane and 29.0% of 17β-dihydroexemestane was inactivated as 17β-dihydroexemestane-17-O-β-D-glucuronide 24 hours after ingestion of exemestane, suggesting that altered 17-dihydroexemestane glucuronidation may play an important role in determining effect of exemestane against breast cancer cells.

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“…Hot flashes are one of the most common side effects reported under tamoxifen and AI therapies (Kittaneh & Glück 2011), with a frequency up to 50% (Shanafelt et al 2002).…”

Section: Hot Flashesmentioning

confidence: 99%

Aromatase inhibitors in the breast cancer clinic: focus on exemestane

Asten¹,

Neven²,

Lintermans³

et al. 2014

Endocrine-Related Cancer

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Breast cancer is the most prevalent type of cancer in women and responsible for significant female cancer-related mortality worldwide. In the Western world, over 80% of breast cancers are hormone-receptor positive for which endocrine therapy is administered. The main anti-estrogen treatments in use consist of selective estrogen-receptor modulators, such as tamoxifen, and third-generation aromatase inhibitors (AIs), such as exemestane, letrozole, and anastrozole. In this review, the focus will lie on exemestane, its clinical use, and its side-effect profile. Exemestane is the only third-generation steroidal AI. Its efficacy as a first-line treatment in metastatic breast cancer has been demonstrated. Therefore, exemestane could be considered a valid first-line therapeutic option, but it also can be used in second-line or further situations. Exemestane is mostly used as part of sequential adjuvant treatment following tamoxifen, but in this setting it is also active in monotherapy. Furthermore, this AI has been studied in the neoadjuvant setting as presurgical treatment, and even as chemoprevention in high-risk healthy postmenopausal women. It may reverse side effects of tamoxifen, such as endometrial changes and thromboembolic disease but may also cause some inconvenient side effects itself. Additionally, there is a lack of total crossresistance between exemestane and nonsteroidal AIs as far as their anti-tumoral efficacy is concerned; moreover the two classes of AIs display a nontotal overlapping toxicity profile. Taking together, exemestane can be considered as a useful treatment option at all stages of breast cancer.

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Exemestane in the Adjuvant Treatment of Breast Cancer in Postmenopausal Women

Cited by 12 publications

References 103 publications

A randomized, double-blind, controlled study of exemestane versus anastrozole for the first-line treatment of postmenopausal Japanese women with hormone-receptor-positive advanced breast cancer

A randomized, double-blind, controlled study of exemestane versus anastrozole for the first-line treatment of postmenopausal Japanese women with hormone-receptor-positive advanced breast cancer

Validation of a Rapid and Sensitive LC-MS/MS Method for Determination of Exemestane and Its Metabolites, 17β-Hydroxyexemestane and 17β-Hydroxyexemestane-17-O-β-D-Glucuronide: Application to Human Pharmacokinetics Study

Aromatase inhibitors in the breast cancer clinic: focus on exemestane

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