Sequential Treatment with Exemestane and Non-Steroidal Aromatase Inhibitors in Advanced Breast Cancer

South West Wales Cancer Institute, Swansea, United Kingdom.
Oncology (Impact Factor: 2.42). 02/2005; 69(6):471-7. DOI: 10.1159/000090985
Source: PubMed


The steroidal aromatase inactivator exemestane has demonstrated activity after prior failure of non-steroidal aromatase inhibitors (including third-generation inhibitors letrozole and anastrozole) in postmenopausal women with advanced breast cancer. If exemestane is used as first anti-aromatase agent, however, it is unclear whether patients can still benefit from letrozole or anastrozole after progression.
Postmenopausal patients with advanced, hormone receptor-positive or -unknown breast cancer were eligible for this study. Patients with no prior exposure to anti-aromatase drugs received exemestane, 25 mg daily, as first anti-aromatase agent. At the time of progression, patients were crossed-over to anastrozole or letrozole if further endocrine therapy was considered appropriate. Patients with prior exposure to anti-aromatase agents were also included in the study, and were given anastrozole or letrozole if they had previously received exemestane, or exemestane if they had previously received anastrozole or letrozole. The primary endpoint of the study was the clinical benefit rate (complete response + partial response + stabilization of disease for >or=24 weeks).
Forty patients received exemestane 25 mg daily as first anti-aromatase agent, with a CB rate of 67.5% (95% CI 52.9-82.0%) and a median time to progression (TTP) of 9.6 months. In 18 patients, letrozole (n = 17) or anastrozole (n = 1) were used after failure of exemestane: the CB rate was 55.6% (95% CI 32.6-78.5%) with a median TTP of 9.3 months. In 23 patients, exemestane was used after failure of letrozole or anastrozole: the CB rate was 43.5% (95% CI 23.2-63.7%) with a median TTP of 5.1 months.
Our study confirms that exemestane is active after prior failure of letrozole or anastrozole. We have also shown that patients can receive exemestane as their first anti-aromatase agent and still benefit from letrozole or anastrozole after progression. This suggests that the partial non-cross resistance between steroidal and non-steroidal anti-aromatase agents is independent of the sequence employed.

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    • "It is especially interesting to review investigations in which therapy has involved another AI (Table 1). For example, responses to formestane have been reported in patients failing aminoglutethimide [34,35], and clinical response to exemestane may follow the development of resistance to non-steroidal AIs [36] and, conversely, patients progressing after exemestane therapy have been shown to derive further benefits from treatment with letrozole or anastrozole [37]. These clinical studies indicate at least a partial non-cross-resistance between steroidal AIs and non-steroidal AIs [20,31,38]. "
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    ABSTRACT: ABSTRACT: Aromatase inhibitors (AIs) have a central role in the treatment of breast cancer; however, resistance is a major obstacle to optimal management. Evidence from endocrine, molecular and pathological measurements in clinical material taken before and after therapy with AIs and data from clinical trials in which AIs have been given as treatment either alone or in combination with other targeted agents suggest diverse causes for resistance. These include inherent tumour insensitivity to oestrogen, ineffective inhibition of aromatase, sources of oestrogenic hormones independent of aromatase, activation of signalling by non-endocrine pathways, enhanced cell survival and selection of hormone-insensitive cellular clones during treatment.
    Breast cancer research: BCR 01/2012; 14(1):201. DOI:10.1186/bcr2931 · 5.49 Impact Factor
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    • "Third-generation aromatase inhibitors (AI) recently became available for the treatment of breast cancer, and a number of randomized trials in postmenopausal women with advanced breast cancer have shown the superiority of AI over standard endocrine agents such as tamoxifen and megestrol acetate [24-26]. There seems to be partial non-cross resistance between different types of AIs [22,27]. Exemestane (a steroidal AI) was shown to be effective after the failure of other non-steroidal AIs. "
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    BMC Cancer 03/2011; 11(1):118. DOI:10.1186/1471-2407-11-118 · 3.36 Impact Factor
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    • "There appeared to be no cross resistance between steroidal and non-steroidal AIs regardless of the sequence, switching between these two subtypes can produce 0–26% objective response rates [70] [71] [72]. While the response rates are small, the substantial percentage of patients (50–62%) achieved stable disease of more than 6 months [72] [73] [74] [75] [76]. The large randomized phase III trial comparing exemestane vs. fulvestrant for second line endocrine therapy after progressing on a non-steroidal AI showed a clinical benefit rate of 32.2% vs. 31.5 "
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    ABSTRACT: Estrogens are known to be important in the growth of breast cancers in both pre and postmenopausal women. As the number of breast cancer patients increases with age, the majority of breast cancer patients are postmenopausal women. Although estrogens are no longer made in the ovaries after menopause, peripheral tissues produce sufficient concentrations to stimulate tumor growth. As aromatase catalyzes the final and rate-limiting step in the biosynthesis of estrogen, inhibitors of this enzyme are effective targeted therapy for breast cancer. Three aromatase inhibitors (AIs) are now FDA approved and have been shown to be more effective than the antiestrogen tamoxifen and are well tolerated. AIs are now a standard treatment for postmenopausal patients. AIs are effective in adjuvant and first-line metastatic setting. This review describes the development of AIs and their current use in breast cancer. Recent research focuses on elucidating mechanisms of acquired resistance that may develop in some patients with long term AI treatment and also in innate resistance. Preclinical data in resistance models demonstrated that the crosstalk between ER and other signaling pathways particularly MAPK and PI3K/Akt is an important resistant mechanism. Blockade of these other signaling pathways is an attractive strategy to circumvent the resistance to AI therapy in breast cancer. Several clinical trials are ongoing to evaluate the role of these novel targeted therapies to reverse resistance to AIs. Article from the special issue on 'Targeted Inhibitors'.
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