Comparative Efficacy of CDK4/6 Inhibitors Plus Aromatase Inhibitors Versus Fulvestrant for the First-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer: A Network Meta-Analysis
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Keywords:
Fulvestrant
Palbociclib
Letrozole
Anastrozole
Aromatase inhibitor
The newer generation aromatase inhibitors (AIs) as a class show efficacy and tolerability benefits over previously established treatments in postmenopausal women with advanced breast cancer. At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) are 41-48 h, 2-4 days, and 27 h, respectively. Time to steady-state plasma levels is 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have only been reported with exemestane. Anastrozole treatment has no impact on plasma lipid levels, whereas both letrozole and exemestane have an unfavorable effect. From indirect comparisons, anastrozole shows the highest degree of selectivity compared with letrozole and exemestane, in terms of a lack of effect on adrenosteroidogenesis. To date, there are no data suggesting any major differences in clinical efficacy between the newer generation AIs anastrozole and letrozole. Based on the observed pharmacological profiles, however, it cannot be assumed that the AIs will display the same tolerability and safety profiles when given for extended periods of time in the adjuvant setting. The effects of anastrozole, letrozole, and exemestane are being investigated in the adjuvant setting, and these data will elucidate the possible long-term consequences of the pharmacological effects reported after short-term exposure.
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Aromatase inhibitor
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Abstract Blocking estrogen receptors with antiestrogens and blocking estrogen synthesis with aromatase inhibitors are two strategies currently being used for reducing the effect of estrogen in postmenopausal estrogen receptor–positive breast cancer patients. To optimize these treatment strategies, we have investigated whether tumor progression can be delayed by combining the pure antiestrogen fulvestrant with the nonsteroidal aromatase inhibitor letrozole. These studies were done in ovariectomized, athymic mice bearing tumors of estrogen receptor–positive human breast cancer cells stably transfected with the aromatase gene (MCF-7Ca). Groups of mice with equivalent tumor volumes were injected s.c. daily with vehicle (control; n = 6), fulvestrant (1 mg/d; n = 7), letrozole (10 μg/d; n = 18), or letrozole (10 μg/d) plus fulvestrant (1 mg/d; n = 5). All treatments were effective in suppressing tumor growth compared with controls (P < 0.001). Tumor volumes of the fulvestrant-treated group had doubled in 10 weeks. After 19 weeks of letrozole (10 μg/d) treatment when tumors had nearly doubled in volume, mice (n = 18) were assigned to second-line therapy with letrozole (100 μg/d; n = 6), tamoxifen (100 μg/d; n = 6), or remained on letrozole treatment (10 μg/d; n = 6). However, tumors continued to increase in volume in these groups. Tumors of animals treated with the combination of letrozole plus Faslodex regressed over 29 weeks of treatment by 45%. Thus, the combination of letrozole plus fulvestrant was more effective in suppressing tumor growth than either letrozole or fulvestrant alone or sequential therapies with tamoxifen or a higher dose of letrozole (100 μg/d).
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Aromatase inhibitor
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Abstract The experimental CDK-inhibitor palbociclib, when combined with the aromatase inhibitor letrozole, significantly extended progression-free survival in women with HER2-/ER+ breast cancer compared with letrozole alone, according to the final results from a phase II clinical trial of the drug.
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Palbociclib
Aromatase inhibitor
CDK inhibitor
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We previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor–positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes.
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Letrozole
Anastrozole
Aromatase inhibitor
Crossover study
Exemestane
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Letrozole
Aromatase inhibitor
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Palbociclib
Fulvestrant
Aromatase inhibitor
Letrozole
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Anastrozole
Letrozole
Aromatase inhibitor
Antiestrogen
Progesterone receptor
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The aromatase inhibitor anastrozole inhibits estrogen synthesis. Fulvestrant binds and accelerates degradation of estrogen receptors. We hypothesized that these two agents in combination might be more effective than anastrozole alone in patients with hormone-receptor (HR)-positive metastatic breast cancer.
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