Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, Pharmacology & Pharmacy, advanced breast cancer, aromatase inhibitor, exemestane, phase I study, postmenopause, AROMATASE INHIBITOR, ENDOCRINE, 4-HYDROXYANDROSTENEDIONE, AMINOGLUTETHIMIDE, Adult, Aged, Androstadienes, Antineoplastic Agents, Breast Neoplasms, Dizziness, Dose-Response Relationship, Drug, Estrogen Antagonists, Estrogens, Female, Headache, Humans, Middle Aged, Nausea, Postmenopause, 0304 Medicinal and Biomolecular Chemistry, 1101 Medical Biochemistry and Metabolomics, 1115 Pharmacology and Pharmaceutical Sciences, Oncology & Carcinogenesis, 3211 Oncology and carcinogenesis, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry

Abstract:

Exemestane is an irreversible, steroidal, oral aromatase inhibitor under evaluation in postmenopausal women with advanced breast cancer. A phase I study was conducted in 27 postmenopausal patients who were candidates for hormone therapy because they had advanced breast cancer and estrogen receptor-positive or unknown status. Most patients were moderately or heavily pretreated. Cohorts of at least three patients received sequentially escalating daily oral doses of 5-600 mg. The median duration of exemestane treatment was 13 weeks (range: 3-166 weeks). The maximal tolerated dose was not reached because of lack of treatment-related grade 3 or 4 toxicity. The most common adverse events, including those not related to treatment, were mild to moderate headache (44% of patients), dizziness (33%), nausea (33%), hot flushes (30%) and tumor-related pain (30%). There were three complete and four partial responses for an objective response rate of 26% (95% CI: 11.1-46.3%) in the intent-to-treat population; the median duration of response was 74 weeks (95% CI: 48-99 weeks). Exemestane, at the dose of 25 mg, maximally suppressed estradiol, estrone and estrone sulfate serum levels to 13, 5 and 10% of baseline, respectively. Exemestane appears to suppress estrogen, be well tolerated and have antitumor activity in postmenopausal women with advanced breast cancer. A large, safe therapeutic window of up to 600 mg was defined. In view of its safety and estrogen-suppression profiles, the most favorable effects were observed at the 25 mg daily dose.