SAN FRANCISCO—The aromatase inhibitor letrozole(Drug information on letrozole) (Femara) may be clinically superior to tamoxifen(Drug information on tamoxifen) (Nolvadex) in breast cancer because, unlike tamoxifen, it has no agonist properties, results of a phase III preoperative endocrine therapy trial suggest.
Examination of the estrogen-regulated proteins trefoil factor 1 (PS2) and progesterone(Drug information on progesterone) receptor (PgR) illustrated a mixed agonist/antagonist effect in breast cancer in response to tamoxifen therapy (although investigators were not able to clearly relate biomarker changes to response rates). In contrast, letrozole therapy strongly and consistently suppressed estrogen-regulated gene expression.
"We didn’t see a close relationship between these agonist effects of tamoxifen and response rates, which goes to show we don’t really understand how tamoxifen works," said Matthew J. Ellis, MB, PhD, clinical director of the Duke University Breast Cancer Program. "A simple view of it didn’t come out of this study."
The double-blind, randomized trial, reported at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 1661), included 324 previously untreated postmenopausal women with large localized or locally advanced hormone-responsive breast cancers that were not amenable to breast-conserving surgery or were considered inoperable. Patients received 4 months of daily letrozole 2.5 mg or tamoxifen 20 mg to reduce tumor size before surgery. Biopsies were taken pre- and post-treatment and analyzed for several biomarkers using immunohistochemistry.
Among patients with biopsy-confirmed estrogen-receptor (ER)/PgR-positive tumors, clinical response rate (partial plus complete response) was significantly higher in the letrozole group (60% vs 41% for tamoxifen, P = .004). As a result, more women in the letrozole group were eligible to undergo breast-conserving surgery (48% vs 36%).
These clinical findings mirror the results of other recent trials in more conventional settings. Notably, a recent 907-patient phase III study showed that letrozole was superior to tamoxifen in time to progression, time to treatment failure, overall response rate, and clinical benefit rate in postmenopausal women with advanced breast cancer (J Clin Oncol 19:2596-2606, 2001).
ER Downregulation
