SAN FRANCISCOThe aromatase inhibitor letrozole (Femara) may be
clinically superior to 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 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
"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,