Letrozole Inhibits Estrogen Activity Better Than Tamoxifen

SAN FRANCISCO—The 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 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

In the immunohistochemistry study presented at ASCO, both drugs down-regulated ER expression. However, the rate of ER loss was greater with tamoxifen than with letrozole. As a result, more patients on tamoxifen were ER negative at the end of 4 months of treatment than were patients on letrozole.

According to Dr. Ellis, this finding has theoretical implications regarding sequence of treatment. For example, using an aromatase inhibitor as initial therapy, followed by tamoxifen in the second-line setting may be preferable. This is because more hormone-dependent tumors may be left after first-line letrozole than after first-line tamoxifen (see box on page 52 for a report on ER-negative second cancers in tamoxifen-treated patients).

Letrozole significantly downregulated PgR expression, as investigators expected. By comparison, tamoxifen treatment resulted in both increases and decreases in PgR expression; the end result was no overall change in distribution of scores reflecting biomarker intensity and frequency of expression.

The same effects were seen with PS2. With letrozole treatment, there was a marked downregulation of PS2; with tamoxifen treatment, there was no overall change in PS2 scores.

Taken together, those findings suggest that investigators may be able to identify tumors in which tamoxifen is working as an agonist and tumors in which tamoxifen is working as an antagonist, he said.

Dr. Ellis called preoperative biological therapy "the wave of the future" for predicting response to therapy in breast cancer. "This kind of study will help us sort out a very serious problem in breast cancer," he said. "We are not very good at predicting which tumors are estrogen dependent and may just need endocrine therapy, and which tumors are ER positive but have lost their estrogen dependence and should be treated with chemotherapy."

As a result, all such patients are offered chemotherapy when many women do not need it, he said. Similarly, many times clinicians assume women have hormone-dependent breast cancer when, in fact, they don’t, and may need chemotherapy.

The next phase of the study, Dr. Ellis said, is to analyze thousands of genes looking for new markers that predict response to endocrine therapy. Using such novel genes, investigators could evaluate chemotherapy vs no chemotherapy in a select group of patients with markers suggesting they will do well on endocrine therapy alone.