NEW YORKLetrozole (Femara) was found to be superior to
tamoxifen (Nolvadex) in the largest study ever conducted of endocrine therapy
in advanced breast cancer, Matthew J. Ellis, MD, PhD, clinical director of the
Duke University Breast Cancer Program, said at the XVIII Chemotherapy
Foundation Symposium. Median time to progression was 41 weeks for letrozole vs
26 weeks for tamoxifen (P = .0001), he said.
The study was the basis for the FDA’s Oncologic Drugs
Advisory Committee’s recommendation that the agency approve the supplemental
new drug application for letrozole’s use as first-line therapy in
postmenopausal women with advanced breast cancer (see article above for details
of the study).
The study addressed a number of points that have been at issue
in endocrine therapy studies, Dr. Ellis said. Among them is the question of the
best way to treat women who relapse after receiving tamoxifen in the adjuvant
setting. Is it better to reintroduce tamoxifen in those patients or to use
Patients in the study who had received prior adjuvant
tam-oxifen and then received letrozole had a response rate of 30%, very similar
to those who had never received tamoxifen, whereas those in whom tamoxifen was
reintroduced after a relapse showed an extremely low response rate of about 8%.
"For me, this solves the mystery. Should you reintroduce
tamoxifen after prior adjuvant use? The answer is: No, you should use an
aromatase inhibitor," he said.
Dr. Ellis explained the rationale behind the trial. "We
have known for a very long time that reducing estrogen levels in women with
premenopausal breast cancer results in gains in survival," he said. After
menopause, however, extra-ovarian synthesis of estrogen still takes place,
driven by the enzyme aromatase, in the skin and adipose tissue, the breast
itself, the brain, and other parts of body.
Tamoxifen targets postmenopausal estrogen by attempting to
block it at the tumor receptor, but that does not always work, Dr. Ellis said.
Many breast cancers are unresponsive to tamoxifen’s action,
despite tumor estrogen-receptor (ER) expression, he said. In addition,
tamoxifen paradoxically stimulates estrogen receptors in the endometrium and
circulation, increasing the risk of endometrial cancer and venous thrombosis.
Selective aromatase inhibitors (SAIs) such as letrozole, he
said, block estrogen synthesis throughout the body by interfering with the P450
enzyme pathway and thus preventing peripheral conversion of adrenal androgens
"Every indication for tamoxifen will be challenged by
letrozole," Dr. Ellis said. He noted that this line of inquiry has
"huge" implications. "For years we had only one drug that workedtamoxifen."
he said. "This trial shows that letrozole is superior to tamoxifen for
first-line therapy of advanced disease in postmenopausal breast cancer. Now, we
really have a chance to learn the best way to treat this disease in other
settings as well."
In a 1-year multicenter trial comparing letrozole and tamoxifen
as preoperative treatment in postmenopausal women with untreated primary breast
cancer, letrozole showed a superior clinical response and increased the odds by
more than 70% that breast-conserving surgery could be performed, compared with
tamoxifen, Dr. Ellis reported.
This study, he said "supports the idea that letrozole is
significantly more active than tamoxifen in this completely treatment-naïve
In the phase IIb/III trial, 337 women were randomized to either
2.5 mg letrozole or 20 mg tamoxifen daily for 4 months prior to surgery.
According to study criteria, all subjects were postmenopausal with ER-positive
and/or proges-terone-receptor-positive primary invasive tumors.
All tumors were unilateral and ineligible at baseline for
breast-conserving surgery, with stages ranging from T2 to T4A, B, or C, but
excluding inflammatory carcinoma. Nodes were 0, 1, or 2, and there were no
distant metastases. There could be no prior endocrine therapy for the disease.
Significantly more women in the letrozole arm had a clinical
response than women in the tamoxifen arm: 55% vs 36% (P < .001).
Particularly intriguing, Dr. Ellis said, was the finding that 45% of subjects
were eligible for breast-conserving surgery after 4 months on letrozole,
compared with only 35% of those in the tamoxifen arm (P = .02).
Women with T2 tumors treated with letrozole had the highest
rate of breast-conserving surgery: 61%. "It is really quite remarkable and
bears further confirmation," he said.