SAN ANTONIOThe aromatase inhibitor letrozole (Femara)
was more effective than tamoxifen (Nolvadex) in reducing tumor size before
surgery and increasing the number of women eligible for breast-conserving
Matthew J. Ellis, MD, PhD, on behalf of the Letrozole Neoadjuvant Breast Cancer
Study Group Breast Cancer Program.
Dr. Ellis, associate professor of medicine and clinical
director, Duke University Breast Cancer Program, Duke University Medical
Center, Durham, NC, presented the multicenter study at the 23rd Annual San
Antonio Breast Cancer Symposium.
The two drugs were compared in an international, randomized,
double-blind study of postmenopausal women with breast cancer. Patients had
large tumors that were estrogen-receptor (ER) and/or progesterone-receptor (PR)
positive and ineligible for breast-conserving surgery prior to neoadjuvant
The study enrolled 337 patients (324 evaluable) who were
preoperatively randomized to receive either 2.5 mg of letrozole (n = 154) or 20
mg of tamoxifen (n = 170) daily for 4 months.
Data on molecular biomarkers, including ER, PR, ErbB1
(epidermal growth factor receptor), and ErbB2, were also presented. The two
groups were well balanced in terms of expression of these proteins. "The
improvement in the letrozole arm was not associated with an imbalance in the
proportion of cases expressing endocrine therapy resistance or sensitivity
markers," Dr. Ellis said.
After 4 months of letrozole treatment, 45% of patients
underwent breast-conserving surgery, compared with 35% of patients receiving
tamoxifen (P = .022). The clinical complete and partial response rate for
letrozole was 55% vs 36% for tamoxifen (P < .001).
After adjustment for tumor size, nodal involvement, and age,
the odds of undergoing breast-conserving surgery were increased by more than
70% for letrozole, compared with tamoxifen.
A small proportion of tumors were found to be ER and PR
negative in the central analysis of hormone-receptor status. In an exploratory
analysis that excluded these cases, letrozole was again significantly more
effective than tam-oxifen with 60% responding and 48% converting to
breast-conserving surgery, Dr. Ellis said.
The study was also designed as a prospective test of the
hypothesis that ErbB1 and ErbB2 expression is associated with resistance to
The number of cases overexpressing ErbB2 was 14%, with 7% of
cases over-expressing ErbB1. A proportion of these cases were found to be ER
and PR negative, so that the true frequency of tumors that express ER and ErbB1
and/or ErbB2 was 15.2%.
The difference in efficacy between letrozole and tamoxifen was
very marked in this subset of tumors: 88% of tumors that expressed this pattern
of predictive biomarkers responded to letrozole vs 21% for tamoxifen (P = .0004
by unadjusted logistic regression analysis).
These data suggest that letrozole was particularly active in
ErbB1- and/or ErbB2-positive tumors that coexpressed ER, he said. In contrast,
the effectiveness of tamoxifen was decreased.
"These data are preliminary but nonetheless
provocative," Dr. Ellis said. Perhaps the most important message from
these studies is that predictive biomarker research should be considered an
essential component of ongoing studies comparing aromatase inhibitors with
tam-oxifen in the adjuvant setting."