SAN ANTONIOThe aromatase inhibitor letrozole(Drug information on letrozole) (Femara) was more effective than tamoxifen(Drug information on tamoxifen) (Nolvadex) in reducing tumor size before surgery and increasing the number of women eligible for breast-conserving therapy, said 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(Drug information on progesterone)-receptor (PR) positive and ineligible for breast-conserving surgery prior to neoadjuvant therapy.
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 tamoxifen therapy.
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."