PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor– and/or progesterone receptor–positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median,...

Superior Efficacy of Letrozole Versus Tamoxifen as First-Line Therapy for Postmenopausal Women With Advanced Breast Cancer: Results of a Phase III Study of the International Letrozole Breast Cancer Group

Until recently, tamoxifen, a nonsteroidal antiestrogen, was the mainstay of endocrine treatment of breast cancer. However, new aromatase inhibitors that are many times more potent and specific than the first such agent, aminoglutethimide, are changing the management of breast cancer in postmenopausal women. This review discusses the role of aromatase inhibitors such as letrozole, anastrozole, and exemestane in the treatment of breast cancer.

Aromatase Inhibitors in Breast Cancer

Purpose: To analyze overall survival (OS) and update efficacy data for letrozole versus tamoxifen as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. Patients and Methods: This multicenter phase III trial randomly assigned 916 patients with hormone receptor–positive or unknown tumors letrozole 2.5 mg (n = 458) or tamoxifen 20 mg (n = 458) daily until disease progression. Optional cross-over was permitted at the treating physician’s discretion. This report updates efficacy at a median follow-up of 32 months. Results: The superiority of letrozole to tamoxifen was confirmed for time to progression (median, 9.4 v 6.0 months, respectively; P < .0001), time to treatment failure (median, 9 v 5.7 months, respectively; P < .0001), overall objective response rate (32% v 21%, respectively; P = .0002), and overall clinical benefit. Median OS was slightly prolonged for the randomized letrozole arm (34 v 30 months, respectively). Although this difference in OS is not signifi...

Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group

PURPOSE: To compare the effects of the two novel, potent, nonsteroidal aromatase inhibitors anastrozole and letrozole on total-body aromatization and plasma estrogen levels. PATIENTS AND METHODS: Twelve postmenopausal women with estrogen receptor–positive, metastatic breast cancer were treated with anastrozole 1 mg orally (PO) and letrozole 2.5 mg PO once daily, each given for a time interval of 6 weeks in a randomized sequence. Total-body aromatization was determined before treatment and at the end of each treatment period using a dual-label isotopic technique involving isolation of the metabolites with high-performance liquid chromatography. Plasma levels of estrone (E1), estradiol (E2), and estrone sulfate (E1S) were determined in samples obtained before each injection using highly sensitive radioimmunoassays. RESULTS: Pretreatment aromatase levels ranged from 1.68% to 4.27%. On-treatment levels of aromatase were detectable in 11 of 12 patients during treatment with anastrozole (mean percentage inhibit...

Influence of Letrozole and Anastrozole on Total Body Aromatization and Plasma Estrogen Levels in Postmenopausal Breast Cancer Patients Evaluated in a Randomized, Cross-Over Study

Aromatase is the enzyme that catalyzes the conversion of androgens to estrogens. Initial studies of its enzymatic activity and function took place in an environment focused on estrogen as a component of the birth control pill. At an early stage, investigators recognized that inhibition of this enzyme could have major practical applications for treatment of hormone-dependent breast cancer, alterations of ovarian and endometrial function, and treatment of benign disorders such as gynecomastia. Two general approaches ultimately led to the development of potent and selective aromatase inhibitors. One targeted the enzyme using analogs of natural steroidal substrates to work out the relationships between structure and function. The other approach initially sought to block adrenal function as a treatment for breast cancer but led to the serendipitous finding that a nonsteroidal P450 steroidogenesis inhibitor, aminoglutethimide, served as a potent but nonselective aromatase inhibitor. Proof of the therapeutic concept of aromatase inhibition involved a variety of studies with aminoglutethimide and the selective steroidal inhibitor, formestane. The requirement for even more potent and selective inhibitors led to intensive molecular studies to identify the structure of aromatase, to development of high-sensitivity estrogen assays, and to "mega" clinical trials of the third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, which are now in clinical use in breast cancer. During these studies, unexpected findings led investigators to appreciate the important role of estrogens in males as well as in females and in multiple organs, particularly the bone and brain. These studies identified the important regulatory properties of aromatase acting in an autocrine, paracrine, intracrine, neurocrine, and juxtacrine fashion and the organ-specific enhancers and promoters controlling its transcription. The saga of these studies of aromatase and the ultimate utilization of inhibitors as highly effective treatments of breast cancer and for use in reproductive disorders serves as the basis for this first Endocrine Reviews history manuscript.

History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target

Letrozole, a new oral aromatase inhibitor: Randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer

A. Bonaventura

Papers

Letrozole, a new oral aromatase inhibitor: Randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer