Superior Efficacy of Letrozole Versus Tamoxifen as First-Line Therapy

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.3.876 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11821477 Superior Efficacy of Letrozole Versus Tamoxifen as First-Line Therapy Aman U. BuzdarxAman U. BuzdarSearch for articles by this author H. MouridsenxH. MouridsenSearch for articles by this author , H. A. Chaudri-RossxH. A. Chaudri-RossSearch for articles by this author Show More M.D. Anderson Cancer Center, Houston, TXUniversity of Copenhagen, DenmarkNovartis Pharma AG, Basel, Switzerland https://doi.org/10.1200/JCO.2002.20.3.876 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01022002In Reply:In the letrozole-tamoxifen study,1 the subset of patients who received prior adjuvant antiestrogen therapy comprised 84 patients (19%) allocated letrozole and 83 (18%) allocated tamoxifen. The treatment-free interval was at least 2 years in 60 patients of this letrozole subset and 66 patients of the tamoxifen subset. In the letrozole subset, 61 patients (73%) had receptor-positive tumors, compared with 56 patients (67%) in the tamoxifen subset, similar to the results reported by Dr Buzdar.The geographic area of origin of patients who had received adjuvant antiestrogen therapy was as follows for letrozole (n = 84): Europe, 51 patients (18%); North America, 16 patients (33%); Rest of the World, 17 patients (15%). For the tamoxifen subset (n = 83), the corresponding figures were as follows: Europe, 59 patients (20%); North America, 14 patients (27%); Rest of the World, 10 patients (9%). The percentages reported refer to the total numbers of patients in the respective treatment arm (n = 453 for letrozole; n = 454 for tamoxifen). It should be noted that even in North America, less than one third of enrolled patients had previously received adjuvant antiestrogen therapy.Buzdar’s suggestion that a lower proportion of patients in Rest of the World countries allocated tamoxifen were exposed to adjuvant tamoxifen implies a different population with a different expected response. This is not borne out by the data, which show that the median times to progression are similar for all regions (Fig 1). The treatment comparisons (hazard ratios) within each geographic area were also very similar (Fig 2). Time to progression of disease was the main end point of our study, and both analysis by predefined geographic area and by prior adjuvant antiestrogen therapy were prespecified in the analysis plan. Fig 1 Kaplan-Meier curves for time to progression of disease by geographic region. Patient numbers for letrozole and tamoxifen, respectively: Whole study, n = 453, n = 454; Europe, n = 288, n = 292; North America, n = 49, n = 51; Rest of World, n = 116, n = 111. Fig 2 Hazard ratios (▪) and 95% confidence intervals (—) for time to progression of disease by geographic region. A hazard ratio less than 1 favors letrozole; greater than 1 favors tamoxifen. Squares are proportional to the number of events. Whole study, P = .0001; Europe, P = .0017; North America, P = .0494; Rest of World, P = .0041.In the studies not involving anastrozole that Buzdar cites in support of higher response rates to tamoxifen, patients had not been previously exposed to antiestrogen treatment, and so the relevance of these publications to our study is unclear.Data of response to tamoxifen in patients previously exposed to adjuvant tamoxifen in the tamoxifen-anastrozole studies have not been published. Buzdar refers to a personal communication, according to which response rates in these subsets of patients were 28.6% and 21.2% in the Nabholtz et al2 and Bonneterre et al3 studies, respectively. However, as published overall response rates to tamoxifen in these studies were 17.0% and 32.6%, respectively, one or other set of response rates would seem to be incorrect or, at best, inconsistent. There is no published information available from these studies about hazard ratios for time to progression in the subsets of patients exposed to adjuvant antiestrogen therapy.With respect to Buzdar’s point about two second-line studies comparing letrozole with megestrol acetate,4, 5 Buzdar himself has addressed in recent correspondence that the populations in the two studies seemed to be quite different, and within the mainly North American study, there were large differences at baseline between treatment arms, especially concerning the presence of bone metastasis and of multiple sites of disease despite randomization and double-blinding of treatments.6 When these differences are taken into account in the analysis, the improved responsiveness of patients receiving letrozole 2.5 mg against megestrol acetate in the mainly North American study is similar to the improved response rates of letrozole 2.5 mg in the mainly European second-line study. This information is currently being prepared for publication in a peer-reviewed journal.1. Mouridsen H, Gershanovich M, Sun Y, et al: 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. J Clin Oncol 19:: 2596,2001-2602, Link, Google Scholar2. Nabholtz A, Buzdar A, Pollak M, et al: Anastrozole is superior to tamoxifen as first-line therapy for advance breast cancer in postmenopausal women: Results of a North American multicenter randomized trial. J Clin Oncol 18:: 3758,2000-3767, Link, Google Scholar3. Bonneterre J, Thürlimann B, Robertson JFR, et al: Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: Results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 18:: 3748,2000-3757, Link, Google Scholar4. Dombernowsky P, Smith I, Falkson G, et al: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: Double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16:: 453,1998-461, Link, Google Scholar5. Buzdar A, Douma J, Davidson N, et al: Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 19:: 3357,2001-3366, Link, Google Scholar6. Buzdar A, Brady C, Chaudri-Ross HA: Reply to: Letrozole in second-line therapy of advanced breast cancer—More questions than answers. J Clin Oncol 19:: 4354,2001-4355, (letter)