Letrozole in Second-Line Therapy of Advanced Breast Cancer: More Questions Than Answers
Authors: John R. Mackey, Anil A. Joy, Aman U. Buzdar, Carolyn Brady, Hilary A. Chaudri-Ross
Journal: Journal of Clinical Oncology (2001)

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.2001.19.23.4353 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11731524 Letrozole in Second-Line Therapy of Advanced Breast Cancer: More Questions Than Answers John R. MackeyxJohn R. MackeySearch for articles by this author , Anil A. JoyxAnil A. JoySearch for articles by this author Aman U. BuzdarxAman U. BuzdarSearch for articles by this author , Carolyn BradyxCarolyn BradySearch for articles by this author , Hilary A. Chaudri-RossxHilary A. Chaudri-RossSearch for articles by this author Show More Cross Cancer Institute, Edmonton, Alberta, CanadaUniversity of Texas, M.D. Anderson Cancer Center, Houston, TXNovartis Oncology, East Hanover, NJNovartis Pharma AG, Basel, Switzerland https://doi.org/10.1200/JCO.2001.19.23.4353 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01122001In Reply:Three large studies1-3 have been conducted with letrozole in the second-line treatment of advanced breast cancer in postmenopausal women. Two studies2,3 have shown that letrozole 2.5 mg/d is superior to letrozole 0.5 mg/d. In the study by Dombernowsky et al,2 letrozole was significantly superior to megestrol acetate in objective response rate (the primary end point; P = .04) and duration of clinical benefit (P = .001). In this study it was also shown that 2.5 mg of letrozole was superior to 0.5 mg in objective response rate (P = .004), time to disease progression (P = .020), time to treatment failure (P = .002), and time to death (P = .03). In the study comparing letrozole with aminoglutethimide,3 there was a survival advantage for patients receiving 2.5 mg of letrozole when compared with both 0.5 mg of letrozole and aminoglutethimide. In addition, 2.5 mg but not 0.5 mg letrozole was superior to aminoglutethimide in time to progression and time to treatment failure. Although the third trial1 does not show a dose response and shows that 0.5 mg but not 2.5 mg was superior to megestrol acetate, the study does not show that 0.5 mg was superior to 2.5 mg. Further exploratory analyses have shown that there were imbalances between treatment arms on some known prognostic factors (eg, dominant osseous disease and disease-free interval less than 24 months), which suggest a disadvantage for the 2.5-mg arm for these prognostic factors, despite double-blind randomized treatment allocation.Pharmacokinetic studies have shown steady-state levels and no evidence of accumulation at doses up to and including 2.5 mg/d.4 The 2.5-mg dose of letrozole has been shown to be safe and effective as first- and second-line treatment in controlled clinical trials involving more than 3,000 patients with hormone-responsive metastatic breast cancer.The possible reasons for the differences between the two studies of Buzdar et al1 and Dombernowsky et al2 have also been addressed by Dr Cocconi, who suggests that methodologic reasons account for the differing results. We do not believe that the differences in the radiologic assessments in the study account for the improved response to letrozole 0.5 mg/d in our study.1 It is more likely that prognostic differences between treatment arms as cited above, in particular in bone involvement, account for the differences in response. As we know, response in bone is difficult to achieve.Differences in outcome between similarly designed studies are not uncommon. For instance, the two anastrozole first-line studies5,6 were similar in design but seemed to include different populations resulting in differing response rates (eg, tamoxifen response rates of 33% and 17%, respectively) and differing median times to progression (for tamoxifen, median times of 8.3 months and 5.6 months, respectively).Regarding the question of time to publication, it is worth noting that in 1999, the manuscript committee recommended that the publication should contain more mature survival data. This obviously has had an impact on the submission for publication.From the available data of large patient populations, 2.5 mg of letrozole is both a safe and effective dose in the endocrine therapy of advanced breast cancer in postmenopausal women.1. 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 Scholar2. Dombernowsky P, Smith I, Falkson G, et al: 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 Scholar3. Gershanovich M, Chaudri HA, Campos D, et al: Letrozole, a new oral aromatase inhibitor: Randomised trial comparing 2.5mg daily, 0.5mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Ann Oncol 9:: 639,1998-645, Crossref, Medline, Google Scholar4. Zamagni C, Maroni A Lelli G, et al: Single and multiple dose pharmacokinetics of letrozole (Femara) in elderly and younger postmenopausal patients with advanced breast cancer. Eur J Cancer 35:292, 1999 (abstr) Google Scholar5. Bonneterre J, Thuerlimann 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 Scholar6. Nabholtz JM, Buzdar A, Pollak M, et al: Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: Results of a North American multicenter randomized trial. J Clin Oncol 18:: 3758,2000-3767, Link, Google Scholar