Rita S Mehta1, William E Barlow1, Kathy S Albain1, Ted A Vandenberg1, Shaker R Dakhil1, Nagendra R Tirumali1, Danika L Lew1, Daniel F Hayes1, Julie R Gralow1, Hannah H Linden1, Robert B Livingston1, Gabriel N Hortobagyi1. 1. From the Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange (R.S.M.); the SWOG Statistics and Data Management Center (W.E.B., D.L.L.) and Seattle Cancer Care Alliance and University of Washington Medical Center (J.R.G., H.H.L.) - both in Seattle; Loyola University Chicago Stritch School of Medicine, Maywood, IL (K.S.A.); London Health Sciences Centre and the National Cancer Institute of Canada Clinical Trials Group, London, ON, Canada (T.A.V.); the Cancer Center of Kansas and Wichita National Cancer Institute Community Oncology Research Program (NCORP), Wichita (S.R.D.); Kaiser Permanente NCORP, Portland, OR (N.R.T.); the University of Michigan, Ann Arbor (D.F.H.); the University of Arizona Cancer Center, Tucson (R.B.L.); and the University of Texas M.D. Anderson Cancer Center, Houston (G.N.H.).
Abstract
BACKGROUND: We previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor-positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes. METHODS: We randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups. RESULTS: Of 707 patients who had undergone randomization, 694 had data available for analysis. The combination-therapy group had 247 deaths among 349 women (71%) and a median overall survival of 49.8 months, as compared with 261 deaths among 345 women (76%) and a median overall survival of 42.0 months in the anastrozole-alone group, a significant difference (hazard ratio for death, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03 by the log-rank test). In a subgroup analysis of the two strata, overall survival among women who had not received tamoxifen previously was longer with the combination therapy than with anastrozole alone (median, 52.2 months and 40.3 months, respectively; hazard ratio, 0.73; 95% CI, 0.58 to 0.92); among women who had received tamoxifen previously, overall survival was similar in the two groups (median, 48.2 months and 43.5 months, respectively; hazard ratio, 0.97; 95% CI, 0.74 to 1.27) (P = 0.09 for interaction). The incidence of long-term toxic effects of grade 3 to 5 was similar in the two groups. Approximately 45% of the patients in the anastrozole-alone group crossed over to receive fulvestrant. CONCLUSIONS: The addition of fulvestrant to anastrozole was associated with increased long-term survival as compared with anastrozole alone, despite substantial crossover to fulvestrant after progression during therapy with anastrozole alone. The results suggest that the benefit was particularly notable in patients without previous exposure to adjuvant endocrine therapy. (Funded by the National Cancer Institute and AstraZeneca; ClinicalTrials.gov number, NCT00075764.).
RCT Entities:
BACKGROUND: We previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor-positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes. METHODS: We randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups. RESULTS: Of 707 patients who had undergone randomization, 694 had data available for analysis. The combination-therapy group had 247 deaths among 349 women (71%) and a median overall survival of 49.8 months, as compared with 261 deaths among 345 women (76%) and a median overall survival of 42.0 months in the anastrozole-alone group, a significant difference (hazard ratio for death, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03 by the log-rank test). In a subgroup analysis of the two strata, overall survival among women who had not received tamoxifen previously was longer with the combination therapy than with anastrozole alone (median, 52.2 months and 40.3 months, respectively; hazard ratio, 0.73; 95% CI, 0.58 to 0.92); among women who had received tamoxifen previously, overall survival was similar in the two groups (median, 48.2 months and 43.5 months, respectively; hazard ratio, 0.97; 95% CI, 0.74 to 1.27) (P = 0.09 for interaction). The incidence of long-term toxic effects of grade 3 to 5 was similar in the two groups. Approximately 45% of the patients in the anastrozole-alone group crossed over to receive fulvestrant. CONCLUSIONS: The addition of fulvestrant to anastrozole was associated with increased long-term survival as compared with anastrozole alone, despite substantial crossover to fulvestrant after progression during therapy with anastrozole alone. The results suggest that the benefit was particularly notable in patients without previous exposure to adjuvant endocrine therapy. (Funded by the National Cancer Institute and AstraZeneca; ClinicalTrials.gov number, NCT00075764.).
Authors: John F R Robertson; Igor M Bondarenko; Ekaterina Trishkina; Mikhail Dvorkin; Lawrence Panasci; Alexey Manikhas; Yaroslav Shparyk; Servando Cardona-Huerta; Kwok-Leung Cheung; Manuel Jesus Philco-Salas; Manuel Ruiz-Borrego; Zhimin Shao; Shinzaburo Noguchi; Jacqui Rowbottom; Mary Stuart; Lynda M Grinsted; Mehdi Fazal; Matthew J Ellis Journal: Lancet Date: 2016-11-29 Impact factor: 79.321
Authors: Richard S Finn; John P Crown; Istvan Lang; Katalin Boer; Igor M Bondarenko; Sergey O Kulyk; Johannes Ettl; Ravindranath Patel; Tamas Pinter; Marcus Schmidt; Yaroslav Shparyk; Anu R Thummala; Nataliya L Voytko; Camilla Fowst; Xin Huang; Sindy T Kim; Sophia Randolph; Dennis J Slamon Journal: Lancet Oncol Date: 2014-12-16 Impact factor: 41.316
Authors: Miguel Martín; Sibylle Loibl; Gunter von Minckwitz; Serafín Morales; Noelia Martinez; Angel Guerrero; Antonio Anton; Bahriye Aktas; Winfried Schoenegg; Montserrat Muñoz; José Ángel Garcia-Saenz; Miguel Gil; Manuel Ramos; Mireia Margeli; Eva Carrasco; Cornelia Liedtke; Grischa Wachsmann; Keyur Mehta; Juan R De la Haba-Rodriguez Journal: J Clin Oncol Date: 2015-02-17 Impact factor: 44.544
Authors: Maura N Dickler; William T Barry; Constance T Cirrincione; Matthew J Ellis; Mary Ellen Moynahan; Federico Innocenti; Arti Hurria; Hope S Rugo; Diana E Lake; Olwen Hahn; Bryan P Schneider; Debasish Tripathy; Lisa A Carey; Eric P Winer; Clifford A Hudis Journal: J Clin Oncol Date: 2016-05-02 Impact factor: 44.544
Authors: Richard S Finn; Miguel Martin; Hope S Rugo; Stephen Jones; Seock-Ah Im; Karen Gelmon; Nadia Harbeck; Oleg N Lipatov; Janice M Walshe; Stacy Moulder; Eric Gauthier; Dongrui R Lu; Sophia Randolph; Véronique Diéras; Dennis J Slamon Journal: N Engl J Med Date: 2016-11-17 Impact factor: 91.245
Authors: Matthew P Goetz; Masakazu Toi; Mario Campone; Joohyuk Sohn; Shani Paluch-Shimon; Jens Huober; In Hae Park; Olivier Trédan; Shin-Cheh Chen; Luis Manso; Orit C Freedman; Georgina Garnica Jaliffe; Tammy Forrester; Martin Frenzel; Susana Barriga; Ian C Smith; Nawel Bourayou; Angelo Di Leo Journal: J Clin Oncol Date: 2017-10-02 Impact factor: 44.544
Authors: Gabriel N Hortobagyi; Salomon M Stemmer; Howard A Burris; Yoon-Sim Yap; Gabe S Sonke; Shani Paluch-Shimon; Mario Campone; Kimberly L Blackwell; Fabrice André; Eric P Winer; Wolfgang Janni; Sunil Verma; Pierfranco Conte; Carlos L Arteaga; David A Cameron; Katarina Petrakova; Lowell L Hart; Cristian Villanueva; Arlene Chan; Erik Jakobsen; Arnd Nusch; Olga Burdaeva; Eva-Maria Grischke; Emilio Alba; Erik Wist; Norbert Marschner; Anne M Favret; Denise Yardley; Thomas Bachelot; Ling-Ming Tseng; Sibel Blau; Fengjuan Xuan; Farida Souami; Michelle Miller; Caroline Germa; Samit Hirawat; Joyce O'Shaughnessy Journal: N Engl J Med Date: 2016-10-07 Impact factor: 91.245
Authors: Rita S Mehta; William E Barlow; Kathy S Albain; Ted A Vandenberg; Shaker R Dakhil; Nagendra R Tirumali; Danika L Lew; Daniel F Hayes; Julie R Gralow; Robert B Livingston; Gabriel N Hortobagyi Journal: N Engl J Med Date: 2012-08-02 Impact factor: 91.245
Authors: Christoph Thomssen; Diana Lüftner; Michael Untch; Renate Haidinger; Rachel Würstlein; Nadia Harbeck; Doris Augustin; Susanne Briest; Johannes Ettl; Peter A Fasching; Frank Förster; Christian M Kurbacher; Hans-Joachim Lück; Norbert Marschner; Lothar Müller; Volkmar Müller; Lidia Perlova-Griff; Isabel Radke; Eugen Ruckhäberle; Iris Scheffen; Eva Schumacher-Wulf; Moritz Schwoerer; Dieter Steinfeld-Birg; Katja Ziegler-Löhr Journal: Breast Care (Basel) Date: 2020-02-10 Impact factor: 2.860
Authors: Costanza Paoletti; William E Barlow; Erin F Cobain; Mattias Bergqvist; Rita S Mehta; Julie R Gralow; Gabriel N Hortobagyi; Kathy S Albain; Lajos Pusztai; Priyanka Sharma; Andrew K Godwin; Alastair M Thompson; Daniel F Hayes; James M Rae Journal: Clin Cancer Res Date: 2021-09-14 Impact factor: 12.531
Authors: Eriseld Krasniqi; Giacomo Barchiesi; Marco Mazzotta; Laura Pizzuti; Alice Villa; Maddalena Barba; Patrizia Vici Journal: Medicine (Baltimore) Date: 2020-07-31 Impact factor: 1.817