title: Phase III Trial Evaluating Letrozole As First-Line Endocrine Therapy With or Without Bevacizumab for the Treatment of Postmenopausal Women With Hormone Receptor-Positive Advanced-Stage Breast Cancer: CALGB 40503 (Alliance).
abstract: To investigate whether anti-vascular endothelial growth factor therapy with bevacizumab prolongs progression-free survival (PFS) when added to first-line letrozole as treatment of hormone receptor-positive metastatic breast cancer (MBC).
  
  
  
  Women with hormone receptor-positive MBC were randomly assigned 1:1 in a multicenter, open-label, phase III trial of letrozole (2.5 mg orally per day) with or without bevacizumab (15 mg/kg intravenously once every 3 weeks) within strata defined by measurable disease and disease-free interval. This trial had 90% power to detect a 50% improvement in median PFS from 6 to 9 months. Using a one-sided α = .025, a target sample size of 352 patients was planned.
  
  
  
  From May 2008 to November 2011, 350 women were recruited; 343 received treatment and were observed for efficacy and safety. Median age was 58 years (range, 25 to 87 years). Sixty-two percent had measurable disease, and 45% had de novo MBC. At a median follow-up of 39 months, the addition of bevacizumab resulted in a significant reduction in the hazard of progression (hazard ratio, 0.75; 95% CI, 0.59 to 0.96; P = .016) and a prolongation in median PFS from 15.6 months with letrozole to 20.2 months with letrozole plus bevacizumab. There was no significant difference in overall survival (hazard ratio, 0.87; 95% CI, 0.65 to 1.18; P = .188), with median overall survival of 43.9 months with letrozole versus 47.2 months with letrozole plus bevacizumab. The largest increases in incidence of grade 3 to 4 treatment-related toxicities with the addition of bevacizumab were hypertension (24% v 2%) and proteinuria (11% v 0%).
  
  
  
  The addition of bevacizumab to letrozole improved PFS in hormone receptor-positive MBC, but this benefit was associated with a markedly increased risk of grade 3 to 4 toxicities. Research on predictive markers will be required to clarify the role of bevacizumab in this setting.
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN. dicklerm@mskcc.org.
authors.forename: Maura N
authors.initials: MN
authors.lastname: Dickler
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Constance T
authors.initials: CT
authors.lastname: Cirrincione
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Moynahan
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Arti
authors.initials: A
authors.lastname: Hurria
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Diana E
authors.initials: DE
authors.lastname: Lake
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Olwen
authors.initials: O
authors.lastname: Hahn
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Schneider
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Debasish
authors.initials: D
authors.lastname: Tripathy
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.affiliation: Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use*; D017698:Postmenopause; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D009570:Nitriles; D014230:Triazoles; D000068258:Bevacizumab; D000077289:Letrozole