title: Treatment-associated musculoskeletal and vasomotor symptoms and relapse-free survival in the NCIC CTG MA.27 adjuvant breast cancer aromatase inhibitor trial.
abstract: OBJECTIVE
  Treatment-emergent symptoms with adjuvant tamoxifen and aromatase inhibitors (AIs) have been associated with superior recurrence-free survival (RFS). We hypothesized that MA.27 anastrozole- or exemestane-treated patients with new or worsening vasomotor and/or joint symptoms would have improved RFS.
  
  
  METHODS
  MA.27 randomly assigned 7,576 postmenopausal women with breast cancer to 5 years of anastrozole or exemestane. Patient-reported symptoms were collected using the Common Terminology Criteria for Adverse Events version 3.0 at protocol-specified baseline and 6- and 12-month clinical visits. Symptoms were considered present with either vasomotor and/or joint complaints. Associations between symptoms and baseline patient characteristics were examined with χ(2) and Fisher's exact tests. Subsequent effects of new or worsening symptoms on RFS were examined with landmark analyses and stratified univariable and multivariable Cox models. We examined the effects of 3-month symptoms arising from unplanned clinic visits as a result of severe toxicity.
  
  
  RESULTS
  Patients were assessable if eligible for the MA.27 trial, received some trial therapy, and had no disease recurrence at the end of a symptom assessment period; 96% of patients (n = 7,306 patients) were included at 6 months, and 96% (n = 7,246) were included at 12 months. Thirty-four percent of patients had baseline symptoms. For patients without baseline symptoms, 25% and 52% had new symptoms by 6 and 12 months, respectively. Neither treatment-emergent nor baseline symptoms significantly impacted RFS (P > .10) in patients with or without baseline symptoms.
  
  
  CONCLUSIONS
  In MA.27, anastrozole or exemestane treatment-emergent symptoms were not associated with improved RFS. Women should be supported through treatment and encouraged to remain on their AI regardless of their symptoms.
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Judith-Anne W
authors.initials: JA
authors.lastname: Chapman
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Cynthia X
authors.initials: CX
authors.lastname: Ma
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: G Thomas
authors.initials: GT
authors.lastname: Budd
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Manuela
authors.initials: M
authors.lastname: Rabaglio
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Le Maitre
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kundapur
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Pedro E R
authors.initials: PE
authors.lastname: Liedke
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Lois E
authors.initials: LE
authors.lastname: Shepherd
authors.affiliation: Vered Stearns, Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; Judith-Anne W. Chapman, Aurélie Le Maitre, Jessica Kundapur, and Lois E. Shepherd, NCIC Clinical Trials Group, Queen's University, Kingston; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Cynthia X. Ma, Siteman Cancer Center, Washington University, St Louis, MO; Matthew J. Ellis, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX; James N. Ingle, Mayo Clinic, Rochester, MN; G. Thomas Budd, Cleveland Clinic, Cleveland, OH; George W. Sledge, Stanford University, San Francisco, CA; Pedro E.R. Liedke and Paul E. Goss, Harvard University; Paul E. Goss, Avon International Breast Cancer Research Program, Massachusetts General Hospital, Boston, MA; Manuela Rabaglio, Inselspital University Hospital and International Breast Cancer Study Group Coordinating Center, Berne, Switzerland; and Pedro E.R. Liedke, Hospital de Clínicas de Porto Alegre and Instituto do Cancer Mãe de Deus, Oncologia, Porto Alegre, Rio Grande do Sul, Brazil. pgoss@partners.org.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Goss
mesh_terms: D000328:Adult; D000368:Aged; D000077384:Anastrozole; D000730:Androstadienes / Q000008:administration & dosage / Q000009:adverse effects*; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects*; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D019584:Hot Flashes / Q000139:chemically induced; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009141:Musculoskeletal System / Q000187:drug effects*; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects*; D014666:Vasomotor System / Q000187:drug effects*
chemical_list: D000730:Androstadienes; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077384:Anastrozole; C056516:exemestane