title: Effect of molecular disease subsets on disease-free survival in randomized adjuvant chemotherapy trials for estrogen receptor-positive breast cancer.
abstract: OBJECTIVE
  The majority of estrogen receptor (ER)-positive cancers are sensitive to endocrine therapy and may not derive much further benefit from chemotherapy, but a subset are potentially chemotherapy sensitive. Molecular diagnostic tests allow the identification of these various subsets with some accuracy. The goal of the current analysis was to examine how the proportion of cases in the various risk (recurrence score [RS]) categories of a commercially available multigene assay influences the power of randomized trials to show benefit from adjuvant chemotherapy.
  
  
  METHODS
  We modeled 10-year disease-free survival (DFS) for hypothetical, two-arm clinical trials that randomly assigned patients with ER-positive breast cancer to endocrine therapy alone or endocrine therapy plus chemotherapy. We varied the proportion of patients in low, intermediate, and high RS categories and used DFS estimates for each risk group based on results from the Southwest Oncology Group 8814 study.
  
  
  RESULTS
  The probability of observing significant improvement in DFS as a result of chemotherapy decreases as the proportion of patients in the low RS category increases. For example, if a trial is designed with 80% power and the actual proportion of low RS patients accrued to the study increases from 40% to 60%, the power drops to 63%.
  
  
  CONCLUSIONS
  Variable accrual of low RS patients into different randomized adjuvant chemotherapy trials may partly explain contradictory results in the literature. Studies can be underpowered to detect improvement with chemotherapy as a result of inclusion of too many patients with low RS. Future adjuvant studies for ER-positive breast cancer will need to consider stratifying patients by molecular subtype.
authors.affiliation: Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, PO Box 301439, Houston, TX 77230-1439, USA. lpusztai@mdanderson.org
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.forename: Kristine
authors.initials: K
authors.lastname: Broglio
authors.forename: Fabrice
authors.initials: F
authors.lastname: Andre
authors.forename: W Fraser
authors.initials: WF
authors.lastname: Symmans
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D011960:Receptors, Estrogen; D012107:Research Design; D018570:Risk Assessment
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen