title: Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer.
abstract: OBJECTIVE
  Overall survival (OS) can be observed only after prolonged follow-up, and any potential effect of first-line therapies on OS may be confounded by the effects of subsequent therapy. We investigated whether tumor response, disease control, progression-free survival (PFS), or time to progression (TTP) could be considered a valid surrogate for OS to assess the benefits of first-line therapies for patients with metastatic breast cancer.
  
  
  METHODS
  Individual patient data were collected on 3,953 patients in 11 randomized trials that compared an anthracycline (alone or in combination) with a taxane (alone or in combination with an anthracycline). Surrogacy was assessed through the correlation between the end points as well as through the correlation between the treatment effects on the end points.
  
  
  RESULTS
  Tumor response (survival odds ratio [OR], 6.2; 95% CI, 5.3 to 7.0) and disease control (survival OR, 5.5; 95% CI, 4.8 to 6.3) were strongly associated with OS. PFS (rank correlation coefficient, 0.688; 95% CI, 0.686 to 0.690) and TTP (rank correlation coefficient, 0.682; 95% CI, 0.680 to 0.684) were moderately associated with OS. Response log ORs were strongly correlated with PFS log hazard ratios (linear coefficient [rho], 0.96; 95% CI, 0.73 to 1.19). Response and disease control log ORs and PFS and TTP log hazard ratios were poorly correlated with log hazard ratios for OS, but the confidence limits of rho were too wide to be informative.
  
  
  CONCLUSIONS
  No end point could be demonstrated as a good surrogate for OS in these trials. Tumor response may be an acceptable surrogate for PFS.
authors.affiliation: Hasselt University, Center for Statistics, Agoralaan, Bldg D, 3590 Diepenbeek, Belgium. tomasz.burzykowski@uhasselt.be
authors.forename: Tomasz
authors.initials: T
authors.lastname: Burzykowski
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Piccart-Gebhart
authors.forename: George
authors.initials: G
authors.lastname: Sledge
authors.forename: James
authors.initials: J
authors.lastname: Carmichael
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lück
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Nabholtz
authors.forename: Robert
authors.initials: R
authors.lastname: Paridaens
authors.forename: Laura
authors.initials: L
authors.lastname: Biganzoli
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
authors.forename: Marijke
authors.initials: M
authors.lastname: Bontenbal
authors.forename: Jacques
authors.initials: J
authors.lastname: Bonneterre
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.forename: Gul Atalay
authors.initials: GA
authors.lastname: Basaran
authors.forename: Patrick
authors.initials: P
authors.lastname: Therasse
mesh_terms: D018943:Anthracyclines / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D015203:Reproducibility of Results; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018943:Anthracyclines; D015415:Biomarkers; D043823:Taxoids