title: Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer.
abstract: The gold standard end point in randomized clinical trials in metastatic breast cancer (MBC) is overall survival (OS). Although therapeutics have been approved based on progression-free survival (PFS), its use as a primary end point is controversial. We aimed to assess to what extent PFS may be used as a surrogate for OS in randomized trials of anti-HER2 agents in HER2+ MBC.
  
  
  
  Eligible trials accrued HER2+ MBC patients in 1992-2008. A correlation approach was used: at the individual level, to estimate the association between investigator-assessed PFS and OS using a bivariate model and at the trial level, to estimate the association between treatment effects on PFS and OS. Correlation values close to 1.0 would indicate strong surrogacy.
  
  
  
  We identified 2545 eligible patients in 13 randomized trials testing trastuzumab or lapatinib. We collected individual patient data from 1963 patients and retained 1839 patients from 9 trials for analysis (7 first-line trials). During follow-up, 1072 deaths and 1462 progression or deaths occurred. The median survival time was 22 months [95% confidence interval (CI) 21-23 months] and the median PFS was 5.7 months (95% CI 5.5-6.1 months). At the individual level, the Spearman correlation was equal to ρ = 0.67 (95% CI 0.66-0.67) corresponding to a squared correlation value of 0.45. At the trial level, the squared correlation between treatment effects (log hazard ratios) on PFS and OS was provided by R(2) = 0.51 (95% CI 0.22-0.81).
  
  
  
  In trials of HER2-targeted agents in HER2+ MBC, PFS moderately correlates with OS at the individual level and treatment effects on PFS correlate moderately with those on overall mortality, providing only modest support for considering PFS as a surrogate. PFS does not completely substitute for OS in this setting.
authors.affiliation: Unit of Biostatistics and Epidemiology, Gustave Roussy, Villejuif; University Paris-Sud, University Paris-Saclay, UVSQ, CESP, INSERM, Villejuif; Plateform Ligue nationale contre le cancer for meta-analyses in oncology, Gustave Roussy, Villejuif, France; Institut Jules Bordet, Université Libre de Bruxelles, Brussels. Electronic address: stefan.michiels@gustaveroussy.fr.
authors.forename: S
authors.initials: S
authors.lastname: Michiels
authors.affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels; Breast International Group (BIG), Brussels, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Pugliano
authors.affiliation: Unit of Biostatistics and Epidemiology, Gustave Roussy, Villejuif.
authors.forename: S
authors.initials: S
authors.lastname: Marguet
authors.affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels.
authors.forename: D
authors.initials: D
authors.lastname: Grun
authors.affiliation: Agaplesion Markus Krankenhaus, Frankfurt am Main, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Barinoff
authors.affiliation: Department of Oncology, University of Edinburgh, Edinburgh, UK.
authors.forename: D
authors.initials: D
authors.lastname: Cameron
authors.affiliation: Rush University Medical Center, Chicago, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cobleigh
authors.affiliation: Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Di Leo
authors.affiliation: Breast Unit, Royal Marsden Hospital, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Johnston
authors.affiliation: Scientific Direction, IRCCS National Cancer Research Centre "Giovanni Paolo II,"Bari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gasparini
authors.affiliation: The Institute of Breast Oncology, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Kaufman
authors.affiliation: Breast Cancer Diseases Unit and Department of Medical Oncology, Saint Louis Hospital, APHP, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Marty
authors.affiliation: German Breast Group, GBG ForschungsGmbH, Neu-Isenburg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Nekljudova
authors.affiliation: The Institute of Breast Oncology, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Paluch-Shimon
authors.affiliation: Department of Pathology, Centre Jean Perrin, EA 4233, University of Auvergne, Clermont-Ferrand, France.
authors.forename: F
authors.initials: F
authors.lastname: Penault-Llorca
authors.affiliation: Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles.
authors.forename: D
authors.initials: D
authors.lastname: Slamon
authors.affiliation: University of Miami School of Medicine, Comprehensive Cancer Research Group Inc, Columbia Cancer Research Network of Florida, Miami, USA.
authors.forename: C
authors.initials: C
authors.lastname: Vogel
authors.affiliation: German Breast Group, GBG ForschungsGmbH, Neu-Isenburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: von Minckwitz
authors.affiliation: IDDI, Louvain-la-Neuve, Hasselt University, Hasselt, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Buyse
authors.affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels; Breast International Group (BIG), Brussels, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Piccart
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D000068878:Trastuzumab / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: HER2; lapatinib; metastatic breast cancer; progression-free survival; surrogate; trastuzumab