title: Surrogacy of progression free survival for overall survival in metastatic breast cancer studies: Meta-analyses of published studies.
abstract: PFS is often used as a surrogate endpoint for OS in metastatic breast cancer studies. We have evaluated the association of treatment effect on PFS with significant HROS(and how this association is affected by other factors) in published prospective metastatic breast cancer studies.
  
  
  
  A systematic literature search in PubMed identified prospective metastatic breast cancer studies. Treatment effects on PFS were determined using hazard ratio (HRPFS), increase in median PFS (ΔMEDPFS) and % increase in median PFS (%ΔMEDPFS). Diagnostic accuracy of PFS measures (HRPFS, ΔMEDPFSand %ΔMEDPFS) in predicting significant HROSwas assessed using receiver operating characteristic (ROC) curves and classification tree approach (CART).
  
  
  
  Seventy-four cases (i.e., treatment to control comparisons) from 65 individual publications were identified for the analyses. Of these, 16 cases reported significant treatment effect on HROSat 5% level of significance. Median number of deaths reported in these cases were 153. Area under the ROC curve (AUC) for diagnostic measures as HRPFS, ΔMEDPFSand %ΔMEDPFSwere 0.69, 0.70 and 0.75, respectively. Classification tree results identified %ΔMEDPFSand number of deaths as diagnostic measure for significant HROS. Only 7.9% (3/39) cases with ΔMEDPFSshorter than 48.27% reported significant HROS. There were 7 cases with ΔMEDPFSof 48.27% or more and number of deaths reported as 227 or more - of these 5 cases reported significant HROS.
  
  
  
  %ΔMEDPFSwas found to be a better diagnostic measure for predicting significant HROS. Our analysis results also suggest that consideration of total number of deaths may further improve its diagnostic performance. Based on our study results, the studies with 50% improvement in median PFS are more likely to produce significant HROSif the total number of OS events at the time of analysis is 227 or more.
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, NJ, USA. Electronic address: madan_g.kundu@novartis.com.
authors.forename: Madan G
authors.initials: MG
authors.lastname: Kundu
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
authors.forename: Suddhasatta
authors.initials: S
authors.lastname: Acharyya
mesh_terms: D019540:Area Under Curve; D001943:Breast Neoplasms / Q000401:mortality* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D012372:ROC Curve; D015996:Survival Rate
keywords: Classification tree; Meta-analysis; Metastatic breast cancer; Overall survival; Progression free survival; ROC curve; Surrogacy; Surrogate threshold effect