Surrogacy of progression free survival for overall survival in metastatic breast cancer studies: Meta-analyses of published studies.

Purpose: 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 HR (and how this association is affected by other factors) in published prospective metastatic breast cancer studies.

Methods: A systematic literature search in PubMed identified prospective metastatic breast cancer studies. Treatment effects on PFS were determined using hazard ratio (HR), increase in median PFS (ΔMED) and % increase in median PFS (%ΔMED). Diagnostic accuracy of PFS measures (HR, ΔMED and %ΔMED) in predicting significant HR was assessed using receiver operating characteristic (ROC) curves and classification tree approach (CART).

Results: 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 HR at 5% level of significance. Median number of deaths reported in these cases were 153. Area under the ROC curve (AUC) for diagnostic measures as HR, ΔMED and %ΔMED were 0.69, 0.70 and 0.75, respectively. Classification tree results identified %ΔMED and number of deaths as diagnostic measure for significant HR. Only 7.9% (3/39) cases with ΔMED shorter than 48.27% reported significant HR. There were 7 cases with ΔMED of 48.27% or more and number of deaths reported as 227 or more - of these 5 cases reported significant HR.

Conclusion: %ΔMED was found to be a better diagnostic measure for predicting significant HR. 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 HR if the total number of OS events at the time of analysis is 227 or more.