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Contemp Clin Trials. 2017 Feb;53:20-28. doi: 10.1016/j.cct.2016.12.004. Epub 2016 Dec 8.

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

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Novartis Pharmaceutical Corporation, East Hanover, NJ, USA. Electronic address:
Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.



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, ΔMEDPFS and %ΔMEDPFS) in predicting significant HROS was 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 HROS 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 HRPFS, ΔMEDPFS and %ΔMEDPFS were 0.69, 0.70 and 0.75, respectively. Classification tree results identified %ΔMEDPFS and number of deaths as diagnostic measure for significant HROS. Only 7.9% (3/39) cases with ΔMEDPFS shorter than 48.27% reported significant HROS. There were 7 cases with ΔMEDPFS of 48.27% or more and number of deaths reported as 227 or more - of these 5 cases reported significant HROS.


%ΔMEDPFS was 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 HROS if the total number of OS events at the time of analysis is 227 or more.


Classification tree; Meta-analysis; Metastatic breast cancer; Overall survival; Progression free survival; ROC curve; Surrogacy; Surrogate threshold effect

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