Surrogate threshold effect based on a meta-analysis for the predictive value of progression-free survival for overall survival in hormone receptor-positive, HER2-negative metastatic breast cancer

Breast Cancer Res Treat. 2019 Aug;176(3):495-506. doi: 10.1007/s10549-019-05262-4. Epub 2019 May 7.


Purpose: Clinical trials investigating therapies for metastatic breast cancer (mBC) generally use progression-free survival (PFS) as primary endpoint, which is not accepted as patient-relevant outcome within the German benefit assessment. Hence a validation of PFS as surrogate endpoint for overall survival (OS) is needed, e.g., in the indication of HR+, HER2-negative mBC.

Methods: A systematic search was conducted. RCT were included if at least one study arm investigated fulvestrant, letrozole, tamoxifen, exemestane, or anastrozole. Additionally, hazard ratios reported for OS/PFS including confidence interval or standard error were mandatory. Pearson correlation coefficient was calculated to estimate the relation of surrogate endpoint PFS and patient-relevant outcome OS as well as the surrogate threshold effect (STE) which is used to determine thresholds for the estimate of the surrogate endpoint.

Results: 16 studies with 5324 patients in total were included in the analyses. The correlation between hazard ratios of PFS and OS was statistically significant (r = 0.72, 95% CI 0.35-0.90) representing a positive linear relationship. STE analysis was applied. The meta-regression model revealed a STE for HRPFS of 0.60 and sensitivity analyses underlined robustness of the results.

Conclusions: Based on the derived STE, it is possible to draw conclusions on a significant effect in OS for a hypothetical trial demonstrating an upper confidence limit of HRPFS < 0.60 in PFS. However, only final OS results are able to confirm if a clinical relevant difference in survival time can be achieved.

Keywords: Breast neoplasms; Overall survival; Progression-free survival; Surrogate threshold effect; Surrogate validation.

Publication types

  • Meta-Analysis
  • Review

MeSH terms

  • Biomarkers, Tumor
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality*
  • Breast Neoplasms / pathology
  • Female
  • Humans
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Prognosis
  • Receptor, ErbB-2 / metabolism*
  • Receptors, Estrogen / metabolism*
  • Receptors, Progesterone / metabolism*
  • Sensitivity and Specificity


  • Biomarkers, Tumor
  • Receptors, Estrogen
  • Receptors, Progesterone
  • ERBB2 protein, human
  • Receptor, ErbB-2