PFS No Surrogate for OS in Metastatic Breast Cancer Trials

Lidia Schapira, MD


March 18, 2016

Progression-Free Survival as Surrogate Endpoint for Overall Survival in Clinical Trials of HER2-Targeted Agents in HER2-Positive Metastatic Breast Cancer

Michiels S, Pugliano L, Marguet S, et al
Ann Oncol. 2016 March 8. [Epub ahead of print]

Study Summary

Breast cancer trialists have debated using progression-free survival as a surrogate for overall survival in randomized controlled trials (RCTs). The current study explores this important question for a subset of patients—those with metastatic HER2-positive breast cancer—through a statistical review of RCTs of HER2-directed therapies.

Studies of lapatinib and trastuzumab for patients with HER2-positive metastatic breast cancer included 2545 patients in 13 RCTs conducted from 1992 to 2008. The authors analyzed the individual data from 1839 patients in nine trials.

The results showed that median survival was 22 months, and median progression-free survival was 5.7 months. The authors studied correlations at the patient and trial levels. They concluded that progression-free survival correlates only moderately with overall survival, and treatment effects have a similar relationship—providing only modest support for considering progression-free survival as a surrogate for or valid indicator of overall survival.


The gold standard endpoint for the evaluation of new therapies in oncology is overall survival. There is no problem of "interpretation" when using this data point. Investigators have used other endpoints that are reached more rapidly in evaluating new therapies. In the advanced breast cancer setting, progression-free survival has been shown to be an appropriate surrogate for evaluation of chemotherapy or anticancer effect and efficacy for several cancers. However, it has not been shown to be a valid surrogate for overall survival in patients with metastatic breast cancer.

This study used an individual-patient meta-analysis from a biologically homogenous patient group (those with HER2-positive, metastatic breast cancer) to assess the extent to which progression-free survival correlated with—and thus could potentially be used as surrogate for—overall survival.

My understanding of statistical reviews is rather limited, but this paper caught my attention because it serves as an important reminder of the need for proper longitudinal analysis to capture the truly meaningful endpoints as we evaluate new therapies.


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