Research in context
Evidence before this study
Although disease-free survival has often been used as a primary endpoint in adjuvant trials of breast cancer, it has not been formally validated as a surrogate for overall survival. This systematic review and meta-analysis was done to evaluate the role of disease-free survival as a surrogate for overall survival in the adjuvant treatment of HER2-positive early breast cancer. In October, 2015, and October, 2016, bibliography databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials), clinical trial registries (Clinicaltrials.gov, EU Clinical Trials Register, WHO International Clinical Trials Registry Platform, and PharmNet.Bund), and trial registries from relevant pharmaceutical companies were searched for published or unpublished randomised clinical trials in HER2-positive early breast cancer on anti-HER2 monoclonal antibodies. Search terms were “breast cancer” and synonyms; “trastuzumab”, “pertuzumab”, or “trastuzumab emtansine”, and synonyms; and “phase 2” or “phase 3” or “phase 4”. Data were provided by investigators for all but one of the nine eligible trials.
Added value of this study
A two-level modelling approach was used to estimate the association between disease-free survival and overall survival (patient-level association) and between the treatment effects on these endpoints (trial-level association). Patient-level associations were strong (rs=0·90 [95% CI 0·89–0·90]). Trial-level associations were moderate or strong, depending on the set analysed (R2 0·75 [95% CI 0·50–1·00] in the full analysis set, 0·84 [0·67–1·00] in the reduced set). These results suggest that disease-free survival has good overall statistical validity as a surrogate for overall survival in the adjuvant treatment of HER2-positive, early breast cancer. These results apply mainly to the adjuvant use of trastuzumab for 12 months and cannot be readily extrapolated to other types of adjuvant anti-HER2 therapy, whether changing the agent (trastuzumab) or the duration of treatment.
Implications of all the available evidence
The levels of association could be sufficient for the purpose of replacing a final endpoint such as overall survival. This surrogacy has implications for trial design as well as for the approval of novel agents. Further studies should assess disease-free survival as a surrogate for overall survival in other breast cancer phenotypes.