Evaluation of pathological complete response as surrogate endpoint in neoadjuvant randomised clinical trials of early stage breast cancer: systematic review and meta-analysis

ObjectiveTo evaluate pathological complete response as a surrogate endpoint for disease-free survival and overall survival in regulatory neoadjuvant trials of early stage breast cancer.DesignSystematic review and meta-analysis.Data sourcesMedline, Embase, and Scopus to 1 December 2020.Eligibility criteria for study selectionRandomised clinical trials that tested neoadjuvant chemotherapy given alone or combined with other treatments, including anti-human epidermal growth factor 2 (anti-HER2) drugs, targeted treatments, antivascular agents, bisphosphonates, and immune checkpoint inhibitors.Data extraction and synthesisTrial level associations between the surrogate endpoint pathological complete response and disease-free survival and overall survival.MethodsA weighted regression analysis was performed on log transformed treatment effect estimates (hazard ratio for disease-free survival and overall survival and relative risk for pathological complete response), and the coefficient of determination (R2) was used to quantify the association. The secondary objective was to explore heterogeneity of results in preplanned subgroups analysis, stratifying trials according treatment type in the experimental arm, definition used for pathological complete response (breast and lymph nodesvbreast only), and biological features of the disease (HER2 positive or triple negative breast cancer). The surrogate threshold effect was also evaluated, indicating the minimum value of the relative risk for pathological complete response necessary to confidently predict a non-null effect on hazard ratio for disease-free survival or overall survival.Results54 randomised clinical trials comprising a total of 32 611 patients were included in the analysis. A weak association was observed between the log(relative risk) for pathological complete response and log(hazard ratio) for both disease-free survival (R2=0.14, 95% confidence interval 0.00 to 0.29) and overall survival (R2=0.08, 0.00 to 0.22). Similar results were found across all subgroups evaluated, independently of the definition used for pathological complete response, treatment type in the experimental arm, and biological features of the disease. The surrogate threshold effect was 5.19 for disease-free survival but was not estimable for overall survival. Consistent results were confirmed in three sensitivity analyses: excluding small trials (ConclusionA lack of surrogacy of pathological complete response was identified at trial level for both disease-free survival and overall survival. The findings suggest that pathological complete response should not be used as primary endpoint in regulatory neoadjuvant trials of early stage breast cancer.