Pooled analysis of distant disease-free survival as surrogate endpoint for overall survival in randomized trial of neoadjuvant therapy for early breast cancer

Pooled analysis of individual patient data from randomized controlled trial of neoadjuvant therapy for early breast cancer conducted by the German Breast Group and the German Gynecological Oncology Breast Study Group was conducted to estimate the surrogacy value of distant disease-free survival (DDFS) for overall survival (OS. The analysis included 11 RCTs, with a total of 15 neoadjuvant treatment comparisons and 12,247 patients. The analysis found a strong association between copula model-based HRs for OS and copula model-based HRs for DDFS (R²_trial=0.01; 95% CI 0.82-1.00). No significant heterogeneity of results was observed across the majority of subgroups analyzed (p_{heterogeneity}>0.05 in all subgroups) with the exception of subgroups defined by tumor molecular features, such as tumor PR status, HER2 status, and molecular subtypes. The analysis found strong surrogacy in HR-negative and HER2-negative tumors and HR-negative and HER2-positive tumors, and lower than weak surrogacy in HR-positive and HER2-negative tumors and HR-positive and HER2-positive tumors. The authors conclude that with adequate follow-up, DDFS is a robust surrogate endpoint for predicting OS in neoadjuvant RCTs for early breast cancer in most contexts.