In a pooled analysis of randomized neoadjuvant trials reported in The Lancet Oncology, Conforti et al found that distant disease–free survival was a “robust” surrogate endpoint for overall survival in many patients with early breast cancer.
Study Details
The analysis included individual patient data from randomized controlled trials of neoadjuvant therapy conducted by the German Breast Group (GBG) and the German Gynecological Oncology Breast Study Group (AGO-B) with data on distant disease–free survival and overall survival. The trial-level measure of surrogacy, R²trial, from two-stage meta-analytical copula methods, was used to quantify the association between treatment effects on distant disease–free survival and overall survival, both overall and in subgroups. R²trial values of 0.7 or higher, 0.69 to 0.5, and less than 0.5 represent strong, moderate, and weak correlations, respectively.
Key Findings
The analysis included 11 trials with 15 neoadjuvant treatment comparisons and a total of 12,247 patients.
A strong association between copula model–based hazard ratios (HRs) for overall survival and copula model–based HRs for distant disease-free survival was observed overall (R²trial = 0.91, 95% confidence interval [CI] = 0.82–1.00).
In the majority of subgroups analyzed, no significant heterogeneity of results was observed (P for heterogeneity > .05). Exceptions were observed in subgroups defined by tumor molecular features, such as tumor progesterone receptor status, HER2 status, and molecular subtypes. In analysis by molecular subtypes, strong surrogacy of distant disease–free survival was observed (R²trial > 0.7), with strong surrogacy in hormone receptor–negative and HER2-negative tumors (R²trial = 0.89, 95% CI = 0.75–1.00) and hormone receptor–negative and HER2-positive tumors (R²trial = 0.73, 95% CI = 0.36–1.00). Weak surrogacy (R²trial < 0.5) was observed for hormone receptor–positive and HER2-negative tumors (R²trial = 0.33, 95% CI = 0.00–0.83) and for hormone receptor–positive and HER2-positive tumors (R²trial = 0.11, 95% CI = 0.00–0.55; P for heterogeneity = .021).
The investigators concluded: “With adequate follow-up, distant disease-free survival is a robust surrogate endpoint for predicting final overall survival outcomes in neoadjuvant [randomized controlled trials] for early breast cancer in most contexts. However, the distant disease-free survival surrogacy appears to be weak for the hormone receptor–positive and HER2-negative and for the hormone receptor–positive and HER2-positive molecular subtypes. These latter findings warrant further investigation in more recent [randomized controlled trials] enrolling higher-risk patient populations.”
Fabio Conforti, MD, of the Division of Medical Oncology, Humanitas Gavazzeni, Bergamo, Humanitas University, Rozzano, Italy, is the corresponding author for The Lancet Oncology article.
Disclosure: The investigators reported no external funding for the study. For full disclosures of all study authors, visit thelancet.com.
