Surrogate End Points for Overall Survival in Neoadjuvant Randomized Clinical Trials for Early Breast Cancer

Area of Science:

• Oncology
• Clinical Trials
• Biostatistics

Background:

• Accurate surrogate endpoints are crucial for accelerating drug development in early breast cancer (BC).
• Overall survival (OS) is the gold standard but requires long follow-up.
• Pathologic complete response (pCR) and invasive disease-free survival (iDFS) are potential surrogate endpoints.

Purpose of the Study:

• To evaluate the trial-level surrogacy of pCR and iDFS for OS in randomized clinical trials (RCTs) for early BC.
• To quantify the association between treatment effects on OS and these surrogate endpoints.

Main Methods:

• Individual patient data from neoadjuvant RCTs were analyzed.
• Weighted linear regression models were used to assess the association between treatment effects on OS and surrogate endpoints (pCR, iDFS).
• The coefficient of determination (R² ) quantified the surrogacy value.

Main Results:

• Eleven RCTs (15 treatment comparisons, 12,247 patients) were included.
• pCR showed a weak association with OS (R² = 0.07).
• iDFS demonstrated moderate surrogacy for OS (R² = 0.46), with strong surrogacy in specific subgroups (e.g., HR-/HER2-, grade 1-2, lobular tumors).
• iDFS surrogacy improved with longer follow-up, plateauing after 48 months.

Conclusions:

• iDFS is an acceptable surrogate for OS in early BC neoadjuvant RCTs, provided sufficient follow-up.
• Surrogacy is robust across most subgroups, except for hormone receptor-positive (HR+) disease.
• The utility of OS as an endpoint for HR+ early BC warrants re-evaluation.