Revisiting surrogacy of pathological complete response for long-term survival in triple negative breast cancer.

Abstract

Background: Pathological complete response (pCR) has been used as a primary endpoint in neoadjuvant trials in early-stage triple negative breast cancer (TNBC) and the Food and Drug Administration (FDA) accepted pCR as a surrogate endpoint for long-term survival outcomes in high-risk early-stage BC for new drug approval. However, there is insufficient trial-level data to robustly support pCR as a surrogate for long-term survival in TNBC.

Methods: A systematic literature review was performed to identify randomized clinical trials of neoadjuvant systemic therapy for patients with clinical stage I-III TNBC. Data of odds ratios (ORs) for pCR, hazard ratios (HRs) for event-free survival (EFS) and overall survival (OS) were extracted. Disease-free survival was used as an alternative when EFS data were unavailable. A linear regression model on a logarithmic scale, coefficient of difference, and 95% confidential interval (CI) were calculated to assess the trial-level association between OR for pCR and HR for OS and EFS.

Results: Eight trials with a total of 2,342 patients were included. Three trials tested immune checkpoint inhibitors. Coefficient of difference (R2) was 0.2 for HR of EFS (95% CI, 0.17 to 0.22, P = .27), and R2 for HR of OS was 0.19 (95% CI, 0.17 to 0.22, P = .33).

Conclusion: There is no strong evidence to support using pCR as a surrogate marker for EFS or OS in early-stage TNBC at the trial level. Because of the necessity of minimizing drug approval delay with reliable long-term outcome, further studies of surrogate markers in early-stage TNBC are warranted.