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

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

Methods: A systematic literature review was performed to identify randomized clinical trials of neoadjuvant systemic therapy for patients with clinical stage I-III triple-negative breast cancer. Data of odds ratios (ORs) for pathological complete response and hazard ratios (HRs) for event-free survival and overall survival were extracted. Disease-free survival was used as an alternative when event-free survival 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 odds ratio for pathological complete response and hazard ratio for overall survival and event-free survival.

Results: Eight trials with 2342 patients were included. Three trials tested immune checkpoint inhibitors. Coefficient of difference (R2) was 0.2 for hazard ratio of event-free survival (95% CI = 0.17 to 0.22, P = .27), and R2 for hazard ratio of overall survival was 0.19 (95% CI = 0.17 to 0.22, P = .33).

Conclusions: There is no strong evidence to support using pathological complete response as a surrogate marker for event-free survival or overall survival in early stage triple-negative breast cancer 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 triple-negative breast cancer are warranted.