Evaluation of pathological complete response as a trial-level surrogate for long-term survival outcomes among triple-negative breast cancer patients receiving neoadjuvant therapy

Abstract

Background: Pathological complete response (pCR) is a commonly used endpoint in neoadjuvant trials for breast cancer (BC). A pooled analysis sponsored by FDA (Cortazar et al, 2014) showed pCR is a significant predictor of survival outcomes; however , it found little association between magnitude of difference in pCR rates and difference in survival between treatment arms in general BC or triple negative BC (TNBC). To reflect more recent evidence, this study aimed to update and focus the evaluation on the trial-level association between pCR and survival outcomes in TNBC. Methods: Randomized controlled trials (RCTs) of neoadjuvant treatments for TNBC were identified through a targeted literature review (TLR) of publications all years through October 2018. RCTs that reported outcomes for both pCR and event-free survival (EFS) or overall survival (OS) in TNBC were included. Similarly as in Cortazar 2014, a weighted linear regression analysis on a logarithmic scale was performed based on odds ratios for pCR and hazard ratios for EFS/OS within each RCT. The coefficient of determination (R 2) was used to measure the trial-level association between the treatment effects on pCR and survival. Scenario analyses were conducted to assess the impact of divergent study designs and pCR definitions across the RCTs. Results: Ten comparisons from 8 RCTs were identified by the TLR, which were all published after the Cortazar study. The primary analysis reported a moderate association between the improvement in pCR and EFS (R 2 ¼0.79). The R 2 between the improvement in pCR and OS was 0.42. Similar association was found in all scenario analyses. Conclusions: Although uncertainty remains as to the validity of the trial-level surro-gate, with availability of more TNBC-focused trials, this study demonstrated substantially stronger trial-level association between pCR and survival outcomes in TNBC compared with the findings in previous studies. With the increasing trend of TNBC-focused drug development, more robust evidence and sufficient amount of data may be available in the near future to address the uncertainty with respect to the association between pCR and long-term survival.