Background: There has been recent interest in using pathological complete response (pCR) as a potential surrogate endpoint for long-term outcomes in the neoadjuvant treatment of high-risk, early-stage breast cancer. Methods: We review the clinical trials that have contributed to our understanding of the association between pCR and long-term outcomes, describe the various definitions of pCR, describe patient populations in which pCR may predict long-term benefit, and discuss the implications of pCR on drug development and accelerated approval for neoadjuvant treatment of breast cancer. Results: Varying definitions of pCR across clinical trials conducted in heterogeneous patient populations make understanding the association of pCR with long-term outcomes challenging. The US Food and Drug Administration established the Collaborative Trials in Neoadjuvant Breast Cancer group to evaluate the potential use of pCR as a regulatory endpoint. The group demonstrated that pCR defined as no residual invasive cancer in the breast and axillary nodes with presence or absence of in situ cancer (ypT0/is ypN0 or ypT0 ypN0) provided a better association with improved outcomes compared to eradication of invasive tumor from the breast alone (ypT0/is). Conclusion: Even though pCR was not validated as a surrogate endpoint for long-term outcomes, the promising data regarding the strong association of pCR with substantially improved outcomes in individual patients with more aggressive subtypes of breast cancer supported the opening of an accelerated approval pathway for patients with high-risk, early-stage breast cancer.
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