Background: Pathologic complete response (pCR) is a proposed surrogate endpoint for predicting long-term clinical benefit on endpoints such as disease-free survival (DFS), event-free survival (EFS), or overall survival (OS). A meta-analysis is needed to establish the magnitude of pCR improvement on a trial level that results in improved DFS, EFS, or OS. Methods: We identified 12 neoadjuvant randomized trials (N = 13,125) with pCR clearly defined and long-term follow-up available for EFS and OS. Trials included AGO 1 (n = 668), ECTO (n = 1355), EORTC 10994/BIG 1–00 (n = 1856), GeparDuo (n = 907), GeparQuattro (n = 1495), GeparTrio (n = 2072), GeparTrio-Pilot (n = 285), NOAH (n = 234), NSABP B18 (n = 760), and NSABP B27 (n = 2411), PREPARE (n = 733), and TECHNO (n = 217). Key objectives of the meta-analysis were to determine: (1) the relationship of pCR to EFS and OS, (2) the definition of pCR that correlates best with long-term outcome, (3) the breast cancer subtypes in which pCR is best correlated with long-term outcome and (4) the magnitude of pCR effect needed to improve EFS and OS. We compared three pCR definitions: absence of invasive cancer and in situ cancer in the breast and axillary nodes (ypT0ypN0), absence of invasive cancer in the breast and axillary nodes with DCIS allowed (ypT0/isypN0), and absence of invasive cancer in the breast with DCIS allowed irrespective of nodal involvement (ypT0/is). Results: Overall 13%, 18% and 22% of patients achieved a pCR defined as ypT0ypN0, ypT0/isypN0, and ypT0/is, respectively. Eradication of tumor from both the breast and lymph nodes (ypT0ypN0 or ypT0/isypN0) was better associated with improved EFS and OS compared to eradication of tumor from the breast alone (ypT0/is). Patients who achieved a pCR (ypT0/isypN0) had an improved EFS (HR = 0.48) and OS (HR = 0.36) compared to those who did not. pCR was uncommon in patients with low-grade hormone receptor-positive (HR+) tumors (7%) and more common in the following tumor subtypes: high-grade HR+ (16%), triple negative (34%), HR+/HER2+ (30%), and hormone receptor-negative (HR−)/HER2+ (50%). Patients with more aggressive tumor subtypes who achieved pCR had greater EFS compared to patients who did not achieve pCR as follows: HR+ high grade (HR = 0.27), HR+/HER2+ (HR = 0.58), HR−/HER2+ (HR = 0.25), and triple negative (HR = 0.24). A trial level analysis on the relationship between pCR effect size and EFS did not show a correlation. Conclusions: Individual patients who attain a pCR, defined as either ypT0ypN0 or ypT0/isypN0, have a more favorable long-term outcome. The data show comparable EFS or OS regardless of the presence or absence of DCIS. For consistency, a standard pCR definition (ypT0ypN0 or ypT0/isypN0) should be used in future trials. Impact of pCR effect is limited to patients with HR+/grade 3, HR−/HER2−, and HER2+ tumors. This meta-analysis did not establish the magnitude of increase in pCR rate needed to predict the superiority of one regimen over another in terms of EFS or OS. This may be due to low pCR rates and the heterogeneity of the patient population included in this meta-analysis. The absolute magnitude of improvement in pCR rate needed to impact long-term outcome may be greater than the observed difference in these trials and may vary according to breast cancer subtype. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-11.

Background: Pathological complete response (pCR) is a proposed surrogate endpoint for predicting long-term clinical benefit on endpoints such as event-free survival (EFS) or overall survival (OS). The CTNeoBC meta-analysis did not validate the surrogacy of pCR for EFS or OS, and there is no precedent for its use as a regulatory endpoint in oncology. Use of the accelerated approval pathway has been proposed for neoadjuvant therapies that substantially improve pCR as a means to expedite widespread access to highly effective therapies for high-risk, early breast cancer. Potential risks of this approach include approving an agent that ultimately does not demonstrate clinical benefit and, in the interim, exposing curable patients to the toxicity of therapy without certainty of benefit. To mitigate the risks of this pathway, enrollment to neoadjuvant trials intended to support accelerated approval should be restricted to patients presenting with high-risk early-stage breast cancer. The 5-year EFS rate by breast cancer subtype in the CTNeoBC meta-analysis population is presented. Methods: We identified 12 neoadjuvant randomized trials (N = 12,993) with pCR clearly defined and long-term follow-up available for EFS and OS. Trials included AGO 1 (n = 668), ECTO (n = 1355), EORTC 10994/BIG 1-00 (n = 1856), GeparDuo (n = 907), GeparQuattro (n = 1495), GeparTrio (n = 2072), GeparTrio-Pilot (n = 285), NOAH (n = 234), NSABP B18 (n = 760), NSABP B27 (n = 2411), PREPARE (n = 733), and TECHNO (n = 217). The key objective of this analysis was to establish a definition of “high-risk” based on the Kaplan-Meier estimates of the 5-year EFS rate in the different clinical breast cancer subtypes (hormone receptor-positive, HER2-positive and triple-negative) analyzed by tumor stage and tumor grade at presentation. Results: The 5-year EFS rate was less than 65% in all the breast cancer subtypes with stage III disease. For patients with stage II disease, the impact of tumor grade varied by hormone receptor status. Patients with hormone receptor-negative breast cancer, regardless of HER2 status had a poor prognosis that was independent of tumor grade. For patients with hormone receptor-positive tumors, regardless of HER2 status, high grade histology was associated with an increased risk of recurrence. 5-year Event-Free Survival Rate (EFS) 5-year EFS Rate Estimate (95% confidence interval)TNMStage IIStage III Grade IIGrade IIIGrade IIGrade IIIHormone Receptor + HER2-83% (80%, 85%)71% (65%, 77%)63% (58%, 69%)51% (42%, 59%)HER2+ HR+81% (75%, 86%)69% (60%, 76%)50% (41%, 59%)48% (37%, 59%)HER2+ HR-61% (51%, 70%)66% (57%, 73%)58% (46%, 69%)46% (36%, 55%)Triple Negative66% (58%, 72%)72% (67%, 76%)38% (27%, 48%)37% (29%, 45%) Conclusions: This analysis estimated the 5-year EFS rate in the breast cancer subtypes from the CTNeoBC meta-analysis population. The HER2-positive population in the meta-analysis was at particularly high risk because most of the patients had locally advanced breast cancer and only 39% of these patients received trastuzumab therapy. We propose defining less than 75% 5-year EFS rate as “high-risk” for the purposes of designing neoadjuvant trials that intend to use pCR to support accelerated approval. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-17-01.