Abstract S1-11: Meta-analysis Results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC)

Abstract

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.

Response and prognosis after neoadjuvant chemotherapy in 1,051 patients with infiltrating lobular breast carcinoma

“…Within the ILC group, none of the survival endpoints were different between pCR and non-pCR patients after neoadjuvant chemotherapy. pCR is a surrogate endpoint for predicting long-term clinical benefit on endpoints such as disease-free or overall survival [9,30]. However, pCR seems especially important for tumours with more aggressive biological features.…”

Neoadjuvant Therapy as a Platform for Drug Development and Approval in Breast Cancer

“…Triple-negative breast cancer (TNBC) and HER2-positive breast cancers were more likely to achieve path CR than hormone receptor (HR þ ) breast cancers, but when present, path CR was associated with significantly improved outcomes in all three subtypes. Another large meta-analysis based on pooling of individual patient data from 12 neoadjuvant randomized controlled trials reported that path CR after neoadjuvant chemotherapy was a strong predictor of improved DFS and OS (10). Moreover, the improved outcomes with path CR were in all the three breast cancer subtypes: HR þ (hazard ratio, 0.49; P < 0.001), HER2 þ (hazard ratio, 0.39; P < 0.001), and TNBC (hazard ratio, 0.24; P < 0.001), though for HR þ tumors, the association was stronger for grade 3 tumors (hazard ratio, 0.27; P < 0.001) than grade 1/2 tumors (hazard ratio, 0.63; P ¼ 0.07).…”

Accelerated Approval for Pertuzumab in the Neoadjuvant Setting: Winds of Change?

“…Importantly, the I-SPY 1 trial (CALGB 150007/150012, ACRIN 6657) showed that pCR is a better predictor of recurrence-free survival by cancer subtype than for all patients as a whole, even among women with high-risk disease (10,11). These results were corroborated by the meta-analysis of randomized neoadjuvant trials (12).…”