Elsevier

The Lancet

Volume 384, Issue 9938, 12–18 July 2014, Pages 164-172
The Lancet

Articles
Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis

https://doi.org/10.1016/S0140-6736(13)62422-8Get rights and content

Summary

Background

Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS.

Methods

We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response—ypT0 ypN0, ypT0/is ypN0, and ypT0/is—for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS.

Findings

We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39–0·51; ypT0/is ypN0: 0·48, 0·43–0·54) and OS (0·36, 0·30–0·44; 0·36, 0·31–0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55–0·66; OS 0·51, 0·45–0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18–0·33; OS: 0·16, 0·11–0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09–0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R2=0·03, 95% CI 0·00–0·25) and OS (R2=0·24, 0·00–0·70).

Interpretation

Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS.

Funding

US Food and Drug Administration.

Introduction

New agents to treat breast cancer have historically been approved first in the metastatic setting, with approval for use in early-stage breast cancer following many years later on the basis of results of large randomised adjuvant trials with long follow-up. Neoadjuvant treatment—systemic therapy delivered before definitive breast cancer surgery—was once reserved to reduce the size and extent of locally advanced tumours, but is now being used more widely. In addition to increasing the likelihood of tumour control and the potential for curability in early breast cancer, neoadjuvant trials allow rapid assessment of drug efficacy and could expedite development and approval of treatments for early breast cancer.1 Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival and overall survival (OS).2, 3, 4, 5

Although pathological complete response has been the most commonly used endpoint in neoadjuvant trials, it has been variably defined, which has made reporting and interpretation of data challenging. One way to optimise the definition of pathological complete response, enable the interpretation of data, and investigate the association between pathological complete response and long-term outcome is via a pooled analysis of neoadjuvant trials. To obtain the requisite number of trials for this pooled analysis, the US Food and Drug Administration established an international working group known as Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) with investigators who had done neoadjuvant trials for which long-term data are available.

We aimed to investigate the potential of pathological complete response as a surrogate endpoint for long-term outcomes. We had four key objectives: to establish the association between pathological complete response and event-free survival (EFS) and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response predicts improved EFS and OS. Here, we present initial results from the CTNeoBC pooled analysis.

Section snippets

Search strategy and selection criteria

We searched PubMed, Embase, and Medline for reports of clinical trials of neoadjuvant treatment of breast cancer published between Jan 1, 1990, and Aug 1, 2011. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years.

Investigators from identified trials were

Results

We identified 12 international neoadjuvant trials: AGO 1 (n=668),7 ECTO (n=1355),8 EORTC 10994/BIG 1-00 (n=1856),9 GeparDuo (n=907),10 GeparQuattro (n=1495),11, 12 GeparTrio (n=2072),13, 14 GeparTrio-Pilot (n=285),15 NOAH (n=334),16 NSABP B-18 (n=1523),17, 18 NSABP B-27 (n=2411),18, 19 PREPARE (n=733),20, 21 and TECHNO (n=217; appendix).22 No major trial was excluded from the pooled analysis. All were randomised controlled trials except for TECHNO,22 which was a single-group study previously

Discussion

In our pooled analysis, we recorded that eradication of tumours from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0 pathological complete response) had a stronger association with improved EFS and OS than did eradication of tumour from the breast alone (ypT0/is). The strongest association between pathological complete response and long-term outcome was in patients with aggressive breast cancer subtypes (triple negative; hormone-receptor-positive, high-grade, and HER2-negative; and

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