Abstract P5-17-01: A definition of a high-risk early-breast cancer population based on data from the collaborative trials in neoadjuvant breast cancer (CTNeoBC) meta-analysis

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. 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.