Abstract P1-07-12: An exploratory correlative biomarker analysis of NSABP FB-7, a phase II randomized trial evaluating neoadjuvant therapy with weekly paclitaxel (P) plus neratinib (N) or trastuzumab (T) or neratinib and trastuzumab (N+T) followed by doxorubicin and cyclophosphamide (AC) with postoperative T in women with locally advanced HER2-positive breast cancer
Authors: Gavin PG , Kim PS , Lipchick C , Langley E , Feng H , Meyer GR , Rim Kim S , Michel JP , Jacobs SA , Srinivasan A , Pogue-Geile KL 
Published: March 2017

Abstract
The NSABP FB-7 trial enrolled HER2-positive breast cancer patients (pts) with locally advanced disease who were randomly assigned to trastuzumab (T) or neratinib (N) or the combination (T+N) with weekly paclitaxel (P) followed by standard AC. A total of 126 pts were randomized to Arm 1 (T+P→AC), Arm 2 (N+P→AC), or Arm 3 (N+T+P→AC). Eligibility criteria included women &gt;18 years of age, ECOG PS 0-1, stage IIB-IIIC invasive breast cancer, HER2-positivity by IHC 3+, FISH, or CISH as determined by local laboratories, hormone receptor positive or negative, LVEF &gt;50%, and adequate laboratory parameters . The primary endpoint was pathologic complete response (pCR) in breast and nodes and was reported at SABCS 2015 (Jacobs et al, abstract # PD5-04). Dual anti-HER2 therapy yielded greater pCR rates than single targeted therapies in the overall cohort, and the magnitude of pCR was highest in HR-negative patients. Since this initial report, an in depth correlative biomarker analysis with clinical outcome has been performed and will be presented.
Methods: In an effort to discover candidate predictive markers of response to study drugs, pre-treatment core biopsy samples (n=59) and post treatment surgical samples (n=17) were obtained from a subset of patients. Samples were collected prospectively from 2011-2014 and stored prior to batch analysis. Retrospective correlation with clinical outcome was performed after datalock of 1st Sept. 2015. Expression and activation of HER family RTKs, including truncated HER2, as well as downstream components of PI3K/AKT and MAPK pathways, were quantified using the multiplexed microarray CEERTMplatform (Collaborative Enzyme-Enhanced Reactive immuno-assay). pCR data were available in n=51 pts from the biomarker cohort. After excluding low tumor content non-evaluable samples, correlative biomarker analysis was performed in n=42 patients. Breast cancer subtypes were assessed with RNA-Seq to assess changes in gene expression and subtypes before and after treatment and association of pathways with pCR. The distribution, in our study population, of MammaPrint and BluePrint scores (Agendia) and their association with pCR will be presented. Results from a custom AmpliSeq (Thermo-Fisher) gene-panel used to assess the variant status of 117 genes potentially relevant to the development of resistance to anti-HER2 therapies, will be presented.
Conclusions: Different patterns of baseline expression and activation levels of several key drivers, such as p95HER2, HER2, HER3, and PI3K, were observed between pCR in Arm1 (T+P→AC) and Arm 2 (N+P→AC). In particular, Arm 2 pCR displayed higher baseline levels of truncated HER2 compared to non-pCR. This exploratory marker analysis generates the hypothesis that high p95HER2 levels as measured by CEERTM may predict the likelihood of response to a neratinib containing regimen in the neoadjuvant setting in locally advanced breast cancer. Other correlatives will be discussed.
Support: Puma Biotechnology, Inc.
Citation Format: Gavin PG, Kim PS, Lipchick C, Langley E, Feng H, Meyer GR, Rim Kim S, Michel JP, Jacobs SA, Srinivasan A, Pogue-Geile KL. An exploratory correlative biomarker analysis of NSABP FB-7, a phase II randomized trial evaluating neoadjuvant therapy with weekly paclitaxel (P) plus neratinib (N) or trastuzumab (T) or neratinib and trastuzumab (N+T) followed by doxorubicin and cyclophosphamide (AC) with postoperative T in women with locally advanced HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-12.