Abstract LB-88: Gene expression signatures predictive of clinical outcome and tumor mutations in refractory NSCLC patients (pts) in the BATTLE trial (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination)
Authors: Heymach John V. , Saintigny Pierre , Kim Edward S. , Byers Lauren A. , Lee J. Jack , Coombes Kevin , Diao Lixia , Wang Jing , Tran Hai , Fan You H. , Tsao Anne , Blumenschein George R. , Papadimitrakopoulou Vassiliki A. , Tang Ximing , Story Michael , Xie Yang , Girard Luc , Weinstein John , Mao Li , Minna John D. , Herbst Roy , Lippman Scott M. , Hong Waun K. , Wistuba Ignacio I. 
Published: July 2012

Abstract
Background: There are currently no established markers to identify pts bearing wild-type EGFR who are likely to benefit from erlotinib (ERLO). The EGFR and Kras pathways, and epithelial to mesenchymal transition (EMT), have been associated with response/resistance to EGFR inhibitors. We developed gene signatures for these pathways and tested whether they were predictive of disease control (DC) and tumor mutations using gene expression profiles from pts in the BATTLE trial, and developed novel markers for ERLO benefit in wt EGFR pts.
Methods: Gene expression profiles (Affymetrix HG1.0ST) from pretreatment core needle biopsies (CNBs) were obtained from 101 BATTLE pts. Pathways signatures were developed using independent datasets from resected NSCLC pts and cell lines. A robust EGFR mutation signature was derived by comparing genes differentially expressed in mutated and wt EGFR lung adenocarcinoma from 3 independent institutions, and validated in three independent sets, both in vivo and in vitro. A KRAS signature was similarly derived. An EMT signature was derived by identifying genes with a bimodal distribution and correlated with known EMT genes (E-cadherin, vimentin, N-cadherin, FN-1) using 54 NSCLC cell lines, and validated in an independent panel of HN cell lines and across different platforms. A novel 5-gene signature was derived using erlotinib-treated BATTLE patients with or without 8 week DC, the primary study endpoint.
Results: The EGFR and Kras signatures predicted EGFR and Kras mutations, respectively, in BATTLE patients (AUC 0.72 by ROC analysis, p=0.03 for EGFR; AUC 0.67, p=0.0.01 for KRas signature). In pts with wt EGFR and Kras, the EMT and 5-gene, but not the EGFR or KRas signatures, were associated with improved DC in ERLO treated pts (EMT signature: 64% for epithelial vs 10% mesenchymal groups, p=0.02; 5-gene: 83% vs 0%, p=&lt;.001) and progression-free survival (PFS). The EGFR, EMT and 5-gene signatures were also significantly associated with in vitro sensitivity to ERLO in NSCLC cell lines. LCN2/NGAL, part of the 5-gene signature, was found to be associated with the epithelial phenotype. Potential therapeutic targets associated with mesenchymal phenotype including Axl were identified by the EMT signature.
Conclusions: Gene expression profiling from CNBs is a feasible approach for predicting response and identifying activated oncogenic pathways and potential therapeutic targets in refractory NSCLC pts. EGFR and Kras signatures predicted mutation status but, in wt EGFR patients, did not predict efficacy. EMT and a novel 5-gene signature including LCN2/NGAL were predictive of DC in pts with wt EGFR treated in BATTLE and merit further investigation as markers of benefit for EGFR inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-88. doi:10.1158/1538-7445.AM2011-LB-88