Abstract 4109: A 5-gene signature (sig) predicts clinical benefit from erlotinib in non-small cell lung cancer (NSCLC) patients (pts) harboring wild-type (wt) EGFR & KRAS
Authors: Saintigny Pierre , Diao Lixia , Wang Jing , Girard Luc , Lin Steven H. , Coombes Kevin R. , Liu Suyu , Lee J. Jack , Weinstein John N. , Xie Yang , Fan You H. , Tang Xi Ming , Kim Edward S. , Herbst Roy S. , Tsao Anne , Blumenschein George R. , Mao Li , Lippman Scott M. , Minna John D. , Hong Waun Ki , Wistuba Ignacio I. , Heymach John V. 
Published: July 2012

Abstract
Background: Despite a low response rate, erlotinib (E) improves survival in a subset of NSCLC pts with wt EGFR but there are no established markers for identifying pts likely to have clinical benefit. We hypothesized that a gene expression sig could be used for this purpose. Material and Methods: We used pretreatment gene expression profiles (Affymetrix HG1.0ST) from 101 chemo-refractory pts in our Biomarkers-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) treated with E, E+bexarotene (EB), sorafenib (S), or vandetanib (V). 24 cases of wt EGFR & KRAS tumors treated with E or EB were compared to train the signature (two-sided t-test), using the primary end-point of the trial [8-week disease control (8wDC)]. Principal component (PC) analysis and a logistic regression model were used to develop the sig. Gene expression profiles from 108 NSCLC cell lines (Illumina), with available E IC50 (N=94) and DNA methylation profiling (N=66, Illumina), were used for in vitro studies. Results: 113 genes were differentially expressed between pts with or without 8wDC (false discovery rate 30%; P=0.004). Leave-one-out cross validation with various gene list lengths produced a 5-gene sig, including lipocalin 2 (LCN2), with a specificity, sensitivity and accuracy of 80% to predict 8wDC. In pts treated with E or EB, using the median sig score, the 8wDC rate in the sig-positive group was 83% compared with 0% in the sig-negative group; the sig did not predict 8wDC in pts treated with S or V (Mantel-Haenszel chi-squared test P=0.023). The improvement in 8wDC in the sig-positive group translated to an increased progression-free survival (PFS) (hazard ratio=0.12, 95% confidence interval: 0.03-0.46, P=0.001; log-rank P=0.0004; median PFS: 12.5 weeks vs. 7.2 weeks). We tested the sig in an independent set of 47 wt EGFR&KRAS cell lines. It predicted E sensitivity with an area under the curve of 78% (P=0.002). The first PC of the sig and the IC50 for E were correlated (r=−0.47, P=0.0009). In 108 NSCLC cell lines, LCN2 gene expression was bimodal and correlated with the IC50 for E (r=−0.46, P=0.001). Degree of methylation and expression level of LCN2 were inversely in wt EGFR & KRAS NSCLC cells (r=−0.79, P&lt;0.0001, N=33). Cell lines with completely unmethylated LCN2 were more sensitive to E compared to those with LCN2 full methylation (N=36) (P=0.006); the difference remained significant in wt EGFR & KRAS cell lines (P=0.014). Conclusion: We identified a 5-gene sig predictive of PFS benefit in NSCLC pts with wt EGFR & KRAS treated with E, but not S or V The sig was also predictive of E sensitivity in vitro. LCN2 was the strongest individual marker of sensitivity and may be epigenetically regulated.
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 4109. doi:10.1158/1538-7445.AM2011-4109