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 &amp; KRAS
Authors: Pierre Saintigny, Lixia Diao, Jing Wang, Luc Girard, Steven H. Lin, Kevin R. Coombes, Suyu Liu, J. Jack Lee, John N. Weinstein, Yang Xie, You H. Fan, Xi Ming Tang, Edward S. Kim, Roy S. Herbst, Anne Tsao, George R. Blumenschein, Li Mao, Scott M. Lippman, John D. Minna, Waun Ki Hong, Ignacio I. Wistuba, John V. Heymach
Journal: Cancer Research (2011)

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 &amp; 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&amp;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 &amp; KRAS NSCLC cells (r=−0.79, P&amp;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 &amp; KRAS cell lines (P=0.014). Conclusion: We identified a 5-gene sig predictive of PFS benefit in NSCLC pts with wt EGFR &amp; 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