Abstract 4819: Gene-expression profiles predict sorafenib efficacy in wild-type EGFR non-small cell lung cancer (NSCLC)
Authors: Pierre Saintigny, George R. Blumenschein, Lixia Diao, Jing Wang, Kevin Coombes, Suyu Liu, Edward Kim, Anne Tsao, Roy Herbst, Christine Alden, Jack J. Lee, Ximing Tang, David Stewart, Merrill Kies, Frank Fossella, Hai Tran, Li Mao, Marshall Hicks, Jeremy Erasmus, Sanjay Gupta, Luc Girard, Michael Peyton, Suzanne Davis, Scott Lippman, Waun Ki Hong, John Minna, Ignacio Wistuba, John Heymach
Journal: Cancer Research (2012)

Abstract Background: Results from our Biomarkers-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) program suggest that patients with chemorefractory wild-type (wt) EGFR NSCLC including those with mutant KRAS may benefit from sorafenib. Using 3 different approaches, we tested the hypothesis that gene expression profiles from wild-type (wt) EGFR tumors may predict sorafenib efficacy by capturing effects on multiple targets. Material and Methods: Baseline tumor biopsies from 37 BATTLE patients (pts) with EGFR wt tumors and treated with sorafenib were profiled (Affymetrix Human Gene 1.ST), as well as 68 EGFR wt NSCLC cell lines with available IC50 to sorafenib (Illumina HumanWG-6 v3.0 expression beadchip). (i) We first developed an In vitro Sorafenib Signature (ISS). Correlation of IC50 with each individual probe expression level was computed. Most significant probes were summarized by the first principal component (PC), and correlated with IC50 of sorafenib. To validate the signature, the first PC was computed in BATTLE samples, and progression-free survival (PFS) of pts with high- vs. low-sensitivity signature was compared based on the median of the first PC. (ii) Alternatively, we developed a Clinical Sorafenib Signature (CSS) using BATTLE samples. We compared 23 (62%) pts who achieved 8-week disease control with 14 (38%) who did not (t-test). Most significant probesets were summarized by the first PC and PFS of pts with a high- vs. low-sensitivity signature were compared. To validate the signature, the first PC was computed in cell lines and correlated with IC50 of sorafenib. (iii) Finally, we tested a previously reported KRAS mutation gene expression signature derived by comparing genes differentially expressed in mutant vs. wt KRAS early stage resected lung adenocarcinomas, in 124 BATTLE samples including 24 mutant KRAS. Results: (i) The ISS included 50 probes. The first PC was correlated with the IC50 of sorafenib (rho = –0.71, P &amp;lt; 0.0001). The ISS was then tested in BATTLE and PFS was significantly different in pts with the high- (median PFS 3.61 months) vs. the low-sensitivity signature (median PFS 1.84 months, log-rank P = 0.0263). (ii) The CSS developed in BATTLE included 80 probesets summarized using the first PC. PFS was significantly different in pts with the high- vs. the low-sensitivity signature (log-rank P &amp;lt; 0.0001). The CSS was then tested in cell lines and the first PC was signicantly correlated with IC50 of sorafenib (rho = 0.24, P = 0.0483). (iii) Finally, the KRAS signature was significantly associated with KRAS mutation, but no association was observed with outcome in pts treated with sorafenib in BATTLE. Conclusion: We report 2 gene expression signatures, ISS and CSS, that predicted benefit from sorafenib in patients with chemorefractory NSCLC and in vitro sensitivity to sorafenib respectively. Further validation is planned in our ongoing BATTLE-2 program. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4819. doi:1538-7445.AM2012-4819