MYC and EIF3H Coamplification Significantly Improve Response and Survival of Non-small Cell Lung Cancer Patients (NSCLC) Treated with Gefitinib

Abstract

We investigated the incidence of eukaryotic translation initiation factor 3 subunit H (EIF3H) and MYC amplification in non-small cell lung cancer (NSCLC) patients, and whether MYC/EIF3H increased gene copy number affected response to Epidermal Growth Factor Receptor tyrosine kinase inhibitors. Metastatic NSCLC patients (n = 54) treated with gefitinib were analyzed for the genomic content of EIF3H and MYC genes by fluorescence in situ hybridization (FISH) using a custom-designed 3-color DNA probe set. Amplification of EIF3H (ratio EIF3H/CEP8 >2), was observed in 10 cases (18.5%), and MYC was coamplified in all. MYC amplification without coamplification of EIF3H was observed in 2 cases (3.7%). Receiver operating characteristic analysis was conducted to identify the cutoff for MYC and EIF3H copy number best discriminating sensitive and resistant populations. MYC FISH positive patients (MYC+, mean > or =2.8) had a significantly higher response rate (p = 0.003), longer time to progression (p = 0.01) and overall survival (OS: p = 0.02) than MYC- (mean <2.8). Similarly, EIF3H FISH positive patients (EIF3H+, mean > or =2.75) had a significantly higher response rate (p = 0.002), longer time to progression (p = 0.01) and OS (p = 0.01) than EIF3H- (mean <2.75). Our results indicate that MYC and EIF3H are frequently coamplified in NSCLC and that a high copy number correlates with increased epidermal growth factor receptor tyrosine kinase inhibitors sensitivity.