Integrative Analysis of Dna Copy Number in Metastatic Nsclc Identifies Drug Sensitivity to Afatinib

Abstract

ABSTRACT Aim: Afatinib (BIBW-2992) has been approved for patients with untreated metastatic non-small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations. Pharmacogenomic studies have found that genome-wide assays allows the unbiased discovery of genomic alterations which are associated with drug response to targeted therapy. The aim of our study was to identify the correlation between DNA copy number profiles and treatment response to afatinib. Methods: Integrative analysis of DNA copy number alterations (CNA) from 32 metastatic NSCLC patients were performed to identify recurrent regions of genomic change associated with primary response to afatinib using the Affymetrix Mapping 250K Nsp SNP array. Copy number-associated transciptome profiling was identified using Affymetrix Human genome U133 Plus 2.0 array. Comparison of candidate genes correlated with copy number variation and clinical outcome of afatinib treatment was conducted by quantitative-PCR (qPCR). Results: Predictive model scores generated from cross-validation were correlated with sensitivity to afatinib. Eight distinct genomic regions were identified in a predictive model for afatinib sensitivity. Regions contained chromosomal gain of EGFR (7p11.2) as well as chromosomal loss of HSD3B2 (1p12) and MTAP (9p21.3). The extreme concordance between DNA copy number and transcript abundance was highly significant for the genes mapping to 7p11.2 in the afatinib-sensitive group. Amplification of CCT6A was related to intrinsic resistance to afatinib. Conclusions: These data show that integrative analysis of DNA copy number analysis can be used to identify genetic alterations which can be used to discover clinically relevant predictors of drug sensitivity to afatinib. Disclosure: All authors have declared no conflicts of interest.