Molecular analysis of the epidermal growth factor receptor (EGFR) gene and protein expression in patients treated with erlotinib in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial BR.21

Abstract

7007 Background: BR.21 demonstrated a significant survival benefit for patients with advanced NSCLC who received erlotinib vs placebo (Shepherd, ASCO 2004). While EGFR expression is common in NSCLC, protein expression by immunohistochemistry (IHC) does not appear to predict response to EGFR tyrosine kinase inhibitors (TKI). Point mutations and/or short deletions in exons 18–22 of the EGFR gene may predict response to EGFR TKIs. In BR.21, EGFR expression by IHC did not predict response. The predictive value of EGFR mutations (MUT) or gene amplification (AMP) on survival have not yet been reported. Methods: 731 patients were randomized to BR.21 (488 erlotinib, 243 placebo). IHC for EGFR expression was evaluated for 325 patients in formalin-fixed, paraffin embedded tumor specimens. 213/325 samples were suitable for molecular analyses for MUT and/or fluorescent in situ hybridization (FISH) studies for AMP. Results: 184/325 samples showed >10% EGFR staining by IHC. The HR for survival was 0.7 for patients with >10% EGFR expression compared to 0.9 for those without. EGFR gene data presently are available for 106/213 patients; this subset was significantly more likely to have had adenocarcinoma (adeno), >1 prior regimen, > time from diagnosis to randomization. 12 mutations/deletions in exons 19 and 21 were identified (10 adeno) in the 106 patients. FISH was performed successfully in 68/106 patients; 20 samples had AMP arising from polysomic gain or high copy number AMP (14/20 adeno). 4 patients had MUT + AMP, 3 MUT without AMP and in 5 patients with MUT, FISH was not successful. In this preliminary subset of 106 patients, 3 had complete or partial response; all 3 patients had AMP but no MUT. Analyses of additional EGFR gene exons and of the remaining samples are ongoing and will be correlated with survival. Conclusion: Erlotinib appears to have a greater effect on survival in patients with EGFR protein expression. In a small, preliminary subset, EGFR amplification appears a better predictor of response than EGFR mutation. Additional gene assays and survival analyses will be completed shortly. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI OSI