Higher Dosage of the Epidermal Growth Factor Receptor Mutant Allele in Lung Adenocarcinoma Correlates with Younger Age, Stage IV at Presentation, and Poorer Survival

Abstract

The clinical significance of epidermal growth factor receptor (EGFR) mutant allele specific imbalance (MASI) in lung adenocarcinomas is unknown. EGFR MASI was characterized by sequencing electropherograms (SEs) and EGFR fluorescence in situ hybridization (FISH) in 96 prospectively tested lung adenocarcinoma patients with a median follow-up of 20 months (all cases were EGFR mutation-positive). In 25 cases, the mutant allele (MA) peak was higher than the wild-type allele (WA) peak, indicating the presence of EGFR MASI (25/96, 26%). The adenocarcinomas with EGFR MASI had a 4.4-fold higher average EGFR/Chromosome Enumeration Probe 7 ratio than carcinomas without MASI (7.9 ± 3.8 versus 1.8 ± 0.6, p = 0.01). A high degree of correlation between the MA/WA ratio (SE) and the EGFR/CEP7 ratio (FISH) (ρ = 0.757, p = 0.003) validated the quantitative nature of SE. Amplification was the most common mechanism of EGFR MASI (13/21, 62%). EGFR MASI was more commonly associated with exon 19 mutations than with exon 21 mutations (19/53, 36%, versus 6/43, 14%, p = 0.015, odds ratio [OR] = 3.4) and in patients younger than 65 years (17/46, 37%, versus 8/50, 16%, p = 0.019, OR = 3.1). Patients with EGFR MASI presented with stage IV disease more frequently (p = 0.01, OR = 3.5) and had a poorer disease-specific survival rate (p = 0.021, 54% versus 83% at 31 months). EGFR MASI in lung adenocarcinomas can be assessed based on SE and can be used to identify younger patients with more aggressive disease.