Significance of EGFR Protein Expression and Gene Amplification in Non-Small Cell Lung Carcinoma

Sanja Dacic, MD, PhD; Melina Flanagan, MD; Kathleen Cieply; Suresh Ramalingam, MD; James Luketich, MD; Chandra Belani, MD; Samuel A. Yousem, MD

Disclosures

Am J Clin Pathol. 2006;125(6):860-865. 

In This Article

Abstract and Introduction

We evaluated epidermal growth factor receptor (EGFR) protein expression by immunohistochemical analysis and EGFR gene amplification by fluorescence in situ hybridization in 199 consecutive newly diagnosed and surgically treated patients with primary non-small cell lung carcinoma (NSCLC) and correlated results with clinicopathologic findings. EGFR protein expression was more common in squamous cell carcinoma (SCC; 17 [26.2%]) than in adenocarcinoma (14 [11.1%]; P = .0076) and more frequently associated with EGFR amplification (8 [14.5%] vs 4 [3.6%] cases; P = .0208). Poor differentiation was associated with a higher average number of EGFR gene copies per cell (mean, 4.18; P = .0322) and a higher EGFR/chromosome 7 ratio (mean, 1.84; P = .0324). N0 disease showed a higher number of EGFR gene copies (mean, 4.196; P = .0163). SCCs demonstrated a higher EGFR/chromosome 7 ratio than adenocarcinomas (mean, 1.95 vs 1.47; P = .0324), particularly T1 tumors (mean, 1.79; P = .0243). Statistical analysis failed to show correlation between outcome and EGFR protein expression and gene amplification in early NSCLC. EGFR protein expression was uncoupled from gene amplification in most cases, although good correlation occurred in a subset of SCCs.

Despite improved surgical techniques and systemic chemotherapy treatments, patients with non-small cell lung carcinoma (NSCLC) have only 5% to 15% 5-year survival after initial diagnosis. The epidermal growth factor receptor (EGFR) that was discovered almost 3 decades ago has emerged as a leading target for the treatment of patients with NSCLC.[1] Inhibition of the EGFR pathway by a monoclonal antibody against the receptor or a small molecular inhibitor of the receptor tyrosine kinase is being evaluated as therapy for various malignant neoplasms. Recently, it has been shown that specific mutations in the EGFR gene may identify lung cancer patients with a good response to the tyrosine kinase inhibitor gefitinib.[2,3,4] These specific mutations most frequently occur in a subset of well- to moderately differentiated adenocarcinomas of the lung, particularly in the Asian, nonsmoker, female population.[5]

Because the response to other targeted agents such as trastuzumab and tamoxifen depends mainly on the level of expression of the target in the tumor, several trials have focused on EGFR protein expression but have failed to predict gefitinib sensitivity by EGFR protein levels as determined by immunohistochemical analysis or immunoblotting.[6,7] On the other hand, the prognostic significance of EGFR gene overexpression in NSCLC is uncertain, although its overexpression has been linked to poor prognosis in various solid tumors, including prostate, breast, colon, ovary, and head and neck.[8,9,10,11]

The significance of EGFR protein overexpression is still controversial.[12,13,14,15] Furthermore, mechanisms other than mutation and amplification might have a role in regulation of EGFR gene expression in NSCLC. Even though 2 EGFR inhibitors have been approved for the treatment of advanced NSCLC and there is increasing knowledge of underlying molecular mechanisms for targeted lung cancer therapies, there are no validated patient selection criteria for therapy with these agents. The focus of our study was to analyze the relationship between EGFR protein expression and gene amplification and to determine the potential prognostic significance of these results.

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