Elsevier

Lung Cancer

Volume 59, Issue 1, January 2008, Pages 111-118
Lung Cancer

Molecular changes of epidermal growth factor receptor (EGFR) and KRAS and their impact on the clinical outcomes in surgically resected adenocarcinoma of the lung

https://doi.org/10.1016/j.lungcan.2007.08.008Get rights and content

Summary

Recent studies have reported that clinical response to epidermal growth factor receptor (EGFR) inhibitors is associated with somatic changes of EGFR in the advanced stage of lung cancer. However, there is no clear data demonstrating whether such molecular changes of EGFR per se can affect the clinical outcome of early stage cancer after surgical resection.

DNA mutations of EGFR and KRAS were investigated in 71 adenocarcinoma patients who received surgical resection. Fluorescence in situ hybridization (FISH) of EGFR gene amplification was performed in 48 samples.

We detected EGFR mutations in 25 patients (35.2%). EGFR mutation was more frequently found in cases with BAC features (13/22 (59.1%):13/49 (26.5%); p = 0.008) and in non-smokers (19/41 (46.3%):7/30 (23.3%); p = 0.047). However, the EGFR mutation was not associated with age, gender, or clinical stage. The amplification of EGFR copy was frequently observed in the female gender (12/29 (41.4%):3/19 (15.8%); p = 0.061) and in the advanced stage (≥Stage IIIA, 9/19 (47.4%):6/29 (20.7%); p = 0.051). KRAS mutations were present in five patients (7.0%) and none of them showed EGFR mutation. KRAS mutations (p = 0.000), male gender (p = 0.001), absence of BAC feature (p = 0.003), advanced stage (p = 0.039), and smoking history (p = 0.030) were poor prognostic factors for overall survival, whereas EGFR mutation (p = 0.184) and amplification (p = 0.756) were not.

The presence of EGFR mutation was not a prognostic factor of the clinical outcome of early lung cancer after surgical resection. This result provides an important message for the protocol design of future trials of EGFR inhibitors in early lung cancer. As the KRAS mutation was a poor prognostic factor and it presents reciprocally with EGFR mutation, KRAS mutation should be investigated in such trials.

DNA mutations of EGFR and KRAS were investigated in 71 adenocarcinoma patients who received surgical resection. Whereas KRAS mutation was a poor prognostic factor, EGFR mutation was not, and its presence per se did not affect the clinical outcome of early lung cancer after surgical resection.

Introduction

Non-small cell lung cancer (NSCLC) is the leading cause of cancer related death in many developed countries and is reported to be the cause of death in more than 1.3 million patients annually worldwide (http://www.who.int/mediacentre/factsheets/fs297/en/). Despite the development of modern treatment modalities, the mortality of lung caner has remained high for several decades. Recently, a better understanding of the biology of NSCLC has emerged and new therapeutic challenges targeting a specific molecule are under development.

One target that has been studied extensively is the epidermal growth factor receptor (EGFR). New therapeutic agents that inhibit EGFR tyrosine kinase (EGFR TK) and several positive clinical trial results pointed at EGFR as an attractive therapeutic target for patients with NSCLC [1], [2], [3], [4].

However, not every patient benefits from treatment with an EGFR TK inhibitor whereas about 10–30% of patients have rapid and often dramatic clinical responses. These observations prompted investigations to determine which patients were most likely to benefit from treatment with EGFR TK inhibitors. Lynch et al. investigated the entire coding region for EGFR in tumor specimens and demonstrated specific mutations in the EGFR gene correlated with clinical responsiveness to the EGFR TK inhibitors and suggested screening for such mutations may identify patients who will have response to EGFR TK inhibitors [5]. As a consequence, interest has grown in the clinical relevance of the EGFR mutation.

Our previous study as well as others’ reported that clinical response to EGFR inhibitors was associated with somatic changes of EGFR in the advanced stage of lung cancer [5], [6], [7], [8], [9], [10]. However, there is no clear data demonstrating whether such molecular change of EGFR per se can act as a prognostic marker in early stage cancer after surgical resection.

This study was designed to investigate the clinical impact of EGFR mutation in patients with adenocarcinoma of the lung and who had undergone surgical resection. We examined whether presence of somatic mutations in the EGFR gene was a prognostic factor to predict the clinical outcomes of patients with lung adenocarcinoma after curative resection.

Section snippets

Sample collection

Among the 653 patients who underwent surgical resection for primary lung cancer between December 2000 and April 2004 at Seoul National University Hospital, we selected 71 patients whose pathologic diagnoses were adenocarcinomas and whose frozen specimens were available from our Lung Cancer Tissue Bank. Informed consents for tissue collection and gene analyses for research purpose were obtained from individual patients preoperatively according to the policy of Lung Cancer Tissue Bank, Cancer

EGFR mutations, EGFR amplification and KRAS mutation

EGFR mutations were observed in 25 patients (35.2%) at 8 different locations (Table 1). Clinical variables, such as age, gender, smoking status, TNM stages, and presence of BAC features were tested as to whether they are associated with EGFR mutation. EGFR mutation was more frequently found in cases with BAC features (p = 0.008) and in never smokers (p = 0.047). However, it was not associated with age, gender, or clinical stage (Table 2). When we tested the association between EGFR mutation and

Discussion

Recent development of EGFR TK inhibitors and positive results in phase II trials lead these drugs as an attractive therapeutic target for patients with NSCLC [1], [2], [3], [4]. However, not all of the trials performed with these agents have been positive. Randomized, double-blind phase III comparison of gefitinib versus placebo as second- or third-line therapy for advanced NSCLC, failed to demonstrate a significant difference in the primary endpoint of median survival (www.astrazeneca.com). In

Conflict of interest statement

None declared.

Acknowledgment

This paper was partially supported by a grant no. 04-2005-032 from the Seoul National University Hospital Research Fund and Sang Koo Hahn Research Fund.

We appreciate Mr. John Kim for his assistance of English grammar and expression.

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