Molecular changes of epidermal growth factor receptor (EGFR) and KRAS and their impact on the clinical outcomes in surgically resected adenocarcinoma of the lung
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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2015, Advances in Medical SciencesCitation Excerpt :Although a great deal of studies clearly demonstrate a predictive value of the activating EGFR and KRAS mutations for identifying non-small cell lung cancer (NSCLC) patients with advanced disease who are likely to benefit from EGFR tyrosine kinase inhibitors (TKIs) [13–17], the impact of gene copy number (CN) alterations remains uncertain [13,14,18,19]. Moreover, a relatively limited number of studies with contradictory results have been performed so far which analyze the prognostic significance of gene alterations in operable NSCLC patients after surgical resection and most of the studies included individuals of Asian ethnicity [20–25]. In order to clarify EGFR pathway aberrations in Polish patients with stage I–IIIA NSCLC and their significance for the post-operative clinical outcome, we examined the incidence of an increased EGFR, KRAS and HER2 gene CN in tumor cells.