Epidermal growth factor receptor gene amplification in surgical resected Japanese lung cancer☆
Introduction
Despite improved surgical techniques and systemic chemotherapy treatments, patients with non-small cell lung carcinoma (NSCLC) have about 15% 5-year survival after initial diagnosis. The epidermal growth factor receptor (EGFR) that was discovered almost three 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 [2], [3], [4], [5], [6]. On the other hand, Cappuzzo et al. reported that EGFR amplification by fluorescence in situ hybridization (FISH) and high EGFR protein expression has been associated with responsiveness to gefitinib [7]. Takano et al. showed that EGFR gene mutation and increased copy numbers both predicted gefitinib sensitivity in patients with recurrent NSCLC [8], although this Japanese report based on polymerase chain reaction (PCR) assay. Recently, several reports have shown that EGFR FISH assay predicted for response to anti-EGFR antibody treatment in colon cancer [9], [10]. On the other hand, the trend for shorter survival in EGFR FISH positive in NSCLC was reported [11], [12].
The prognostic association of EGFR overexpression in lung cancer is a controversial issue. Different conclusions regarding prognostic significance may reflect differences in detection methods, reagents, assay cutoff points, and population characteristics. The EGFR gene, located on chromosome 7p12, has been found amplified in low frequency by Southern blot [13] and polymerase chain reaction analyses [14], [15]. To determine the EGFR increased copy number and correlation with clinico-pathological features in Japanese NSCLC, we retrospectively performed FISH and immunohistochemistry, according to the Cappuzzo criteria [7]. The findings were compared to the clinico-pathologic features of lung cancer.
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Patients
This was a retrospective study and the study group included 109 lung cancer patients who had undergone surgery at the Department of Surgery II, Nagoya City University Medical School. Written informed consent was obtained and the institutional ethics committee of the Nagoya City University Medical School approved the study. The lung tumors were classified according to the general rule for clinical and pathological record of lung cancer in Japan. All tumor samples were immediately frozen and
EGFR gene copy number by FISH
First we assessed EGFR copy number by FISH according to the Cappuzzo et al. criteria [7]. High polysomy for the EGFR gene was present 27.5% (n = 30), and gene amplification in 5.5% (n = 6) (Fig. 1). For FISH-positive tumors, the proportions of well, moderately, and poorly differentiated histopathology were 45.7% (16/35), 40% (14/35), and 14.3% (5/35), respectively. One case was adenosquamous carcinoma. And for FISH-negative tumors, the corresponding proportions were 65.7% (46/70), 20.0% (14/70),
Discussion
We obtained findings that EGFR increased copy number, detected by FISH according to the Cappuzzo et al. criteria, was associated with shorter survival of NSCLC, even within the EGFR-mutant cases. This was in agreement with the recent reports that EGFR gene amplification was prognostic factor for NSCLC [5], [12]. Another report suggested that NSCLC patients with resected tumors carrying high EGFR gene copy number have a tendency to a shorter survival [20]. In a phase III placebo-controlled study
Conflict of interest
None declared.
Acknowledgements
We thank Nihon Gene Research Laboratories Inc. (Drs. Narusawa and Shimada) for suggesting that they use fluorescence in situ hybridization to test for epidermal growth factor receptor gene amplification.
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Grant Sponsor: AstraZeneca Research Grant 2004, Grand-in-Aid for Research in Nagoya City University (2006), and Grants-in-Aid for Scientific Research, Japan Society for the Promotion of Science (JSPS) (Nos. 19390367, 18390381, 18659407).