E-cadherin expression and epidermal growth factor receptor mutation status predict outcome in non-small cell lung cancer patients treated with gefitinib

Department of Pulmonary Medicine/Infection and Oncology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan.
Oncology Reports (Impact Factor: 2.3). 03/2008; 19(2):377-83. DOI: 10.3892/or.19.2.377
Source: PubMed


It is known that an epidermal growth factor receptor (EGFR) gene mutation(s) is present in a percentage of non-small cell lung cancers (NSCLCs). Gefitinib, an inhibitor of the tyrosine kinase activity of EGFR, is effective on most of them. The EGFR mutation status alone cannot fully predict the response to gefitinib and the prognosis for the patients. We hypothesized that information on the expression levels of phosphorylated-EGFR and -Akt, and E-cadherin, alone or in combination with information on the EGFR mutation, may refine our ability of prediction. We investigated 24 NSCLCs that had recurred after surgery and were treated with gefitinib. Specimens resected by surgery were subjected to the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp reaction to determine the EGFR mutation status, and to immunohistochemical staining of phosphorylated-EGFR and -Akt, and E-cadherin to determine their expression levels. The EGFR mutation status was predictive of responsive disease (complete response: CR + partial response: PR) and controlled disease (CR + PR + stable disease: SD). Positive E-cadherin staining was predictive of longer time to progression (12.4 vs. 5.9 months, p<0.05) and overall survival (OS) (18.4 vs. 13.0 months, p<0.05). Together the patients with an EGFR mutation and the patients with positive E-cadherin staining defined a patient group with a median OS of 18.4 months and excluded the patient group with the median OS of 3.7 months. Neither p-Akt nor p-EGFR staining was associated with the response and survival. In patients with surgically resected NSCLC tumors, the EGFR mutation status and E-cadherin staining can select patients who will benefit from gefitinib therapy.

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    • "Several hypotheses for this differential response have been proposed. As tumor cells dedifferentiate and take on a more mesenchymal phenotype, EMT mechanisms may be involved in modulating EGFR activation and signaling or in activating alternative downstream targets that do not rely exclusively on the EGFR pathway (such as AKT), resulting in a decreased response to EGFR inhibitors (Figure 4) [Voulgari and Pintzas, 2009; Miyanaga et al. 2008; Andle and Rustgi, 2006] Data suggest that E-cadherin expression (a reliable marker of EMT) may be responsible for inhibiting EGFR activity by decreasing receptor mobility and ligand affinity [Andle and Rustgi, 2006; Yauch et al. 2005; Fedor-Chaiken et al. 2003]. Immunohistochemical staining of E-cadherin and vimentin in 62 unselected primary NSCLCs revealed the frequency of the epithelial phenotype (E-cadherin positivity) to be significantly greater in people with EGFR mutations than in the wild-type EGFR tumors [Deng et al. 2009]. "
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    • "Such a technique has been applied to search for K-Ras mutations in various tumour samples (Sun et al, 2002; Chen et al, 2004; Taback et al, 2004; Däbritz et al, 2005; Luo et al, 2006; Miyake et al, 2007). This method was also used to detect EGFR mutations in NSCLC (Nagai et al, 2005; Soh et al, 2006; Sutani et al, 2006; Tanaka et al, 2007; Miyanaga et al, 2008). As NSCLC, in particular adenocarcinoma, could often be mixed with normal cells, the aim of this study was to estimate the possibility to increase the sensitivity of the detection of K-Ras mutations on an EGFR-targeted naive NSCLC cohort, even in cases of low tumour cellularity and to evaluate its routine clinical usefulness. "
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