Epidermal growth factor receptor messenger RNA expression, gene dosage, and gefitinib sensitivity in non-small cell lung cancer
ABSTRACT Epidermal growth factor receptor (EGFR) mRNA expression and EGFR gene dosage by quantitative PCR in tumor samples obtained from patients with gefitinib-treated non-small cell lung cancer were analyzed in order to determine the association with treatment outcome, clinical, and biological features [EGFR copy number by fluorescent in situ hybridization (FISH), EGFR tyrosine kinase mutations, and EGFR protein expression].
EGFR mRNA expression was measured by real-time quantitative reverse transcription-PCR in 64 patients, and EGFR gene dosage was analyzed by real-time quantitative PCR in 82 patients from paraffin-embedded specimens.
EGFR mRNA expression was higher in responders to gefitinib as compared with nonresponders (P = 0.012). Patients with high EGFR mRNA expression (>5.01) had 43% response probability, whereas patients with low EGFR mRNA expression had 8% response probability (P = 0.006). Patients with high EGFR mRNA expression had longer median progression-free (5.3 versus 2.8 months, P = 0.028) but not overall survival (13.8 versus 10.9 months, P = 0.87). EGFR mRNA expression was higher in FISH-positive patients (P = 0.001) and in patients with positive EGFR immunostaining (P < 0.001) but not in patients with EGFR mutations (P = 0.19). EGFR gene dosage did not predict response (P = 0.54), progression-free (P = 0.73), or overall survival (P = 0.89). EGFR gene dosage was not associated with FISH positivity (P = 0.15), relative mRNA expression (P = 0.27), EGFR mutation status (P = 0.39), and EGFR protein expression (P = 0.35).
EGFR mRNA expression is a predictive biomarker for response to gefitinib and to progression-free survival after gefitinib treatment. EGFR gene dosage is neither predictive for response nor progression-free nor overall survival.
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ABSTRACT: Cancer is one of the major dreaded diseases causing high mortality. Lung cancer is second in position of all cancer related deaths and mainly divided into two morphologic sub-types: small-cell lung cancer and non-small cell lung cancer (NSCLC). NSCLC is an aggressive neoplasm which hardly responds to any conventional chemotherapy. Epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinase that is mainly over-expressed in NSCLC. EGFR is mainly involved in the pathogenesis and progression of different carcinoma. In vivo and in vitro studies suggest that EGFR and EGF like peptides are often over-expressed in human NSCLC and these proteins are able to induce cell transformation. The conventional therapies mostly inhibit the EGFR activity and expression level in human NSCLC with the use of some EGFR-inhibitors like HKI-272, EKB569, CL-387785 etc. and some synthetic chemotherapeutic drugs like erlotinib, gefitinib, plumbagin, docetaxel, cisplatin etc., alone or in combination of two or more drugs. These therapies selectively act by competitive inhibition of the binding of adenosine triphosphate to the tyrosine kinase domain of the EGFR, resulting in inhibition of the EGFR signaling pathway. But these chemotherapeutic drugs have some cytotoxic activities to the normal cells and have some adverse side-effects. Recent studies on some traditional alternative therapies including some herbal and plant extracts, active ingredients like curcumin, different homeopathic drugs, etc. can target EGFR-signalling in NSCLC with less toxic side-effects are being currently developed.05/2013; 3(2). DOI:10.5667/tang.2012.0048
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ABSTRACT: The epidermal growth factor receptor (EGFR) and KRAS gene status in paired primary non-small cell lung cancer (NSCLC) and metastatic tumours has been investigated by many studies, but remains controversial. We systematically reviewed studies in English of EGFR and KRAS gene status in primary and corresponding metastatic NSCLC up to 15 January 2014. Studies were selected rigorously from PubMed, EMBASE, as well as Cochrane Library databases. We carried out a meta-analysis to clarify EGFR mutations, EGFR amplification, positive rate of EGFR protein expression and KRAS mutations in primary and corresponding metastatic NSCLC. Our data suggested that the overall EGFR mutation rate, gene copy number, protein expression were not different between primary tumours and corresponding metastases, with the pooled odd ratios and 95% confidence interval 1.043 (0.686–1.586, P = 0.844), 0.604 (0.355–1.027, P = 0.063) and 1.447 (0.948–2.208, P = 0.087), respectively. The overall KRAS mutation rate of primary tumours was not different from that of matched metastases, with the odds ratio and 95% confidence interval being 1.224 (0.808–1.856, P = 0.340). The discordant rates of EGFR and KRAS mutations in paired primary and metastatic NSCLC were 14.5 and 16.7%, respectively. Among the discordant gene mutations in primary and metastatic lesions, the frequency of occurrence of mutation was not different from the frequency of loss of mutation for EGFR (P = 0.093) and KRAS gene (P = 0.227). These results indicate that EGFR and KRAS mutations are present frequently in metastases and occur before metastasis. Therefore, routine analysis of EGFR or KRAS gene status both in primary and metastatic tumours is not recommended.Clinical Oncology 10/2014; 27(1). DOI:10.1016/j.clon.2014.09.014 · 2.83 Impact Factor
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ABSTRACT: Activating epidermal growth factor receptor (EGFR) mutations are recognized biomarkers for patients with metastatic non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). EGFR TKIs can also have activity against NSCLC without EGFR mutations, requiring the identification of additional relevant biomarkers. Previous studies on tumor EGFR protein levels and EGFR gene copy number revealed inconsistent results. The aim of the study was to identify novel biomarkers of the response to TKIs in NSCLC by investigating whole genome expression at the exon-level. We used exon arrays and clinical samples from a previous trial (SAKK19/05) to investigate the expression variations at the exon-level of 3 genes potentially playing a key role in modulating treatment response: EGFR, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and vascular endothelial growth factor (VEGFA). We identified the expression of EGFR exon 18 as a new predictive marker for patients with untreated metastatic NSCLC treated with bevacizumab and erlotinib in the first line setting. The overexpression of EGFR exon 18 in tumor was significantly associated with tumor shrinkage, independently of EGFR mutation status. A similar significant association could be found in blood samples. In conclusion, exonic EGFR expression particularly in exon 18 was found to be a relevant predictive biomarker for response to bevacizumab and erlotinib. Based on these results, we propose a new model of EGFR testing in tumor and blood.PLoS ONE 09/2013; 8(9):e72966. DOI:10.1371/journal.pone.0072966 · 3.53 Impact Factor