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.
"Another study noted increased response rate and prolonged progression-free but not overall survival in patients treated with gefitinib (Dziadziuszko et al., 2006). Recently, two consecutive studies reported that patients with EGFR exon 19 deletions had a longer survival than patients with EGFR L858R point mutations. "
[Show abstract][Hide abstract] 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.
"In this trial, EGFR mRNA expression was predictive of response to gefitinib therapy and for PFS after treatment, while EGFR gene dosage was not associated with a response to therapy or outcome. Also, high EGFR mRNA expression was correlated with increased EGFR gene copy number as evaluated by FISH . These findings support the use of qPCR to determine EGFR mRNA expression in NSCLC. "
[Show abstract][Hide abstract] ABSTRACT: Lung cancer is the leading cause of cancer deaths world-wide. Recent advances in cancer biology have led to the identification of new targets in neoplastic cells and the development of novel targeted therapies. At this time, two targeted agents are approved by the FDA in advanced non-small cell lung cancer (NSCLC): the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib, and the anitangiogenic bevacizumab. A third agent, cetuximab, which was recently shown to enhance survival when used with cisplatin and vinorelbine as first line therapy for advanced NSCLC, will likely be approved by regulatory agencies. With more than 500 molecularly targeted agents under development, the prospects of identifying novel therapies that benefit individual patients with lung cancer are bright.
"However, the point mutation T790M and an insertion mutation in exon 20 were associated with resistance to TKIs (Gazdar and Minna, 2005). Furthermore, recent studies have shown that the expression of EGFR as assessed by gene copy number, mRNA and protein levels could be used to predict responsiveness to therapy with TKIs (Hirsch et al, 2005; Taron et al, 2005; Dacic et al, 2006; Dziadziuszko et al, 2006; Endo et al, 2006). In addition, several clinicopathological characteristics, such as adenocarcinoma histology, non-smoking history, female gender and Asian origin, are also associated with a higher probability of response to TKIs, whereas the presence of K-RAS mutations seems to be correlated with primary resistance to these agents (Tokumo et al, 2005; Tsao et al, 2005; van Zandwijk et al, 2007). "
[Show abstract][Hide abstract] ABSTRACT: In non-small-cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) and K-RAS mutations of the primary tumour are associated with responsiveness and resistance to tyrosine kinase inhibitors (TKIs), respectively. However, the EGFR and K-RAS mutation status in metastases is not well studied. We compared the mutation status of these genes between the primary tumours and the corresponding metastases of 25 patients. Epidermal growth factor receptor and K-RAS mutation status was different between primary tumours and corresponding metastases in 7 (28%) and 6 (24%) of the 25 patients, respectively. Among the 25 primary tumours, three 'hotspot' and two non-classical EGFR mutations were found; none of the corresponding metastases had the same mutation pattern. Among the five (20%) K-RAS mutations detected in the primary tumours, two were maintained in the corresponding metastasis. Epidermal growth factor receptor and K-RAS mutations were detected in the metastatic tumours of three (12%) and five (20%) patients, respectively. The expressions of EGFR and phosphorylated EGFR showed I 0 and 50% discordance, in that order. We conclude that there is substantial discordance in EGFR and K-RAS mutational status between the primary tumours and corresponding metastases in patients with NSCLC and this might have therapeutic implications when treatment with TKIs is considered.
British Journal of Cancer 10/2008; 99(6):923-9. DOI:10.1038/sj.bjc.6604629 · 4.84 Impact Factor
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