A multicentre phase II gene expression profiling study of putative relationships between tumour biomarkers and clinical response with erlotinib in non-small-cell lung cancer

Abstract

Background: Identification of appropriate markers for predicting clinical benefit with erlotinib in non-small-cell lung cancer (NSCLC) may be able to guide patient selection for treatment. This open-label, multicentre, phase II trial aimed to identify genes with potential use as biomarkers for clinical benefit from erlotinib therapy.Methods: Adults with stage IIIb/IV NSCLC in whom one or more chemotherapy regimen had failed were treated with erlotinib (150 mg/day). Tumour biopsies were analysed using gene expression profiling with Affymetrix GeneChip® microarrays. Differentially expressed genes were verified using quantitative RT–PCR (qRT–PCR).Results: A total of 264 patients were enrolled in the study. Gene expression profiles found no statistically significant differentially expressed genes between patients with and without clinical benefit. In an exploratory analysis in responding versus nonresponding patients, three genes on chromosome 7 were expressed at higher levels in the responding group [epidermal growth factor receptor (EGFR), phosphoserine phosphatase (PSPH) and Rap guanine nucleotide exchange factor 5 (RAPGEF5)]. Independent quantification using qRT–PCR validated the association between EGFR and PSPH overexpression, but not RAPGEF5 overexpression, and clinical outcome.Conclusions: This study supports the use of erlotinib as an alternative to chemotherapy for patients with relapsed advanced NSCLC. Genetic amplification of the EGFR region of chromosome 7 may be associated with response to erlotinib therapy.

Quantitative Chemical Proteomics Profiling Differentiates Erlotinib from Gefitinib inEGFRWild-Type Non–Small Cell Lung Carcinoma Cell Lines

“…EMT will be more relevant for invasive tumor growth in vivo, and clinical studies have already shown the link between E-cadherin (CDH1) levels and response to erlotinib (12). The retrospective analysis presented here on data from the MERIT trial confirms that patients with higher expression of E-cadherin (CDH1) have an increased clinical benefit from treatment with erlotinib, as previously published (18). A similar analysis has been conducted on gefitinib by Kook and colleagues and did not show any correlation of E-cadherin expression with response rate or with progression-free survival and overall survival in patients with inoperable stage IIIB/IV NSCLC treated with gefitinib (37).…”

“…The next steps were to investigate a potential structural explanation for this binding discrepancy between the 2 compounds, as well as using an EMT-inducible cellular model to assess their respective functional effect on EMT. These findings were further correlated with gene expression data from the MERIT open-label, multicenter, phase II clinical trial, which aimed to identify genes with potential as biomarkers for clinical benefit from erlotinib therapy (18).…”

“…Tumor biopsies were analyzed using gene expression profiling with Affymetrix GeneChip Human Genome U133A Array (Affymetrix). All gene expression results described here (fold changes and P values) are derived from the statistical analysis already reported (18). We specifically looked at differences between gene expression profiles of patients with and without clinical benefit from erlotinib.…”

High EGFR mRNA expression is a prognostic factor for reduced survival in pancreatic cancer after gemcitabine-based adjuvant chemotherapy

“…Many studies have identified activating EGFR gene mutations in only a small number of cases in PDAC patients (33,34). However, Tan et al demonstrated that higher genetic amplification of the EGFR region of chromosome 7 is associated with better clinical responses to erlotinib treatment in advanced NSCLC patients (35). Therefore, there is a possibility that quantitative analysis of EGFR mRNA expression levels could be helpful in predicting sensitivity to erlotinib in PDAC patients.…”

Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies

“…Furthermore, as showed in the TRIBUNE phase Ⅲ trial, it was first studied in United States, Asia and Europe, but did not have consistent results following approval by the US Food and Drug Administration (FDA) and European Medicine Agency (EMEA) in firstline chemotherapy patients [27,30,61,62,68] . The genetic mutation of EGFR in exons 19 and 21 of chromosome 7 demonstrated an association with response to erlotinib [40,68] . Therefore, erlotinib is approved for the treatment of patients with refractory disease.…”