1. ¹Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
2. ²Biostatistics and Data Management Section, National Cancer Institute, Bethesda, MD, USA
3. ³Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
4. ⁴Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands
5. ⁵Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Correspondence: Dr G Giaccone, E-mail: giacconeg@mail.nih.gov

Received 6 May 2008; Revised 12 August 2008; Accepted 20 October 2008; Published online 2 December 2008.

Abstract

The purpose of this study is to evaluate the prognostic value of the combined assessment of multiple molecular markers related to the epidermal growth factor receptor (EGFR) pathway in resected non-small cell lung cancer (NSCLC) patients. Tumour specimens of 178 NSCLC patients were collected and analysed for EGFR and KRAS mutation status by DNA sequencing, and for EGFR copy number by fluorescent in situ hybridisation. Tissue microarrays were generated and used to determine the expression of multiple EGFR pathway-related proteins by immunohistochemistry. We analysed the association between each marker and patient prognosis. Univariate analyses for each clinical variable and each molecular marker were performed using Kaplan–Meier curves and log-rank tests. From these results, we selected the variables KRAS mutations and expression of cytoplasmic EGFR, granular pERK, nuclear pSTAT3, cytoplasmic E-cadherin and cytoplasmic pCMET to enter into a Cox proportional hazards model, along with stage as the strongest clinical variable related with prognosis. Of the EGFR-related markers evaluated here, the markers EGFR, pERK, pSTAT3, E-cadherin, pCMET and mutations in KRAS were associated with survival when analysed in combination in our patient cohort, with P=0.00015 as the P-value for a test of the additional impact of markers on prognosis, after taking stage into consideration. Confirmation of the impact of these markers in independent studies will be necessary.