Combined analysis of molecular and clinical predictors of gefitinib activity in advanced non-small cell lung cancer: Epidermal growth factor receptor mutations do not tell the whole story

Athanassios Argiris, Thomas Hensing, Anjana Yeldandi, Smita Patel, Adekunle Raji, Charles Sturgis, Gregory Masters, William Gooding, Michael Pins, Jill Kolesar

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been introduced in the standard therapy of non-small-cell lung cancer (NSCLC), but they benefit a minority of patients. The study of molecular markers may identify the subset of patients who are the most appropriate to treat with these agents. METHODS: We analyzed 43 patients with advanced NSCLC who were treated with gefitinib, an oral EGFR tyrosine kinase inhibitor, were included in analysis. We evaluated EGFR in tumor tissue by using immunohistochemistry and fluorescence in situ hybridization. We also studied downstream molecules (AKT, ERK, p38 MAPK) and their activation status and the presence of EGFR mutations in tumor tissue in exons 18-21. RESULTS: Three patients had tumors with EGFR mutations, all of which had EGFR gene amplification with a ratio of 2 or greater (p= 0.001). There was no correlation between EGFR protein expression and gene amplification. Six patients (14%) achieved an objective response and nine (21%) had stable disease; the median survival was 162 days. EGFR mutations, high levels of AKT protein expression, rash of any grade, and no history of smoking were predictive of disease control (objective response plus stable disease). Only 3 of 15 patients (20%) with disease control had an EGFR mutation. On multivariate analysis, rash and AKT were independent predictors of disease control. Patients with rash survived longer than patients without rash. CONCLUSIONS: EGFR mutation-positive tumors are present in a small fraction of patients who achieve disease control with gefitinib. Other molecular markers, such as AKT, need to be further evaluated. Clinical parameters remain major determinants of gefitinib activity in NSCLC.

Original languageEnglish (US)
Pages (from-to)52-60
Number of pages9
JournalJournal of Thoracic Oncology
Volume1
Issue number1
DOIs
StatePublished - Jan 1 2006
Externally publishedYes

Keywords

  • Epidermal growth factor receptor
  • Gefitinib
  • Non-small-cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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