Abstract

BackgroundGefitinib, a small molecule tyrosine kinase inhibitor of the Epidermal Growth Factor Receptor (EGFR), has shown limited efficacy in the treatment of lung cancer. Recognized clinical predictors of response to this drug, specifically female, non-smoker, Asian descent, and adenocarcinoma, together suggest a genetic basis for drug response. Recent studies have addressed the relationship between response and either sequence mutations or increased copy number of specific receptor tyrosine kinases. We set out to examine the relationship between response and the molecular status of two such kinases, EGFR and HER2, in 39 patients treated with gefitinib at the BC Cancer Agency.MethodsArchival patient material was reviewed by a pathologist and malignant cells were selectively isolated by laser microdissection or manual recovery of cells from microscope slides. Genomic DNA was extracted from 37 such patient samples and exons 18–24, coding for the tyrosine kinase domain of EGFR, were amplified by PCR and sequenced. EGFR and HER2 copy number status were also assessed using FISH in 26 samples. Correlations between molecular features and drug response were assessed using the two-sided Fisher's exact test.ResultsMutations previously correlated with response were detected in five tumours, four with exon 19 deletions and one with an exon 21 missense L858R point mutation. Increased gene copy number was observed in thirteen tumours, seven with EGFR amplification, three with HER2 amplification, and three with amplification of both genes. In our study cohort, a correlation was not observed between response and EGFR mutations (exon 19 deletion p = 0.0889, we observed a single exon 21 mutation in a non-responder) or increases in EGFR or HER2 copy number (p = 0.552 and 0.437, respectively).ConclusionNeither mutation of EGFR nor increased copy number of EGFR or HER2 was diagnostic of response to gefitinib in this cohort. However, validation of these features in a larger sample set is appropriate. Identification of additional predictive biomarkers beyond EGFR status may be necessary to accurately predict treatment outcome.

Highlights

  • Gefitinib, a small molecule tyrosine kinase inhibitor of the Epidermal Growth Factor Receptor (EGFR), has shown limited efficacy in the treatment of lung cancer

  • In the previous study of 61 patients, those with Asian ethnicity and adenocarcinoma histology displayed a preferential response to gefitinib

  • In eight of thirty-eight tumours assessed we found ten mutations, five of which have been previously correlated with response (Figure 3)

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Summary

Introduction

A small molecule tyrosine kinase inhibitor of the Epidermal Growth Factor Receptor (EGFR), has shown limited efficacy in the treatment of lung cancer. The FDA has approved the use of two EGFR-targeted molecules, gefitinib ("Iressa" from Astra Zeneca) and erlotinib ("Tarceva" from Genentech/Roche) in the second- and third-line treatment of lung cancer Both of these drugs were designed to reversibly bind the ATP-binding pocket of the EGFR tyrosinekinase domain, thereby inhibiting autophosphorylation and stimulation of downstream signalling pathways resulting in inhibition of proliferation, delayed cell cycle progression, and increased apoptosis. In international phase II trials, ~28% of Japanese patients responded to gefitinib versus ~10% of patients of European descent as assessed by symptom improvement and tumour shrinkage [3,4] These population-specific findings have suggested that response to these drugs has a genetic component regional environmental factors have not been discounted

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