Review
Mutations of the epidermal growth factor receptor in non-small cell lung cancer – Search and destroy

https://doi.org/10.1016/j.ejca.2005.07.031Get rights and content

Abstract

The targeting of the ATP binding pocket of the epidermal growth factor receptor (EGFR) tyrosine kinase, by the small molecule drugs gefitinib and erlotinib, represents a promising new therapeutic strategy in non-small cell lung cancer. However, it is now apparent that only a subset of patients responds to such treatment. Two publications in early 2004 reported the presence of activating mutations in the EGFR tyrosine kinase gene conferring exquisite sensitivity to these drugs. Several publications have since reported prospective data consistent with this finding. This brief review summarises the mutation data from 15 such studies in terms of mutation frequency by clinicopathological features and correlation with response to tyrosine kinase inhibition. A new paradigm for the routine detection of such mutations is needed to facilitate patient selection for treatment and further studies.

Introduction

Lung cancer is the leading cause of cancer-related death in the developed world. Recent statistics demonstrate that the disease accounts for around 183,000 fatalities across Europe with over 33,000 of these in the UK 1, 2. There is an estimated incidence of 1.2 million new cases each year worldwide [3]. Non-small cell lung cancer (NSCLC) makes up 80% of all primary pulmonary tumours. For advanced NSCLC median survival remains poor at 7.9 months and only approximately one third of patients survive for one year or more despite conventional combination chemotherapy. Moreover, such therapy is associated with considerable toxicity 4, 5. Clearly, there is a requirement for the development of more effective systemic treatment with fewer side-effects.

Recent unravelling of the molecular aspects of cancer biology and improvements in biotechnology and clinical pharmacology have permitted the development of novel drugs against specific targets associated with oncogenic drive as part of the new therapeutic armoury. An example is inhibition of the epidermal growth factor receptor (EGFR) system. To date, two classes of drugs have been licensed in this area: small molecule tyrosine kinase inhibitors (TKI) and monoclonal antibodies to the EGFR. The clinical studies however, show only modest numbers of clinical responders. One area of current research focuses upon the identification of distinguishing factors between those who derive benefit from those who do not – information which will aid patient selection. The last twelve months have seen a flood of publications documenting mutations within the EGFR gene and their correlation with tumour sensitivity to tyrosine kinase inhibition. In this brief review, we aim to bring together and summarise the mutation data from 15 scientific reports and discuss the possible impact on the therapy of NSCLC.

Section snippets

EGFR as a molecular target for cancer therapy

The erb-B (HER) family is one of several known receptor tyrosine kinase systems involved in cellular signalling 6, 7 and comprises four different receptors of which EGFR (erbB1) was the first discovered; the other family members are erbB2 (HER2), erbB3 (HER3) and erbB4 (HER4). The structure of EGFR consists of an extracellular ligand-binding domain, a transmembrane domain and a cytoplasmic component containing a tyrosine kinase entity. The erb-B family of receptors transduce effects of

EGFR tyrosine kinase inhibition

Currently, two tyrosine kinase inhibitors are in clinical use: gefitinib and erlotinib 16, 17. These small-molecule agents compete with and prevent the binding of adenosine triphosphate (ATP) at the ATP-binding region within the EGFR tyrosine kinase thereby inhibiting tyrosine residue phosphorylation and signalling. Trials of single agent use in chemotherapy-refractory NSCLC patients have demonstrated response rates of 9–18% and median survival ranged from 6.7 to 8.4 months 18, 19, 20, 21.

EGFR mutations are common in East Asian female non-smokers

The middle of 2004 saw two separate reports published describing mutations within the TK domain of the EGFR in NSCLC 26, 27. Since then, a multitude of data has emerged from different groups from around the world. The EGFR gene consists of 118 kbp in 28 exons; the TK domain is encoded within exons 18–21. Fifteen studies 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 have reported mutational analyses of this area in over 3000 cases of NSCLC (Table 1). The overall mutation rate

Mutation hotspots in the TK domain

Although a variety of different mutations are seen spanning the entire EGFR TK domain, 89% reside in exons 19 and 21 (Fig. 1). Of note are two particular mutations: deletion of amino acids 746–750 in exon 19 (del(746–750)) and leucine to arginine substitution at 858 in exon 21 (L858R) which together account for approximately 66% of all alterations (Fig. 2). Interestingly, the majority of other mutations seen in exon 19 are variants of del(746–750) and approximately 80% involve the deletion of

Sensitivity to TK inhibition

Patients with NSCLC responsive to gefitinib or erlotinib are more likely to harbour mutations than not (76.7% vs 23.3%). However, 12.3% of those NSCLCs carrying mutations still progress on TKIs underlining the imperfect correlation. Furthermore, there are probably alternative mechanisms conferring sensitivity given that not all responders carry mutations; this is exemplified by the fact that 86.8% of those achieving stable disease possess wild-type EGFR. It may be that some other mechanism

Other mutations within the EGFR system

Apart from within the EGFR TK domain, few other mutations have been observed in other receptors of the EGFR family. 1011 assorted tumour samples and cell lines have been sequenced for HER2 mutations amongst which only 20 have been found; 17 of these are from NSCLC tumours (overall HER2 mutation rate in NSCLC: 2%). Notably, all but one of these mutations are exon 20 in-frame duplications or insertions 50, 51. To date no data is available as to correlation of HER2 mutations with tumour

Do EGFR TK mutations occur in other epithelial tumours?

DNA sequencing of 243 other epithelial tumours in one study, has shown no EGFR TK mutations [31]. However, there has been a recent report of mutations in 3 of 41 (7.3%) cases of squamous cancer of the head and neck; interestingly, all were exon 19 deletions of residues 746–750, the most common deletion found in NSCLC; however, all 3 patients were male smokers [53]. It will be important to determine if cases of this genotype may also be sensitive to gefitinib or erlotinib therapy.

Mutations in NSCLC: search and destroy

Clearly, the presence of EGFR TK mutations partially correlates with tumour sensitivity to currently available TKIs. Such mutations have also been shown to confer resistance to conventional chemotherapy. There are therefore major implications to therapeutic decision-making – perhaps the earlier use of gefitinib or erlotinib is justified in such patients. It is just a matter of time before patients with newly-diagnosed NSCLC and their relatives will insist upon EGFR genotyping to aid clinical

Conflict of interest statement

None declared.

Acknowledgement

This work is supported by a grant administered by the University Of Kent.

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