• Home  ›
• Diagnostic tests  ›
• Colorectal  ›
• EGFR

 

The Epidermal Growth Factor Receptor (EGFR) Pathway - Gene and Protein Alterations

          Key facts

• EGFR plays a key role in the growth and survival of many solid tumour types
• A wide range of small molecule and antibody-based therapeutics that target EGFR are currently available or in development
• Alterations in the gene encoding EGFR and its protein product may lead to altered response to EGFR-targeted treatments

The Epidermal Growth Factor Receptor (EGFR; also known as EGFR1 and HER1) is a validated anticancer target, against which there are several new agents currently licensed for use, and many newer agents in various stages of development. The importance of EGFR lays in its key role as a receptor tyrosine kinase, controlling two major cellular signalling pathways, one stimulating cell proliferation and growth, and the other controlling the so-called survival pathway (see Figure 1).

 

In a variety of cancers these pathways appear to be dysfunctional. This can arise in a number of ways; through chronic activation of the EGFR receptor itself, or through the presence of activating mutations in certain genes encoding downstream intermediates in the two pathways activated by EGFR, namely RAS, RAF, and PI3K.

Which is the correct test?

In different cancer types, in particular those of lung and colorectum, certain subsets of patients have been shown to benefit from these therapies. In non-small-cell lung cancer there is compelling evidence that response to both gefitinib (Iressa™) and erlotinib (Tarceva™) is associated with EGFR gene copy number, as well as with the presence of certain activating mutations of the EGFR gene. The picture is less clear with respect to the expression of the receptor protein itself, and the use of immunohistochemistry to evaluate levels of expression is of questionable utility.

In colorectal cancer there is also evidence that response to the EGFR-targeting antibody treatments cetuximab (Erbitux™) and panitumumab (Vectibix™) is linked to gene copy number, as detected by Fluorescence In Situ Hybridisation (FISH). In addition, for these agents it is suggested that they are suitable only for patients who demonstrate over-expression of EGFR protein, as detected by immunohistochemistry.

While the picture is less clear in breast cancer, some relationships have been established. Activating mutations of the EGFR gene are not seen in breast cancer, nor is amplification common. However; a significant proportion of breast cancers do show enhanced expression of EGFR protein by immunohistochemistry; these tumours are often high grade, hormone receptor-negative, and with high proliferation. It has been suggested that these patients might benefit from antiEGFR-targeted therapies.

It is also recognised that some patients may respond to newer agents targeted specifically at EGFR, while not over-expressing EGFR protein, and there remain questions about which test is appropriate for demonstrating utility of these agents.

A breast tumour immuno-stained for EGFR with the DAKO PharmDx kit.

 EGFR evaluation at Source Bioscience

FISH for amplification and gene copy number

Source Bioscience offers a validated, standardised EGFR FISH test, which can be used to demonstrate EGFR gene amplification or increased copy number due to polysomy. FISH evaluation to identify EGFR gene amplification is assessed visually over a number of representative areas within the sample to account for heterogeneity. The sample is assigned a score in the form of a ratio, relating the number of copies of the EGFR gene to the number of copies of chromosome 7. A score of >2 indicates gene amplification.

 Mutations and other polymorphisms

We also offer the CE-marked Therascreen™ EGFR29 Mutation Test, which is suitable for FFPE archival material, and detects the 29 most common somatic mutations found in the EGFR gene. several of which are known to affect sensitivity to small molecule inhibitors of this receptor. The results of mutation tests are reported as positive or negative for the presence of a particular mutation and the relative frequency of that mutation in the tumour sample.

Note: There is a growing body of evidence that certain inherited gene alterations (SNPs or single nucleotide polymorphisms) in the EGFR gene may be linked to treatment response in breast and lung cancers. Testing for polymorphisms is also available through Source BioScience Healthcare (please contact us for details).

EGFR protein expression

Immunohistochemical evaluation of EGFR protein expression in tumour samples is also available using the DAKO PharmDx kit. Tumour samples immunostained for EGFR are assessed visually by a registered pathologist and assigned a semi-quantitative score based upon criteria of staining intensity and distribution, using an FDA-approved algorithm.

Reference:

Jimeno and Hidalgo (2006) Pharmacogenomics of epidermal growth factor (EGFR) inhibitors. Biochim Biophys Acta 1766:217

Cappuzzo et al. (2005) Epidermal Growth Factor Receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643

Moroni et al. (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6:279

Chan et al. (2006) The role of the epidermal growth factor receptor in breast cancer. J Mammary Gland Biol Neoplasia 11:3