EGFR and cancer
EGFR stands for Epidermal Growth Factor Receptor. In humans, EGFR can also be called ErbB-1 or HER1. EGFR is a cell-surface receptor that binds epidermal growth factors, resulting in the activation of various signalling pathways inside the cell. These signalling pathways can have various effects, including cell growth, proliferation and migration. EGFR activation requires several steps, including the binding of a growth factor to EGFR on the outside of the cell, and activation of an intracellular part of EGFR, which acts as a tyrosine kinase enzyme.
EGFR protein is encoded by the EGFR gene. When the gene is not mutated, the protein functions normally. However, certain mutations in the EGFR gene result in the expression of EGFR protein that is constitutively active. This causes uncontrolled cell growth and proliferation – a hallmark of a cancer cell. Such EGFR gene mutations can be found in several types of cancer, and are thus called oncogenic (cancer-causing). In cancer, oncogenic EGFR mutations are normally found only in the tumour and are not inherited.
EGFR signalling pathway causes cell growth and proliferation via several signalling molecules, including KRAS and BRAF. Oncogenic mutations in also these genes may cause cancer. The relevance of different genes may depend on the type of cancer.
The identification of the role of EGFR signalling pathway in cancer has led to the development of anti-cancer therapeutics directed against the EGFR protein, including Gefitinib (Iressa®, AstraZeneca) and Erlotinib (Tarceva®, Roche) for non-small-cell lung cancer, and Panitumumab (Vectibix®, Amgen) and Cetuximab (Erbitux®, Merck Serono) for colorectal cancer. The first two are small compound inhibitors of the intracellular tyrosine kinase region of EGFR, whereas the latter two are antibody proteins that block the extracellular region of EGFR.
EGFR gene mutations and EGFR tyrosine kinase inhibitors
The best studied oncogenic EGFR mutations are situated in the tyrosine kinase region of the EGFR gene. Oncogenic EGFR tyrosine kinase mutations tend to cause constitutive activation, on which the tumour relies to maintain its growth; no growth factor is required for EGFR signalling. Therefore, certain anticancer therapeutics that target the EGFR tyrosine kinase are only or especially effective in tumours with a mutated EGFR tyrosine kinase gene.
These therapeutics include Gefitinib (Iressa®) for non-small cell lung cancer (NSCLC). The European Medicines Acency has approved Gefitinib as first line treatment of NSCLC in patients whose tumours have mutated EGFR gene. In the UK, National Institute for Health and Clinical Excellence (NICE) has approved Gefitinib for 1st line treatment of adults with locally advanced or metastatic NSCLC as long as the tumour has mutated EGFR gene. This authorisation is based on evidence from a pivotal Phase III study comparing IRESSA with chemotherapy, IPASS.
EGFR mutation testing in NSCLC
The tumours of all NSCLC patients considered for Gefitinib therapy must be tested for the presence of EGFR mutations before the drug can be prescribed, as Gefitinib is unlikely to be effective in patients without EGFR mutations.
Lab21 offers highly sensitive EGFR mutation testing using CE-certified methods. Our test turnaround time is only 5 working days.
References- National Institute for Health and Clinical Excellence: TA192 (non-small-cell, first line) – gefitinib: guidance, 28 July 2010.
- Kim et al.Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): A randomised phase III trial. Lancet 2008; 372(9652): 1809-1818.
- Mok T. Phase III, Randomised, Open-Label, First-Line Study Of Gefitinib Vs Carboplatin/Paclitaxel (C/P) In Clinically Selected Patients With Advanced Non-Small-Cell Lung Cancer (NSCLC), Presented at the European Society of Medical Oncology meeting, Stockholm. Abs LBA2, 2008. (IPASS)
- Newton CR, Graham A, Heptinstall LE et al. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res. 1989; 17: 2503-2516.
- Whitcombe D, Theaker J, Guy SP, Brown T, Little S. Detection of PCR products using self-probing amplicons and fluorescence. Nat Biotechnol. 1999; 17: 804-807.
- Sharma SV, Bell DW, Settleman J et al. Epidermal growth factor receptor mutations in lung cancer. Nature Reviews Cancer, 2007; 7: 169-181.
EGFR testing process
To request EGFR mutation testing, the first point of contact is the dedicated Lab21 Customer Services Team who handle:
- Test Requests and Customer Support
- Liaison with Sample Retention Sites for sample retrieval
- Reporting of the Results
Test turnaround time is 5 working days from the receipt of the sample at Lab21.
EGFR mutation testing requires sections of a formalin-fixed, paraffin embedded (FFPE) tumour block, which are used for extraction of tumour DNA. This DNA is then used for detection of EGFR mutations by real-time PCR. Lab21 uses the real-time PCR test for EGFR Mutations developed by DxS (now Qiagen). It is a highly selective and robust real-time PCR test combining Scorpions and ARMS® (allele specific PCR technologies), which detects the 6 key types of EGFR mutations. The EGFR mutations that are detected in the test are:
- 19 deletions in exon 19
- L858R
- L861Q
- G719X (detects the presence of G719S, G719A or G719C but does not distinguish between them)
- S7681
- 3 insertions in exon 20 (detects the presence of any of 3 insertions, but does not distinguish between them)
The test is CE-certified and detects 1% of mutant DNA in a background of 99% wild type genomic DNA.EGFR Mutation Test from Lab21
EGFR Customer Services
Phone 0845 6778107 (UK)
+44 (0)1223 395450 (Intl) Email egfr@lab21.com