Genetic Abnormalities - EGFR

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Reviewed by: HU Medical Review Board | Last reviewed: January 2017.

An estimated 10 percent of patients with non-small cell lung cancer (NSCLC) in the United States have a tumor mutation associated with EGFR, which stands for epidermal growth factor receptor. EGFR mutations are most often found in tumors in female patients who have never smoked (patients are considered “never smokers” if they have smoked less than 100 cigarettes in their lifetime). The tumors are likely to be adenocarcinoma. However, EGFR mutations are not exclusive to this type of NSCLC or non-smokers– mutations have also been found in smokers and in other tumor types.^1,2

Role of EGFR

EGFR is one of several receptor tyrosine kinases (RTKs). RTKs are cell-surface receptors that partner with ligands, proteins which activate the receptor to cause a specific action in the cell. ³

In its normal capacity, EGFR triggers cell growth and division. Damage to the genes causes normal cells to change and become cancer cells. When there is a mutation to the EGFR gene, the malignant (cancerous) cells are activated to divide, grow faster, and survive.^2,4

Targeting EGFR

The presence of EGFR mutation on tumor cells generally occurs on its own without other genetic mutations, including KRAS mutations, ALK, and others. The presence of EGFR can influence response to targeted therapy, making testing for these mutations an important part for tailoring treatment to a specific patient.^2,5

Drugs that target EGFR are known as EGFR tyrosine kinase inhibitors (TKIs), including Tarceva (erlotinib), Iressa (gefitinib), and Gilotrif (afatinib). While these therapies show promise for NSCLC with EGFR mutations, drug resistance can occur, with cancer cells no longer responding to the treatment. Clinical trials have studied which treatments work best in particular patients, leading to the discovery of several unique mutations within EGFR.^2,5

Mutations to EGFR

The genes within the cells are made up of DNA (deoxyribonucleic acid). DNA is constructed of chemical building blocks called nucleotides, of which there are four: adenine (A), thymine (T), guanine (G) and cytosine (C). The sequence of these nucleotides creates the code or biological instructions for the cell. Cancer occurs when there is damage to these instructions, causing uncontrolled cell growth that invades surrounding or distant tissue. Exons are portions of the genes that are responsible for coding amino acids, which are the building blocks of proteins.^4,6

There are several different mutations that researchers have identified with EGFR:

EGFR kinase domain duplication

This mutation results in a duplication of EGFR exons 18-25. This mutation potentially displays an increased sensitivity (ability of the drug to successfully attack the cancer cells) to treatment with TKIs.

EGFR c.2156G>C (G719A)

This mutation affects exon 18, resulting in an amino acid substitution from a glycine (G) to an alanine (A). This mutation displays an increased sensitivity to treatment with TKIs.

EGFR c.2155G>T (G719C)

This mutation affects exon 18, resulting in an amino acid substitution from a glycine (G) to a cysteine (C). This mutation displays an increased sensitivity to treatment with TKIs.

EGFR c.2155G>A (G719S)

This mutation affects exon 18, resulting in an amino acid substitution from a glycine (G) to a serine (S). This mutation displays an increased sensitivity to treatment with TKIs.

EGFR exon 19 deletion

This mutation shows deletions at exon 19 and displays an increased sensitivity to treatment with TKIs.

EGFR exon 19 insertion

This mutation shows insertions (additional code) at exon 19 and displays an increased sensitivity to treatment with TKIs.

EGFR exon 20 insertion

This mutation shows insertions at exon 20 and displays a decreased sensitivity to treatment with TKIs.

EGFR c.2290_2291ins

This mutation shows an insertion at exon 20 and displays an increased sensitivity to treatment with TKIs.

EGFR c.2369C>T (T790M)

This mutation affects position 790 on the gene, resulting in an amino acid substitution from a threonine (T) to a methionine (M). This mutation displays a decreased sensitivity to first and second generation TKIs but an increased sensitivity to third generation (mutant specific) TKIs, like Tagrisso (osimertinib) and rociletinib (still in experimental phase, awaiting FDA approval).

EGFR c.2573T>G (L858R)

This mutation affects position 858 on the gene, resulting in an amino acid substitution from a leucine (L) to an arginine (R). This mutation displays an increased sensitivity to treatment with TKIs.

EGFR c.2582T>A (L861Q)

This mutation affects position 861 on the gene, resulting in an amino acid substitution from a leucine (L) to a glutamine (Q). This mutation displays an increased sensitivity to treatment with TKIs. ²

EGFR c.2303G>T (S768I)

This mutation affects position 768 on the gene, resulting in an amino acid substitution from a serine (S) to an isoleucine (I). This mutation potentially displays an increased sensitivity to treatment with second generation TKIs.