EGFR Mutation Testing
When you have been diagnosed with non-small cell lung cancer; when you are being treated with an EGFR-targeted tyrosine kinase inhibitor, but the cancer progresses
In many cases preparation is minimal, but it will depend upon how the cancer cells are being obtained. You will receive instructions from your healthcare practitioner based on the procedure being used to obtain the sample.
EGFR is a short name for the Epidermal Growth Factor Receptor gene. DNA from tumor cells is tested for mutations in this gene. In certain situations, DNA that has been shed from tumor cells in one's blood can also be tested and may be informative (liquid biopsy).
The EGFR gene provides instructions for a cell to make a specialized type of protein called a receptor, which is located on the surface of the cell. A receptor recognizes and binds to other substances, and the binding typically has a specific effect on the cells. EGFR is one of a group of receptors called receptor tyrosine kinases that help regulate cell growth, division, survival, and death. This regulation is a very complex process. Receptor tyrosine kinases like EGFR transmit signals from the surface of the cell to pathways within the cell.
In normal cells, binding of epidermal growth factor to its receptor on the cell surface is an important signal that can promote cell growth and proliferation. Certain mutations called "activating mutations" in the EGFR gene can result in excessive signaling for growth and uncontrolled proliferation of cancer cells.
Treatments that target EGFR are an effective therapy for certain cancers. Examples of EGFR-targeted therapy include drugs such as gefitinib and erlotinib, which are small molecules called tyrosine kinase inhibitors (TKIs) that enter cancer cells and impede signaling through the EGFR pathway. These drugs have been shown to be useful in treating non-small cell lung cancer (NSCLC), if the tumor has a mutation making it sensitive to the drug. If one of these sensitizing mutations is detected with an EGFR mutation test, then EGFR-targeted tyrosine kinase inhibitors are much more likely to be of benefit for treating the tumor.
How is it used?
This test is helpful to direct therapy. It detects the presence of mutations in the EGFR gene in the DNA of the tumor cells to help determine whether someone with non-small cell lung cancer (NSCLC) may benefit from targeted therapy with tyrosine kinase inhibitors (TKIs) such as gefitinib or erlotinib. Specific EGFR mutations can lead to uncontrolled growth of cancer cells. TKIs can block the action of EGFR to inhibit cancer cell growth.
An EGFR mutation test may be ordered by itself or as part of a panel (a series of tests to detect mutations in other genes such as KRAS, ALK and ROS1). Each of these tests may be used to help determine whether a person's lung cancer will respond to targeted therapy and which type will be of more benefit.
Additionally, testing may be used after treatment is initiated to determine whether the cancer has acquired new mutations that make it resistant to the current treatment. For example, one of the known resistance mutations, specifically T790M, may be detected and can then be targeted with a different drug that has been designed especially for this particular mutation.
When is it ordered?
EGFR mutation testing is ordered after an individual has been diagnosed with non-small cell lung cancer, especially adenocarcinoma.
When a patient has already been treated with an EGFR-targeted tyrosine kinase inhibitor but does not appear to be responding favorably to the treatment, the healthcare practitioner may order additional EGFR mutation testing on a new sample, to check for specific EGFR mutations that may account for lack of a favorable response. A new sample of tumor tissue, or sometimes a blood sample, is required to determine whether the cancer has acquired new mutations that make it resistant to the current treatment.
What does the test result mean?
If an individual's lung cancer has an sensitizing EGFR mutation, then an EGFR-targeted tyrosine kinase inhibitor (TKI) may be effective in treating the tumor. If no sensitizing mutation is detected by the EGFR test, then the tumor is less likely to respond to TKI therapy. Sometimes an EGFR mutation is detected, but it indicates that the cancer will not respond to a TKI. Pathologists and cancer specialists (oncologists) help interpret the precise significance of the exact EGFR mutation identified for each patient.
Is there anything else I should know?
EGFR mutation testing is usually optimized to detect EGFR mutations that have demonstrated significance, but there may be uncommon or unique EGFR mutations present in a tumor that are not detected.
Although a mutation may be present in the tumor cells, if there is very little tumor tissue and/or when there are insufficient tumor cells present that contain the mutation, the test may result in "no mutation detected" despite the mutation being present in a minority of tumor cells.
Because the amount of tumor DNA in a blood sample is uncertain, testing a blood sample (also called a liquid biopsy) is generally not preferred. However, in situations where insufficient tumor cells are available for molecular testing from a tissue biopsy, or in situations where a tissue biopsy is not able to be taken, a blood test (liquid biopsy) may be an acceptable alternative testing method.
The well-known sensitizing EGFR mutations typically result in changes to small areas of EGFR protein. Testing for these types of mutations is commonly done by techniques such as real-time PCR or next-generation sequencing.
What other testing might be done?
ALK and/or ROS1 mutation testing are recommended to determine whether a person's tumor would be likely to respond to specific targeted therapies that are effective when an ALK or ROS1 mutation is detected. Testing for mutations in other genes (e.g., KRAS) may be offered for lung cancer patients if there is enough tissue sample available.
How long does it take for EGFR testing results?
EGFR mutation testing is not available in every laboratory. If a healthcare practitioner sends a sample to a reference laboratory and depending on the test method used, the results may take a few days to several days before they are available.
Can I have my blood tested instead of having a tissue biopsy?
For diagnosis of your tumor, you will need a conventional tissue biopsy. In addition, blood tests for circulating tumor DNA (ctDNA), also called liquid biopsies, may be done to detect EGFR mutations in the tumor that can predict potential responsiveness or resistance to targeted therapies.
- CtDNA testing may be used to detect mutations that make the tumor sensitive to targeted therapy (sensitizing mutations). However, ctDNA testing is known to sometimes give false-negative results (meaning the mutation is present but not detected by the ctDNA testing). For this reason, the FDA recommends a tissue biopsy if the liquid biopsy is negative (doesn't detect a sensitizing mutation).
- In addition, a liquid biopsy may be used to detect an EGFR T790M mutation, which causes resistance to targeted therapy. However, data are currently limited on this, so a liquid biopsy may be used only if a tissue biopsy cannot be obtained.
Also, patients may wish to consult their health insurance company as to whether this blood testing would be covered.
What is the difference between EGFR (also known as HER-1) and HER-2?
EGFR and HER-2 are both members of the same family of cell membrane receptors. When either EGFR or HER-2 is significantly increased in a cancer, it often indicates a more aggressive tumor and a poorer patient prognosis. The primary differences between EGFR and HER-2 testing are that they are ordered to help evaluate different types of cancer and that the drugs that have been developed to target them are specific for that particular receptor, EGFR or HER-2. HER-2 is evaluated in breast cancer and cancer of the stomach and esophagus (gastroesophageal adenocarcinoma).
Are there other types of testing that evaluate EGFR in tumors?
There are tests available that identify other changes in EGFR known as gene amplification, which means an abnormally increased number of copies of the EGFR gene are present in the tumor cells. Another type of test looks at the amount of EGFR protein present on the tumor cells. These tests are not helpful for identifying patients with lung cancer who may benefit from EGFR-targeted tyrosine kinase inhibitor therapy. However, they may have a role in other types of cancer. For example, sometimes tests for EGFR gene amplification are used to determine the likely course (prognosis) of cancer of the head and neck.
Besides lung cancer, are there other types of cancers that have increased EGFR protein?
Other types of cancer that may have increased EGFR protein present include colon cancer, glioblastoma (a type of brain cancer), and cancers of the head and neck, breast, and pancreas. EGFR blocking agents are routinely used for treatment of metastatic colon cancer and are used with some head and neck cancers. The utility of EGFR inhibitors and their correlation with EGFR mutations in different types of cancers hasn't been fully established but continues to be investigated.