ALK Mutation (Gene Rearrangement)
When you have been diagnosed with non-small cell lung cancer and your doctor is considering a therapeutic management plan that may include an ALK kinase inhibitor such as crizotinib
A sample of tumor tissue
ALK is a short name for the anaplastic lymphoma receptor tyrosine kinase gene. This test detects specific rearrangements in the ALK gene in the DNA of cancer cells and tissue. The presence of these changes makes it more likely that a person with non-small cell lung cancer will respond to a targeted drug therapy.
The ALK gene codes for a protein called anaplastic lymphoma kinase. It is part of a family of proteins called receptor tyrosine kinases that transmit signals into cells and are thought to help regulate the proliferation of nerve cells.
About 5% of people who have non-small cell lung cancer, the most common type of lung cancer, have an alteration on chromosome 2 that leads to the fusion of the ALK gene with another gene called EML4 and results in the production of an EML4-ALK fusion protein. It is a rare mutation most commonly seen in people who have never smoked or are light smokers, especially women of Asian descent.
This gene mutation and abnormal protein production promotes the uncontrolled growth of cancer cells, but it also makes it more likely that the affected person will respond to a drug that targets the abnormal protein (an ALK kinase inhibitor, such as crizotinib) and less likely that the person will respond to tyrosine kinase inhibitors that target the EGFR (epidermal growth factor receptor).
There are several different methods of testing for ALK mutations, but all of them involve evaluating either the ALK gene rearrangement or the altered ALK protein in tumor tissue.
How is the sample collected for testing?
Is any test preparation needed to ensure the quality of the sample?
No test preparation is needed.
How is it used?
ALK mutation analysis is used primarily to determine if a person with adenocarcinoma non-small cell lung cancer is likely to respond to an ALK kinase inhibitor drug therapy, such as crizotinib. This testing detects the presence of the most common ALK gene rearrangements in the DNA of cells in tumor tissue or the abnormal protein produced by the mutated gene in order to help guide cancer treatment.
This testing is typically ordered along with or as a follow-up test to EGFR and KRAS mutation testing. If a non-small cell lung cancer has an EGFR mutation and lacks a KRAS mutation, then the affected person is likely to respond to an anti-EGFR drug therapy (tyrosine kinase inhibitor) and further testing is usually not necessary. However, if the tumor is negative for an EGFR mutation, then the person is not likely to respond to an anti-EGFR tyrosine kinase inhibitor. ALK mutation testing is then used to determine whether the person's tumor would be likely to respond to an ALK kinase inhibitor.
If a person's tumor is negative for the most common ALK gene rearrangements, tests for other less common mutations not detected by the current test or tests for the altered ALK protein may be used to help predict therapeutic responses. In some cases, testing for the altered ALK protein may be preferred over ALK gene rearrangement testing.
Two main methods of testing include:
- Fluorescent in situ hybridization (FISH)—this method looks at the genetic level for presence of the gene rearrangement; it is currently the gold standard for evaluating non-small cell lung cancer tumors.
- Immunohistochemistry (IHC)—this method detects the altered ALK protein; IHC is not widely available but is gaining in use.
When is it ordered?
An ALK mutation test is usually ordered after an individual has been diagnosed with non-small cell lung cancer, especially adenocarcinoma. It is ordered when a person's tumor is unlikely to respond to a tyrosine kinase inhibitor and the health practitioner is considering an ALK kinase inhibitor drug therapy.
What does the test result mean?
If the cancer tissue contains a specific ALK gene rearrangement mutation or altered ALK protein, then the affected person is likely to benefit from an ALK kinase inhibitor drug therapy such as crizotinib and is not likely to benefit from anti-EGFR drug therapies.
A person whose cancer does not have an ALK gene rearrangement is not likely to benefit from ALK kinase inhibitor drug therapy.
A person could have a negative test result if the tumor tissue sample is insufficient and/or when the cancer is heterogeneous (some cells contain the mutation and others do not). Additionally, there may be rare ALK mutations that are not detected by routine testing that looks for only the most common mutations.
Is there anything else I should know?
ALK gene rearrangements are most often seen in light smokers or non-smokers with adenocarcinoma non-small cell lung cancers, especially women of Asian descent. Although this is a relatively rare mutation, the total number of people affected by lung cancer each year means that the test and potential drug therapy is applicable to thousands of people.
ALK mutations may also be seen in some T-cell lymphomas.
Should everyone with lung cancer have ALK mutation testing?
Is it necessary to repeat an ALK mutation test?
This is not usually necessary but might occur if the health practitioner thought that the first sample tested might have been insufficient.
Can I receive ALK kinase inhibitor drug therapy and still not benefit from it?
Yes, most people whose lung cancer has the ALK gene rearrangement will respond, but a percentage will not. Each person and each cancer is different. Also, a person may respond initially and then become resistant to the treatment.
Can I take an ALK kinase inhibitor drug therapy without being tested?
In most cases, this is not recommended. The drugs have been developed with specific associations and your lung cancer is not likely to respond if you do not meet the identified criteria.
Can this test be performed by my local laboratory?
Can this test be performed on my blood instead?
No, it is not the genetics of the person that is being evaluated; it is the genetic makeup of the cancer.