Also Known As:
EML4-ALK Fusion Protein
ALK Gene Rearrangement
ALK Gene Fusion

Formal Name:
ALK (Anaplastic Lymphoma Receptor Tyrosine Kinase) Gene Rearrangement

This article was last modified on June 28, 2021

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EGFR Mutation Testing

At a Glance

Why Get Tested?

To detect an ALK gene rearrangement in tumor tissue in order to guide non-small cell lung cancer therapy

When To Get Tested?

When you have been diagnosed with non-small cell lung cancer and your health care practitioner is considering a therapeutic management plan that may include an ALK kinase inhibitor such as crizotinib

Sample Required?

A tumor tissue sample is obtained through a biopsy procedure or sometimes collected during surgery. The tumor tissue is typically evaluated by a pathologist prior to testing.

Test Preparation Needed?

Usually no preparation is needed.

What is being tested?

ALK is a short name for the anaplastic lymphoma receptor tyrosine kinase gene. This test detects specific rearrangements in the ALK gene in 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 regulate cell growth.

About 4-5% 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 (fusion partner). The most common ALK fusion partner is a 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.

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.

Common Questions

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 ALK gene rearrangements in tumor tissue.

The test is typically ordered along with or as a follow-up test to EGFR and ROS1. If a non-small cell lung cancer has an EGFR 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.

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 ALK fusions.
Immunohistochemistry (IHC)—this method detects the altered ALK protein; IHC is an acceptable alternative to FISH.
Next generation sequencing (NGS) —this method detects ALK fusions and identifies the fusion partner gene, which may have some clinical significance.
Polymerase chain reaction (PCR)—this method detects known ALK fusions; however, it cannot identify novel fusions.

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.

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.

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.

Should everyone with lung cancer have ALK mutation testing?

Testing is not generally indicated unless a person has non-small cell lung cancer.

Is it necessary to repeat an ALK mutation test?

This is not usually necessary but might occur if the health care practitioner thought that the first sample tested might have been insufficient. In the rare instances where the original biopsy tissue is not sufficient, a new biopsy will be collected from the patient following the biopsy procedure.

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?

It may be available in some larger laboratories and hospitals designated as Comprehensive Cancer Centers by the National Cancer Institute, but most often it will be sent to a reference laboratory.

Can this test be performed on my blood instead?

Yes, ALK rearrangements could be detected in the DNA of tumor cells that is shed in the blood; however, it is not as reliable as the tissue-based test. Blood testing could be useful when no tissue is available for testing, but the procedure is still investigational.

View Sources

Sources Used in Current Review

2018 review performed by Mutasim Elfahal, PhD, DABCC.

Lindeman NI, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Mol Diagn. 2013 Jul;15(4):415-53.

Lindeman NI, et al. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Mol Diagn. 2018 Mar;20(2):129-159.

Lusky, Karen. Molecular tumor board: a patient with ALK-rearranged lung cancer. Cap Today February 2018.

Chia PL, Mitchell P, Dobrovic A, John T. Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors. Clin Epidemiol. 2014 Nov 20;6:423-32.

Sources Used in Previous Reviews

Markman, M. (Updated 2013 July 15). Genetics of Non-Small Cell Lung Cancer. Medscape Reference [On-line information]. Available online at http://emedicine.medscape.com/article/1689988-overview. Accessed July 2013.

Lindeman, N. et. al. (2013 June). Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors, Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med v 137, [On-line information]. Available online at http://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2012-0720-OA. Accessed July 2013.

Wallander, M. et. al. (Updated 2013 July) Lung Cancer. ARUP Consult [On-line information]. Available online at http://www.arupconsult.com/Topics/LungCancer.html?client_ID=LTD. Accessed July 2013.

(Revised 2012 March 21). Crizotinib. American Cancer Society [On-line information]. Available online at http://www.cancer.org/treatment/treatmentsandsideeffects/guidetocancerdrugs/crizotinib. Accessed July 2013.

Chustecka, Z. (2012 September 30). Crizotinib Now Standard of Care for ALK+ NSCLC. Medscape Medical News from the 2012 European Society for Medical Oncology (ESMO) Congress [On-line information]. Available online at http://www.medscape.com/viewarticle/771853. Accessed July 2013.

Markman, M. (2012 April 4). How Does Genetics Affect Outcomes in Nonsmokers With NSCLC? Medscape Today News from Cancer v 118: 729-739. [On-line information]. Available online at http://www.medscape.com/viewarticle/761054. Accessed July 2013.

(2013 June 17). Crizotinib Improves Progression-Free Survival in Some Patients with Advanced Lung Cancer. National Cancer Institute [On-line information]. Available online at http://www.cancer.gov/clinicaltrials/results/summary/2013/crizotinib-NSCLC0613. Accessed July 2013.

(Reviewed 2011 March). ALK. Genetics Home Reference [On-line information]. Available online at http://ghr.nlm.nih.gov/gene/ALK. Accessed July 2013.

Mulcahy, N. (2012 March 22). NSCLC Guidelines From NCCN Full of Change. Medscape Medical News [On-line information]. Available online at http://www.medscape.com/viewarticle/760722. Accessed July 2013.

(Updated 2010 June) Getting the Facts, Anaplastic Large Cell Lymphoma. Lymphoma Research Foundation [On-line information]. Available online at http://www.lymphoma.org/atf/cf/%7B0363cdd6-51b5-427b-be48-e6af871acec9%7D/ANAPLASTIC10.PDF. Accessed July 2013.

(2012 May 16). Drug used in NIH-supported trial shows benefit in children with previously treated cancers. National Cancer Institute [On-line information]. Available online at http://www.cancer.gov/newscenter/newsfromnci/2012/crizotinib. Accessed July 2013.

Nelson, R. (2011 August 26). FDA Approves New Drug for Advanced NSCLC. Medscape Medical News [On-line information]. Available online at http://www.medscape.com/viewarticle/748675. Accessed July 2013.

Nelson, R. (2012 October 25). Crizotinib Receives Conditional Marketing Approval in Europe. Medscape Medical News [On-line information]. Available online at http://www.medscape.com/viewarticle/773280. Accessed July 2013.

(Revised 2012 October 18). Tumor Markers. American Cancer Society [On-line information]. Available online through http://www.cancer.org. Accessed July 2013.

Yi E., et al. Correlation of IHC and FISH for ALK Gene Rearrangement in Non-small Cell Lung Carcinoma: IHC Score Algorithm for FISH. Journal of Thoracic Oncology March 2011 – Volume 6 – Issue 3 – Pp 459-465. Available online at http://journals.lww.com/jto/Fulltext/2011/03000/Correlation_of_IHC_and_FISH_for_ALK_Gene.8.aspx#. Accessed November 2013.

Gregory J. Tsongalis, PhD, HCLD, CC, Professor of Pathology, Director, Molecular Pathology, Dartmouth Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Lebanon, NH.

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ALK Mutation (Gene Rearrangement)