Genetic testing helps determine whether any specific gene mutations are driving your lung cancer. Once a mutation is identified, your cancer treatment can be modified to target it.
Gene mutations, whether inherited or acquired, play an important role in the development of cancer.
A gene mutation in the lungs can cause non-small cell lung cancer (NSCLC). Different mutations can affect your treatment decisions and outcomes.
Many mutations involved in NSCLC have already been identified. This has helped researchers develop drugs that target some of those specific mutations.
Knowing which mutations are driving your cancer can give your doctor an idea of how the cancer will behave. This can help determine which drugs are most likely to be effective.
It can also help identify drugs that are unlikely to aid in your treatment.
Genetic testing after a diagnosis of NSCLC is important because it helps your doctor personalize your treatment. Genetic testing isn’t currently useful in small cell lung cancer.
Other names for genetic testing include:
- genomic testing
- molecular analysis
- molecular testing
In your initial cancer biopsy, a pathologist will take a sample of your lung tissue and check it for the presence of cancer. Often, some of the tissue sample from this biopsy can be used for genetic testing.
If there’s not enough of the tissue sample left over from your initial biopsy, then the pathologist may take a blood sample and test it for gene mutations. This is known as a liquid biopsy.
Other genetic tests are described below.
Fluorescence in situ hybridization (FISH)
In the fluorescence in situ hybridization (FISH) technique, a pathologist takes human-made pieces of DNA and adds them to a tissue or cell sample.
These DNA pieces contain fluorescent molecules. The DNA pieces will only bind to certain parts of the chromosomes in the tissue or cell sample.
When the pathologist views the sample under a special fluorescent microscope, the areas where the DNA pieces have attached to the chromosomes will light up or glow. This can reveal where certain genes, such as those that have mutated, are located.
In addition, the FISH technique can reveal if:
- you have too many copies of a particular gene or chromosome
- there’s anything atypical about your chromosomes
The FISH technique can also be used to help diagnose noncancerous conditions, such as infections.
Immunohistochemistry is a versatile staining technique. It uses human-made antibodies to reveal whether gene mutations or other biomarkers are present on the surface of your cells.
An antibody is a type of protective immune protein. An antigen is a foreign substance, such as a protein or bacteria, that triggers an immune response in the body.
Every antibody naturally recognizes and binds to particular antigens. The antibodies used in some forms of immunohistochemistry are engineered to bind to antigens involved in cancer.
The human-made antibodies will be added to a sample of your cells. Your cancer cells will turn a particular color when the antibodies attach to antigens involved in cancer. This makes it easier for the pathologist to see which antigens are present.
This technique is more widely available than FISH, but FISH produces more accurate test results.
Next-generation sequencing (NGS)
DNA sequencing is a method of examining a DNA sample and verifying the proper order of each DNA building block.
If any of these building blocks appear out of sequence, it could be evidence of a gene change, such as a mutation.
In next-generation sequencing (NGS), the sample is run through a machine that’s able to process multiple DNA sequences all at once. It’s much faster than traditional DNA sequencing.
Did you know?
Results from genetic testing usually take 1—2 weeks. Results from some methods, like fluorescence in situ hybridization (FISH) and immunohistochemistry, may be available in just a few days.
NSCLC accounts for
NSCLC can be divided into these subtypes:
- Adenocarcinoma: Adenocarcinoma starts in young cells that secrete mucus. It’s usually found in outer parts of the lung. It tends to occur in people assigned female at birth more often than in people assigned male at birth. It’s also more common in younger people. Adenocarcinoma is generally a slow-growing cancer, making it more discoverable in the early stages.
- Squamous cell carcinoma: Squamous cell carcinoma starts in the flat cells that line the inside of your lung’s bronchi, or airways. This subtype is likely to start near the main bronchi in the middle of the lungs. Squamous cell carcinoma has fewer available treatments than non-squamous forms of NSCLC.
- Large cell carcinoma: Large cell carcinoma can start anywhere in the lung and can be quite aggressive.
- Other subtypes: Less common subtypes include adenosquamous carcinoma and sarcomatoid carcinoma. Adenosquamous carcinoma cells and sarcomatoid carcinoma cells both have the combined features of two different types of cancer cells.
The vast majority of NSCLC cases are either adenocarcinoma or squamous cell carcinoma, with adenocarcinoma being the most common NSCLC subtype.
Once you know which subtype of NSCLC you have, the next step is usually to determine the specific gene mutations that might be involved.
Genetic tests can screen for hundreds of mutations. These are some of the most common mutations in NSCLC:
- TP53: Tumor protein p53 (TP53) mutations occur in around 50% of NSCLC cases.
- KRAS: KRAS mutations are involved about 30% of the time.
- EGFR: Around 10%–15% of lung cancers in the United States test positive for the epidermal growth factor receptor (EGFR) mutation. It’s common in people with NSCLC who’ve never smoked. Variations include the EGFR exon 19 deletion mutation, EGFR exon 20 insertion mutation, and EGFR exon T790M mutation.
- ALK: Anaplastic lymphoma kinase (ALK) mutations are found in
about 5%of NSCLC cases. This mutation tends to involve younger people, nonsmokers, or light smokers with adenocarcinoma. The ALK gene sometimes fuses with a gene known as echinoderm microtubule-associated protein-like 4 (EML4).
- MET and METex14: Mesenchymal–epithelial transition (MET) mutations occur in
up to 5%of NSCLC cases. A subtype called MET exon 14 deletion (METex14) affects around 3% of NSCLCs.
- PIK3CA: The phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation occurs in up to 5% of NSCLCs. It’s more common in squamous cell carcinomas than in adenocarcinomas.
Less common gene mutations associated with NSCLC include:
- human epidermal growth factor receptor 2 (HER2)
- neurotrophic tyrosine receptor kinase (NTRK)
There are many treatments for NSCLC. Because NSCLCs can differ, treatment must be carefully considered.
Detailed testing can tell you if your tumor has particular gene mutations or proteins. Targeted therapies are designed to treat the specific characteristics of the tumor.
Below are some targeted therapies for NSCLC.
Sotorasib (Lumakras) is the first KRAS inhibitor available for treatment.
EGFR inhibitors block the signal from the EGFR gene that encourages growth. They may target one or multiple types of EGFR mutations.
Examples include these oral medications:
- afatinib (Gilotrif)
- dacomitinib (Vizimpro)
- erlotinib (Tarceva)
- gefitinib (Iressa)
These EGFR inhibitors can eventually stop working. When that happens, your doctor may order an additional tumor biopsy to see whether your cancer has mutations that may respond to osimertinib (Tagrisso). It’s also an EGFR inhibitor.
Necitumumab (Portrazza) is an EGFR inhibitor that’s given via intravenous (IV) infusion. It must be combined with the chemotherapy drugs gemcitabine (Infugem) and cisplatin.
EGFR exon 20 insertion
There are two medications available to treat this mutation:
- amivantamab-vmjw (Rybrevant), an antibody treatment
- mobocertinib (Exkivity), an EGFR inhibitor
They’re given to people who’ve already tried chemotherapy.
Therapies that target abnormal ALK proteins include:
- alectinib (Alecensa)
- brigatinib (Alunbrig)
- ceritinib (Zykadia)
- crizotinib (Xalkori)
- lorlatinib (Lorbrena)
These medications can be used in place of chemotherapy or after chemotherapy has stopped working.
If you have the EML4-ALK mutation, you would also receive one of these treatments.
MET and METex14
Cancers involving the METex14 mutation can be treated with the following targeted therapies:
- capmatinib (Tabrecta)
- tepotinib (Tepmetko
There are currently no targeted therapies for other MET mutations.
Other targeted therapies
There are no established targeted therapies for lung cancers with the NRAS, PIK3CA, and TP53 mutations.
Other targeted therapies include:
- BRAF V600E (a subtype of BRAF): dabrafenib (Tafinlar) and trametinib (Mekinist), which must be combined
- HER2: fam-trastuzumab deruxtecan-nxki (Enhertu)
- NTRK: entrectinib (Rozlytrek) and larotrectinib (Vitrakvi)
- RET: pralsetinib (Gavreto) and selpercatinib (Retevmo)
- ROS1: ceritinib (Zykadia), crizotinib (Xalkori), entrectinib (Rozlytrek), and lorlatinib (Lorbrena)
The Food and Drug Administration (FDA) has only approved ceritinib (Zykadia) and lorlatinib (Lorbrena) to treat ALK-positive lung cancer.
However, a doctor may still prescribe if you have ROS1-positive lung cancer. This is known as off-label drug use.
OFF-LABEL DRUG USE
Off-label drug use means a drug that’s approved by the Food and Drug Administration (FDA) for one purpose is used for a different purpose that hasn’t yet been approved.
However, a doctor can still use the drug for that purpose. This is because the FDA regulates the testing and approval of drugs but not how doctors use drugs to treat their patients.
So your doctor can prescribe a drug however they think is best for your care.
Tumors need to form new blood vessels to continue to grow. Your doctor may prescribe one of these therapies to block new blood vessel growth in advanced forms of NSCLC:
- bevacizumab (Avastin), which may be used with or without chemotherapy
- ramucirumab (Cyramza), which can be combined with chemotherapy and is usually given after another treatment is no longer working
Other treatments for NSCLC may include:
- palliative therapy to ease symptoms
Clinical trials are a way to test the safety and effectiveness of experimental therapies that aren’t yet approved for use. Talk with your doctor if you’d like to learn more about clinical trials for NSCLC.
If you have been diagnosed with lung cancer or are concerned about symptoms, speak with your doctor about all of your options.
Genetic testing can tell you and your doctor more about your treatment needs.
Targeted therapies for NSCLC are some of the most promising treatments so far, and their number continues to grow.
We can expect to see advances as researchers learn more about specific gene mutations that cause NSCLC to progress. More research is being done to increase effectiveness and create a better outlook.