Overview of EGFR Exon 20 Insertion Mutations

A Genetic Subtype of Non-Small Cell Lung Cancer

If you have non-small cell lung cancer, you might have been told that your cancer is positive for EGFR (EGFR+). EGFR is a gene that can become mutated in some people with non-small cell lung cancer. When the gene for EGFR is mutated, it may cause a cancer to grow more rapidly.

However, not all mutations in EGFR act the same when they are part of a cancer. One specific type is called an exon 20 insertion mutation. People with this type of cancer mutation won’t respond as well to certain kinds of therapies, tyrosine kinase inhibitors.

Unfortunately, people with this type of EGFR mutation have fewer good treatment options than people with some other types of mutations in EGFR. 

Cancer patient in oncology unit

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What Are EGFR Mutations?

Cancers are partly caused by genetic mutations—changes in the DNA that a person carries. Usually, by the time a person develops a cancer, the cancerous cells have accumulated multiple genetic changes.

But not everyone who develops lung cancer has the same types of mutations in their cancer cells. Certain mutations in specific genes can change the way their proteins act. Because of a mutation, a protein that works to carefully regulate cell division might not work normally anymore.

This can happen if a person gets a mutation in a specific gene called EGFR (epidermal growth factor receptor). More EGFR protein than normal might be made, and the EGFR might not act the way it should. This can cause cells to grow and divide more often than normal.

EGFR is only one type of mutation that can be involved in the development of non-small cell lung cancer. Some people with this type of cancer have this mutation, but others don’t. If you have a mutation in EGFR, that is sometimes called being EGFR-positive (EGFR+). 

Other Important Mutation Types

Some people with lung cancer have other important mutations as well, such as those in genes called KRAS or ALK

Mutations in EGFR and some other genes are important because their presence guides treatment recommendations. In other words, certain therapies work better for people who have such mutations.

What Is an EGFR Exon 20 Insertion Mutation? 

Different types of mutations can affect the EGFR gene. The exon 20 insertion mutation is one specific type of mutation. In this type, a bit of genetic material gets accidentally inserted into a specific region of the gene (called exon 20).

This type of mutation is less common than some other types of mutations in EGFR. Of people with non-small cell lung cancer who have mutations in EGFR, about 4% to 12% have this type of mutation. This makes it the third most common type of mutation in EGFR.

Different specific types of mutations in EGFR affect a cancer cell in different ways. The new EGFR-type protein made by a cancer cell isn’t exactly the same for these different mutations. That’s why certain therapies are only effective for people who have specific types of EGFR mutations. 

Diagnosis

If you have been diagnosed with non-small cell lung cancer, your doctor will almost certainly recommend that you be tested for EGFR mutations. This is especially recommended for those with the adenocarcinoma type of non-small cell lung cancer.

About 85% of people with lung cancer have what is called “non-small cell” lung cancer instead of the “small cell” lung cancer type.

EGFR mutation testing can help determine your best treatment options. Genetic testing is used, most often on a sample from the affected lung tissue taken from a lung biopsy. Less commonly, it might be taken from a blood sample, called a liquid biopsy. But this is usually only done if a lung biopsy isn’t an option.

Technicians in a lab then look at the DNA in the cancer and see if EGFR is mutated. They also analyze the specific type of mutation in EGFR (such as the exon 20 insertion mutation). 

Often, when a person is getting tested for EGFR, they will be tested for other important genetic alterations in their cancer as well. For example, it might be performed along with tests in genes such as:

  • KRAS
  • ALK
  • ROS1
  • BRAF

Through identifying these specific alterations, your clinician may be able to deliver treatment specifically targeted to your cancer type.

Treatment

Unfortunately, non-small cell lung cancer is most often first diagnosed after the disease is fairly advanced. If this is the case, treatment doesn’t usually completely cure the disease. Instead, the goal is to limit cancer spread and decrease symptoms.

Historically, chemotherapy was the recommended treatment for most people with non-small cell lung cancer. For example, a platinum-based chemotherapy (such as those based on cisplatin or carboplatin) might be used to reduce cancer growth and prolong life.

EGFR Inhibitors (Tyrosine Kinase Inhibitors) for Certain EGFR Mutations

In the early 2000s, researchers discovered that a subgroup of people with non-small cell lung cancer responded very well to new types of treatment: Iressa (gefitinib) and Tarceva (erlotinib). These people were also more likely to be women, Asians, and non-smokers as compared to people who didn’t show improvement with these treatments. 

In fact, some people do much better with these treatments than with the standard treatments of chemotherapy. Ultimately, it was discovered that people with EGFR mutations tended to do better with these medications—called EGFR inhibitors—than people without these mutations.

EGFR inhibitors are also referred to as tyrosine kinase inhibitors, for the general type of enzyme that they block. These therapies could help turn off the overactive EGFR and slow cancer growth in the majority of people with mutations in EGFR that are sensitive to tyrosine kinase inhibitors. 

These and related therapies eventually became the therapy of choice for most people who had EGFR mutations. However, scientists eventually realized that not all people with EGFR mutations responded well to these therapies. 

People who had certain less common types of mutations in EGFR did not show much improvement with this class of treatments. This included people with the exon 20 insertion type mutations. Because of the specific shape of the abnormal EGFR protein, these drugs couldn’t turn off the overactive EGFR.

The insertion mutation in exon 20 isn’t the only uncommon type of mutation in EGFR. Some of the other less common types of mutations also do not respond well to treatment with EGFR inhibitors. 

Treatment When Positive for the EGFR Exon 20 Insertion Mutation

Unlike people with more common mutations in EGFR, EGFR inhibitors are not usually recommended for people with this mutation type. The EGFR inhibitor type drugs just don’t work well for such individuals. Instead, chemotherapy (such as one based on a platinum agent) is usually the treatment of choice for people with advanced disease.

If your disease is less advanced, surgery and/or radiation therapy may be an option. Some types of immunotherapy may also be an option for some people. Additionally, you may combine one or more of these therapies, depending on the situation.

Chemotherapy may cause worse side effects than the EGFR inhibitors, but treatments that can prevent or improve these symptoms are readily available. Overall, the prognosis is poorer for people with this type of mutation than for those with the more common types of EGFR mutations. 

Clinical Trials

Scientists are actively working to find therapies that can treat people who have cancer with this mutation type more effectively. 

The hope for the future is that more targeted therapies will be found to treat people with this specific type of EGFR mutation. A number of clinical trials are investigating potential agents that might be effective. Some of these are agents or combinations of agents approved for other types of non-small cell lung cancer. Others are brand-new therapies.

Scientists are also working on treatments that may help people with other types of non-small cell lung cancer in addition to those with this mutation type.

Prognosis

People with the exon 20 insertion mutation in EGFR tend not to live as long as people who have other types of mutations in EGFR that respond to tyrosine kinase inhibitors. But a lot will depend on your cancer stage and the other specifics of your medical situation. Your oncologist can give you an idea of what you might expect.

There’s a lot to learn about this type of cancer, but take your time in exploring your treatment options. Your healthcare team will help tailor a treatment plan that makes the most sense for you.

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