What Is Exon Insertion Mutation in Non-Small Cell Lung Cancer (NSCLC)?

If you have been diagnosed with advanced non-small cell lung cancer, your doctors would have ordered tests on a tumor sample (biopsy) to identify specific genes and proteins unique to the tumor. These tests can help identify targeted treatments available to you.

EGFR (epidermal growth factor receptor) is a protein on cells that helps them grow. A mutation in the gene for EGFR can make it grow too much, which can cause cancer. 

Two rare EGFR insertion mutations, in exon 19 and exon 20, can provide doctors with treatment options in advanced lung cancers that were not available just a few years ago. In this article, we will look at the exon insertion mutations in NSCLC, including how they are diagnosed and treated.

Doctor looking through microscope in laboratory


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Types of Exon Insertion Mutation in NSCLC

An exon insertion mutation is a specific type of mutation in the EGFR gene. In this type, a bit of genetic material is inserted accidentally into a specific region of the gene.

There are two exon insertion mutations in NSCLC—exon 19 and exon 20. These are very rare, with exon 19 insertion occurring in 1% of all EGFR mutations and exon 20 insertion occurring in 4% of EGFR mutations.

Other Types of Genetic Mutations in NSCLC

Often, when a person is getting tested for EGFR, they will be tested for other important genetic alterations. These include:

  • KRAS: About 20% to 25% of NSCLCs have changes in the KRAS gene.
  • ALK: About 5% of NSCLCs have a change in the ALK gene.
  • ROS1: About 1% to 2% of NSCLCs have a rearrangement in the ROS1 gene.
  • RET: A small percentage of NSCLCs have changes in the RET gene.
  • BRAF: About 5% of NSCLCs have changes in the BRAF gene.
  • MET: A small percentage of NSCLCs have certain changes in the MET gene that make them more likely to respond to some targeted drugs.

Exon Mutation NSCLC Symptoms

There are no symptoms specific to the genetic mutation of NSCLC. Exon insertion mutations are most often associated with lung adenocarcinomas, and symptoms may not appear during the early stages of the disease.

Adenocarcinoma tumors appear on the outer areas of the lungs. Since they are not near the airways, breathing may not be affected until the cancer has progressed to an advanced stage.

When symptoms do appear, they are similar to the signs associated with other types of lung cancer, including:

Causes and Risk Factors

According to research, certain races and ethnicities are more susceptible to EGFR mutations. Mutations in the EGFR gene occur in 10% to 20% of White and at least 50% of Asian NSCLC patients.

There are several common factors related to EGFR mutations. Those more likely to have the mutation are patients diagnosed with NSCLC who are:

While the EGFR gene is most often associated with adenocarcinomas, some types of squamous cell carcinoma are affected by the protein as well.

Diagnosis

If you are diagnosed with advanced-stage NSCLC, your doctor will almost certainly recommend testing for genetic mutations, particularly if you have been diagnosed with lung adenocarcinoma.

Genetic testing is usually based on a tissue sample taken from the affected lung during a lung biopsy. The DNA of the tumor cells is analyzed to determine if it contains any mutations in the genes.

Doctors may also be able to check for the mutations via a special blood test called a liquid biopsy, which analyzes DNA that has been shed from tumor cells in your blood.

Once they have a sample, lab technicians will look at the DNA of the cancer cells and see if there is a mutation. They also analyze the specific type of mutation, which is how they can determine if there is an exon 19 or 20 insertion mutation.

The findings of the genetic tests will help determine your best treatment options. Your healthcare team may be able to deliver targeted therapies specifically designed for your cancer and genetic type.

Treatment

Lung cancer with EGFR mutations is often not diagnosed until the disease is at stage 3 or 4, so treatment doesn't usually focus on curing the cancer; instead, it's aimed at managing the spread and relieving symptoms.

Historically, chemotherapy had been the first course of treatment for almost all cases of advanced NSCLC, but targeted therapy drugs approved by the Food and Drug Administration (FDA) are now the main choice for treating tumors with EGFR mutations.

Exon 19 Insertion

EGFR inhibitors block the signals that cancers with the EGFR mutation need to grow. These include:

  • Gilotrif (afatinib)
  • Iressa (gefitinib)
  • Tagrisso (osimertinib)
  • Tarceva (erlotinib)
  • Vizimpro (dacomitinib)

The choice of a particular EGFR inhibitor depends on many factors, including your overall health, your specific type of lung cancer, and your treatment goals. Talk through the pros and cons of each option with your doctor.

Common side effects of all EGFR inhibitors include:

  • Skin problems
  • Diarrhea
  • Mouth sores
  • Loss of appetite

Skin problems can include an acne-like rash on the face and chest, which in some cases can lead to skin infections.

Exon 20 Insertion

While EGFR inhibitors can help many people with EGFR gene mutations, they don’t help everyone. Studies have shown that cancer cells with an exon 20 insertion mutation are much less likely to respond to these drugs.

However, other drugs that target cancer cells with an exon 20 mutation are now available and are typically used after chemotherapy has been tried:

  • In May 2021, the FDA approved Amivantamab (Rybrevant) for use in metastatic NSCLC with exon 20 insertion mutation. This drug is given as an infusion into a vein (IV).
  • In September 2021, the FDA approved Mobocertinib (Exkivity), a drug taken as pills, typically once a day.

Treatment Resistance

Unfortunately, though lung cancers may respond very well to targeted therapy medications at first, they almost always become resistant over time. When this happens, doctors look to other targeted therapy drugs or new approaches to treatment, which may include combining treatments.

Prognosis

The prognosis for NSCLC with EGFR gene mutations depends on multiple factors, including:

  • The stage of the cancer at the time of diagnosis (how far it has spread)
  • Your age and overall health
  • The cancer’s response to treatment
  • The type of mutation

Several case studies have reported partial responses for small numbers of exon 19 insertion patients treated with EGFR inhibitors. However, the durability of response has been extremely variable, ranging from 5.9 months to 24 months.

People with the exon 20 insertion mutation in EGFR tend to have a poorer prognosis, due to their resistance to EGFR inhibitors. New treatments are available, with more in clinical trial stages, which means there may be more options available for those diagnosed with this mutation.

Summary

An exon insertion mutation is a specific type of mutation in the EGFR gene. In this type, a bit of genetic material is inserted accidentally into a specific region of the gene.

Exon 19 and 20 insertion mutations in NSCLC are rare. You should be offered genetic testing when you are diagnosed with lung cancer, and the results will help guide your treatment plan. While the prognosis for these types of mutations is poor, new drugs are in development to help prolong life.

A Word From Verywell

Research into genetic mutations in NSCLC is happening at a rapid pace, and your doctor should be up to date on the treatment recommendations. If you don’t feel comfortable with the answers you are receiving, seek out a second opinion. 

While a cure is not available for advanced lung cancer, treatments can ease symptoms and help prolong life.

Reach out to friends and family if you are finding your diagnosis overwhelming. Living with rare cancer can be lonely, so do consider joining a support community.

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10 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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