EGFR Gene Mutation

The EGFR gene mutation is one of the most important genetic changes found in lung cancer, offering hope for patients through targeted treatments that specifically attack cancer cells while sparing healthy tissue.

Table of contents

• What is EGFR?
• Understanding EGFR Mutations
• Who is Most Likely to Have EGFR-Positive Lung Cancer?
• Testing for EGFR Mutations
• Types of EGFR Mutations
• Treatment Options
• When Treatment Stops Working

What is EGFR?

EGFR stands for epidermal growth factor receptor, which is a protein that naturally exists on the surface of cells throughout your body. This protein plays an important role in helping healthy cells grow, divide, and respond to their environment^[2][3].

The EGFR protein sits in the cell membrane like a switch, with one end inside the cell and one end sticking out. When certain proteins attach to the outer part of EGFR, they send signals to the cell telling it to grow and divide. Under normal circumstances, this process is tightly controlled and helps maintain healthy tissues^[3].

The EGFR gene provides the instructions for making this EGFR protein. When this gene works correctly, it helps regulate normal cell growth. However, when mutations or changes occur in the EGFR gene, the protein may not work properly, leading to uncontrolled cell growth that can cause cancer^[2][3].

Understanding EGFR Mutations

An EGFR mutation refers to a change or damage in the portion of DNA that carries the recipe for making EGFR proteins. When a mutation occurs in the EGFR gene, it causes the production of higher than normal amounts of EGFR protein, or causes the EGFR protein to remain stuck in the “on” position. This leads to cells constantly receiving signals to grow and divide, resulting in the growth and spread of cancer cells^[2][10].

Most EGFR mutations in lung cancer occur during a person’s lifetime rather than being inherited from parents. These are called somatic mutations and are present only in cancer cells, not in all cells of the body. In very rare cases, an EGFR mutation can be inherited as a germline mutation, passed directly from a parent to a child^[3][5][7].

The EGFR mutation was the first “actionable” or targetable genetic change discovered in people with lung cancer. This means it was the first mutation for which doctors could develop specific treatments that target the abnormal protein to stop cancer cell growth^[2][6].

Who is Most Likely to Have EGFR-Positive Lung Cancer?

EGFR mutations are found in approximately 10 to 15 percent of lung cancer cases in the United States. However, this percentage increases significantly to 35 to 50 percent in people of Eastern Asian descent. These mutations are most commonly found in a type of non-small cell lung cancer called lung adenocarcinoma^[2][6][10].

EGFR-positive lung cancer is more common in certain groups of people. It occurs more frequently in women than in men. It is also much more common in people who have never smoked or who have only smoked a little. While tobacco smoking is linked to most lung cancers, EGFR-positive lung cancer often develops in never-smokers^[2][6][8].

Young adults with lung cancer are also more likely to have EGFR mutations. These mutations are present in roughly 50 percent of lung cancers in young adults. Additionally, people of Asian or East Asian heritage have a higher likelihood of having EGFR-positive lung cancer compared to other populations^[2][6][10].

Testing for EGFR Mutations

After receiving a lung cancer diagnosis, it is essential to undergo comprehensive biomarker testing to determine whether your cancer has an EGFR mutation or other genetic changes. This testing should be completed before starting any treatment, including chemotherapy or immunotherapy, because knowing your mutation status helps doctors choose the most effective treatment for your specific cancer^[2][6].

The most common way to test for EGFR mutations is through a tissue biopsy. During this procedure, doctors remove a small sample of tissue from your lung cancer tumor. This might be done using a needle or a thin tube called a bronchoscope that passes through your mouth or nose into your lungs. The tissue sample is then tested in a laboratory to check for genetic mutations, including EGFR changes^[2][6][8].

In some cases, doctors may use a liquid biopsy, which is a blood test that looks for cancer cells circulating in your blood. This type of testing may be used when there is not enough tissue available for a standard biopsy or when a tissue biopsy cannot be performed safely. Blood-based testing is showing promise as an alternative or complement to tissue biopsies^[6][8].

It is important to ensure that the laboratory uses comprehensive testing methods, such as next generation sequencing, which can identify many different types of mutations at once. Current guidelines recommend that tumors be tested for at least eight different biomarkers to provide the most complete information for treatment planning^[2][8].

Types of EGFR Mutations

There are many different types of EGFR mutations, with more than 70 or even 200 known variations depending on the classification system used. Different mutations affect the DNA in different ways. Some EGFR mutations cause pieces of genetic material to be missing, and these are called deletions. Other mutations add genetic material, called insertions. Still other mutations involve changes to single building blocks of DNA, called point mutations^[6][8][11].

The most common EGFR mutations are called classical EGFR mutations. These account for nearly 90 percent of all EGFR mutations and include exon 19 deletions and L858R point mutations in exon 21. These classical mutations tend to respond best to targeted therapies^[6][8][11].

Less common types include exon 20 insertion mutations, which occur in about 10 percent of EGFR-positive cases. These mutations historically have been more difficult to treat, but new medications have been developed specifically for them. Another important mutation is T790M, which often develops as a resistance mechanism when cancer stops responding to initial treatments^[11][15][25].

Treatment Options

EGFR-positive lung cancer is most often treated with a type of medication called targeted therapy. Unlike chemotherapy, which affects many cells in the body, targeted therapy specifically finds and attacks cancer cells based on their genetic characteristics. This approach often results in better responses and fewer side effects compared to traditional chemotherapy^[2][6][11].

The main type of targeted therapy used for EGFR-positive lung cancer is called tyrosine kinase inhibitors, or TKIs. These drugs work by blocking the signals that tell cancer cells to grow and spread. When you take a TKI, the drug prevents the EGFR protein from sending growth signals to the cancer cells, which helps keep the cancer under control^[6][16].

There are currently eight FDA-approved EGFR TKIs available for treatment. Most of these are approved for the common EGFR mutations like exon 19 deletions and L858R mutations. Some examples include osimertinib (Tagrisso), afatinib (Gilotrif), gefitinib (Iressa), erlotinib (Tarceva), and dacomitinib (Vizimpro). For patients with exon 20 insertion mutations, specific drugs like mobocertinib (Exkivity) and sunvozertinib (Zegfrovy) have been approved^[6][8][16].

These targeted drugs are typically taken as pills, making them convenient for patients. While they can have side effects such as skin rashes, dryness, and diarrhea, these effects are often manageable with proper support from your healthcare team. Your doctor will choose which TKI is best for you based on your specific type of EGFR mutation, the stage of your cancer, and your overall health^[5][6].

Osimertinib (Tagrisso), a third-generation EGFR TKI, has become the standard first-line treatment for EGFR-mutated non-small cell lung cancer. This medication is particularly effective and can also penetrate the blood-brain barrier better than other drugs, making it useful for controlling cancer that has spread to the brain^[11][16].

When Treatment Stops Working

Even though EGFR-positive lung cancers initially respond very well to targeted therapies, the cancer will almost always develop resistance to the drug at some point. The length of time before resistance develops varies from patient to patient. Some people respond to treatment for many years, while others may experience resistance sooner. The average time until the drug stops working is often measured in months to years^[5][6][16].

When cancer develops resistance to a first-line TKI, doctors can perform additional genetic testing to understand why the treatment stopped working. The most common resistance mechanism is the development of a T790M mutation, which occurs in approximately 30 to 50 percent of patients who develop resistance to first- or second-generation EGFR TKIs. For patients with this resistance mutation, osimertinib (Tagrisso) can be an effective next treatment option^[6][15][16].

Other resistance mechanisms include changes in other genes, such as MET gene alterations, or the development of a C797S mutation. When resistance develops to osimertinib or other treatments, your doctor may recommend additional testing to identify the specific cause of resistance. This information helps guide decisions about next-line treatments, which might include different targeted therapies, chemotherapy, clinical trials, or combination treatments^[11][15].

Research is actively ongoing to develop new therapies for patients who have developed resistance to available treatments. Clinical trials are testing novel drugs with new mechanisms of action, including antibody-drug conjugates and EGFR-MET bispecific antibodies. These advances offer hope that EGFR-positive lung cancer may become a chronic condition that can be managed over many years^[11][16].