Non-small cell lung cancer (NSCLC) develops when certain cells mutate in a person’s lungs. By testing for specific genetic mutations, doctors can individualize a person’s treatment. As some people may be more resistant to certain treatments than others, genetic testing can greatly improve their outlook.

Lung cancers begin in the lungs and can spread to other parts of the body. Doctors classify lung cancer types according to the size and shape of the cancer cells seen under a microscope. Around 13% of lung cancers are small-cell lung cancers (SCLC), and 84% are NSCLC.

NSCLC is an umbrella term that includes several subsets, like adenocarcinoma, squamous cell, and large cell carcinoma.

Many people receive a diagnosis of NSCLC after it has spread to other parts of their body. Changes in the DNA of the tumor cells can make the cancer spread faster. By better understanding the DNA in these mutations, doctors can identify the most effective treatment for a person.

According to the Lung Cancer Foundation of America, everyone with a lung cancer diagnosis should undergo this type of biomarker testing.

This article discusses the genetic mutations most common among people with NSCLC. It also looks at genetic testing for these mutations, and how these mutations influence a person’s treatment choices.

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The body consists of millions of cells, and different kinds of cells have different functions. Human cells are constantly dying, dividing, and growing. The genes within a person’s cells control this process of cellular development.

Genes act a little like instruction manuals for the body to follow to produce new cell matter. Genetic mutations are changes within the genes that can alter the instructions that regulate cell death, division, and growth.

Some genetic mutations can cause cells to develop in uncontrolled and unusual ways. These mutations lead to the growth of tumors, some of which can be cancerous.

Genetic mutations are a natural part of life, and many are harmless. However, when the cells in a person’s lungs mutate in certain ways, NSCLC can develop.

These NSCLC-causing mutations can arise randomly. However, scientists estimate that roughly 90% of lung cancers are linked to tobacco use. Other causes include:

  • alcohol use
  • exposure to ionizing radiation
  • exposure to radon
  • exposure to asbestos

Learn more about the importance of genes.

There are many different kinds of genetic mutations. When an expert tests this sample of lung tissue, they will look for genetic mutations that scientists know can cause NSCLC.

A 2020 study found various NSCLC mutations, including to the following genes:

  • EGFR
  • BRAF
  • ALK
  • RET
  • NTRK
  • ROS1
  • HER2
  • KRAS

EFGR Exon 20 gene

Around 30% of NSCLC tumors result from a mutation in the epidermal growth factor receptor (EGFR) gene. Between 85% and 90% of EGFR mutations involve Exon 19 and Exon 21 mutations. The remaining 10% to 15% involve less common mutations, such as Exon 20 insertion mutation. The Exon 20 mutation is growing in prevalence due to researchers’ better understanding of rare gene mutations in NSCLC.

People with Exon 20 insertion mutations do not respond well to erlotinib, gefitinib, and the second-generation EGFR inhibitor afatinib. This means treatment may be more limited in this group.

However, researchers have developed candidate inhibitors that target the EGFR exon 20 insertion mutant kinase. This means that, in the future, these medications may be an effective treatment option for people with this molecular subtype of NSCLC.

Genetic testing means that doctors can personalize treatment plans based on the mutations they identify in a person’s cells.

For example, researchers in the 2020 study mentioned above analyzed the genes of 256 people in China with NSCLC. They found that the most common genetic mutations among these participants were to the EGFR, ERBB2, and KRAS genes. Of the total participants, 63% had two or more mutations.

One participant had an uncommon mutation in two genes. This means one of the genes could develop a resistance to certain medications, which directed doctors to use a different type of treatment that might be more effective.

When doctors know which genetic mutations are associated with a person’s NSCLC, they can use an agent such as tyrosine kinase inhibitors (TKIs) to provide the best, most personalized treatment possible.

TKIs are drugs that can travel through the cell membrane. By stopping various genes and proteins from doing their jobs, these drugs interfere with the processes that cause cancer cells to grow and divide.

Different genetic mutations require different TKIs. Although many such drugs exist, doctors tend to use some more than others. For instance, the National Cancer Institute (NCI) lists the following common TKIs:

  • EGFR inhibitors: erlotinib, gefitinib, afatinib, osimertinib, dacomitinib
  • BRAF inhibitors: dabrafinib
  • ALK inhibitors: crizotinib, entrectinib, ceritinib, alectinib, brigatinib, and lorlatinib
  • RET inhibitors: selpercatinib
  • NTRK inhibitors: larotrectinib
  • ROS1 inhibitors: crizotinib and entrectinib

As the list indicates, some TKIs can target multiple genetic mutations. For instance, crizotinib can target ROS1 and ALK.

Other mutations have proven more resistant to existing TKIs. However, scientists are working hard to develop more effective treatment options.

For example, a 2019 study from Korea reports that earlier research did not find HER2 TKIs to be very effective. However, the same study notes that some newer drugs may better target the HER2 gene. These include:

  • ado-trastuzumab emtansine (T-DM1)
  • afatinib
  • dacomitinib

Similarly, the NCI notes that a KRAS inhibitor known as sotorasib may reduce tumor size in people with NSCLC who have a mutation in that specific gene.

Learn more about treatment options for NSCLC.

According to the NCI, doctors perform genetic testing by first taking a small sample of abnormal-looking tissue from a person’s lungs. This is known as a biopsy. Doctors do this by using a very fine needle, which sucks up the sample of lung tissue.

They can locate the tissue by using imaging technology, like a CT scan, or performing a procedure known as a bronchoscopy, which involves inserting a flexible fiberoptic scope into the person’s airway. Sometimes, the scope has an ultrasound probe at the tip to help locate cancerous tissue.

The doctors then send the sample to a laboratory for testing, where it can diagnose the type of cancer and its stage.

Once doctors suspect that someone’s symptoms may be NSCLC, they can use various techniques to reach a diagnosis.

Imaging techniques can help doctors detect lung tumors and track their development. These can include:

Doctors can also use laboratory tests to look for cancer cells. For example, in sputum cytology, a doctor investigates a sample of mucus from a person’s cough.

Other laboratory tests require more invasive procedures to collect a sample for testing. For instance, doctors may test lung tissue for cancer cells by performing a lung biopsy. Doctors may also need to investigate the fluid between a person’s chest and lungs.

According to the American Cancer Society, lung cancer typically presents with the following symptoms:

In rare cases, lung cancer can also cause shoulder pain, hand muscle atrophy, and Horner syndrome, a disruption of the nerves that control a person’s eyes and face.

Doctors can sometimes mistake lung cancer for conditions that have similar symptoms. These include:

It is also possible for someone’s lung cancer to develop in a symptomless way, at least in the early stages. Indeed, a 2018 article notes that most lung cancer diagnoses occur during the more advanced stages of the disease.

Specific gene mutations can cause NSCLC. Doctors can choose the most effective treatment by identifying which genes have mutated in a person’s lungs. Since not everyone with NSCLC has the same gene mutations, this treatment will vary from person to person.

Receiving personalized treatment based on genetic testing can significantly improve the outlook of a person with NSCLC.