If you have non-small-cell lung cancer (NSCLC), your disease began with changes to your genes. These changes, called "mutations," cause your lung cells to grow out of control.

Scientists are learning more and more about the way these gene changes help the cancer grow and spread. There are new drugs, called targeted therapy, that zero in on the specific mutations you have.

After you're diagnosed with NSCLC, you may get tested to see which mutation you have. This helps your doctor decide on your treatment plan and if a targeted therapy is a good idea for you.

How Gene Mutations Happen

What are genes? Genes are pieces of DNA inside each of your cells. They tell the cell what to do and how to divide, which is the way cells multiply. Scientists give each gene a name to remember them.

What are gene mutations? Mutations are permanent changes in your DNA. They can affect how a cell works. For example, they may have an impact on how it grows and divides.

Why do you get gene mutations? Sometimes mutations are passed to you from your parents. These are called "inherited" or "hereditary" gene changes. In lung cancer, mutations usually aren't inherited. Instead, the changes are what doctors call "acquired" mutations. They happen during your lifetime.

Things outside your body, like breathing in tobacco smoke, lead to gene mutations. Air pollution, certain chemicals, and radon gas are also causes. In a small portion of lung cancer cases, these acquired gene mutations are just random things that happen. Your DNA changes inside your cell without any outside trigger.

How do gene mutations cause cancer? Changes in your DNA can have two big effects:

"Turn on" the genes that help your cells grow, divide, or stay alive.

"Turn off" the genes that make sure cells divide or die at the right time.

The result of all these changes to your genes: Some cells become cancerous and grow out of control.

Types of Gene Mutations

Researchers are working all the time to look for new kinds of gene mutations. So far, they've discovered more than a dozen that are linked to NSCLC.

Some mutations are more common than others. Your mutation might be one of these:

The Most Common Gene Mutations in People With NSCLC

Who gets gene mutations

The type of gene mutation you have often depends on what kind of lung cancer you have. There are three main types of NSCLC:

  • Squamous carcinoma. The cancer begins in squamous cells, the flat cells that line the inside of the lung airways.
  • Adenocarcinoma. The disease starts in cells that release substances, like mucus.
  • Large cell carcinoma. This cancer shows up in any part of the lung.

Anyone can get a gene mutation that causes lung cancer. But scientists have noticed that some mutations tend to show up more often in certain groups of people, like smokers or nonsmokers, or men or women.

Here's how some common mutations affect the way your cancer grows, and who's likely to get them.

EGFR

This gene controls a protein called "epidermal growth factor receptor." This protein helps your cells grow and divide. An EGFR mutation is more common in women, people who don't smoke, and those with the adenocarcinoma type of NSCLC.

KRAS

The KRAS gene plays a role in making a protein called K-Ras, which helps cells grow and divide. You're more likely to have a KRAS mutation if you have the adenocarcinoma type of NSCLC.

FGFR1

A mutation on this gene also affects how your cells grow and spread. It's more likely to happen if you have the squamous carcinoma type of NSCLC. Smoking also raises your risk of this mutation.

ALK

In this mutation, two genes fuse together to create a new one. ALK mutations often show up in people who never or rarely smoked and have the adenocarcinoma type of NSCLC. It's also more common in younger people, such as those in their 50s, and men.

MET

When you have this kind of mutation, there's a glitch that creates too many copies of the MET gene. This causes cells to live too long, divide, and spread. It happens if you have the squamous or adenocarcinoma types of NSCLC.

PIK3CA

This gene plays a role in how your cells grow and divide. You're more likely to have a mutation on this gene if you're a smoker. It also happens if you have the squamous or adenocarcinoma type of NSCLC. Your doctor may also mention mutations on the AKT, PTEN, or mTOR genes, which are linked to PIK3CA.

BRAF

A change to this gene is more common if you have the adenocarcinoma type of NSCLC.

ROS1

This mutation is similar to the ALK one. It's more likely to happen if you have the adenocarcinoma kind of NSCLC, haven't smoked, and are younger.

NTRK

In this mutation, the NTRK gene fuses with other genes. Research shows men and women from all age groups and NSCLC types can have this happen. Smokers and nonsmokers alike can also get it.

RET

This type of mutation happens only if you have the adenocarcinoma kind of NSCLC. It's more common in nonsmokers.

HER2

A mutation on this gene encourages the growth of cancer cells. This most often happens if you have adenocarcinoma NSCLC. It's more common among women and people who never or rarely smoked.

Tests for Gene Mutations

Doctors can check a sample of your lung cancer tissue -- or, in some cases, a blood sample -- to find out what kind of gene mutation you have. You may hear your doctor call these kinds of tests by many different names, such as "biomarker," "molecular," or "genomic" testing.

How does your doctor get a tissue sample? You'll need to have a procedure to remove a small amount of tissue. Your doctor will recommend one based on where your tumor is located.

Some procedures that your doctor may suggest are:

  • Bronchoscopy. A doctor puts a thin, flexible tube with a light and camera on the end through your mouth or nose. It travels to your lungs. Tiny tools pass through the tube to take tissue samples.
  • Transthoracic needle biopsy. A doctor uses a CT or ultrasound to put a needle into your chest and remove tissue or fluid.
  • Video-assisted thoracoscopic surgery (VATS). A surgeon makes a small cut in your chest to put in a special video camera and take samples.
  • Mediastinoscopy. Your doctor puts a thin, flexible tube with a light and camera on the end through a cut in your breastbone. They move it to the area between your two lungs, called the mediastinum, to take a sample.

How long does it take to get results? After your sample reaches the lab, it takes about 1 to 4 weeks.

How does your doctor decide which test you should get? It partly depends on what kind of NSCLC you have. Most of the targeted treatments for gene mutations are for the adenocarcinoma and large cell carcinoma type.

Your doctor may also suggest certain tests that are better at screening specific mutations. Some tests deliver results faster than others, and some may cost more than others.

Technology keeps changing, but right now, these are the kinds of tests your doctor may suggest you get:

Sequencing

Why you get it. It's one of the earliest tests for checking gene mutations. Doctors don't use this method as often, because it's not as sensitive as newer tests.

How it works. The test checks the entire length of a single gene to find a mutation.

Allele-specific testing

Why you get it.This test searches for one mutation. It's faster, less expensive, and more accurate than sequencing. It's useful for multiple genes, including EGFR, MET, BRAF, HER2, and KRAS.

How it works. It analyzes DNA for one specific mutation.

Next-generation sequencing (NGS)

Why you get it. It can spot more mutations than sequencing or allele-specific testing. Instead of running a series of tests for different mutations, you may only need one NGS test. It's usually faster than other tests. Your doctor does the test on samples of your tissue or blood.

How it works. NGS uses computer technology to sequence many fragments at once. It checks multiple genes.

Fluorescence in-situ testing (FISH)

Why you get it. It can be helpful to identify ALK, ROS1, and RET mutations.

How it works. Researchers use short fragments of single-stranded DNA called "probes" attached to a colored dye. When these probes bind to your DNA, they map out certain genetic material.

Immunohistochemistry (IHC)

Why you get it. It's used to detect ALK and ROS1 mutations. IHC is usually cheaper and faster than FISH testing.

How it works. IHC tests proteins attached to a fluorescent dye. They're added to your tissue sample, where they bind to DNA. This helps highlight genetic changes.

Liquid biopsies

Why you get it. Liquid biopsies are blood tests that measure DNA that's shed from tumor cells. They're used to detect EGFR mutations, although scientists are also studying other genes. The advantage of this test is that you don't need to have a procedure to get a tissue sample. You also get the results faster.

How it works.Technicians examine DNA to check for specific mutations.

Choosing a Treatment for Your Gene Mutation

Learning which gene mutation you have helps your doctor figure out if you can use a targeted treatment -- and which one is best. You may also get other treatments, like chemotherapy and radiation.

Targeted therapies zero in on the mutations that help cancer cells grow, divide, and spread. Because they target cancer cells and not healthy ones, they usually have fewer side effects than other cancer treatments. Most of them work in one of two ways:

  • Monoclonal antibodies are proteins that attach to certain targets on cancer cells. They may kill the cells, cause them to self-destruct, or stop their growth.
  • Small-molecule drugs are tiny enough to enter cells. They can stop the process that helps cancer cells divide and spread.

Although scientists are learning more and more about gene mutations, only some gene changes can be treated with targeted therapy. Some treatments are now approved by the FDA. Others are prescribed "off label" by doctors, which means the drugs are approved for other conditions besides NSCLC. Still other drugs are available only if you join a clinical trial.

There are "approved" treatments for these gene mutations:

  • EGFR
  • ALK
  • ROS1
  • BRAF
  • NTRK

There are "off-label" treatments for these gene mutations:

  • HER2
  • MET
  • RET

There are clinical trials for these gene mutations:

  • KRAS
  • PIK3CA
  • AKT1
  • PTEN

There are many different targeted therapies for NSCLC. Your doctor will choose one based on your genetic mutation.

For example, an EGFR inhibitor blocks the EGFR protein from telling cancer cells to grow. For cancers with an ALK mutation, a change in the gene creates an abnormal protein. It tells cells to grow and spread. ALK inhibitors target this protein.

Clinical Trials

Clinical trials are studies that check to see if new treatments are safe and work right. Many of these trials are trying to find out if drugs can target specific gene changes.

Why you might want to join one. Some trials give you a chance to try new drugs that aren't available yet for the general public. These medicines may work better than the ones that have already been approved by the FDA. In some cases, the cost of the treatment may be covered by the study sponsor.

What to expect. Your doctor will see if your type of gene change matches a specific drug that's getting tested in a trial. If it does, you'll meet the researchers. They'll explain the details and answer your questions. You'll sign a written consent form to join the study.

Before you start, you'll likely get a physical exam and some testing. During treatment, you may get extra checkups and care from your health care team.

​Reviewed By Neha Pathak, MD on December 11, 2020​

American Association for Cancer Research Progress Report: "Liquid Biopsy Approved for Lung Cancer."

American Cancer Society: "Clinical Trials: What You Need to Know," "Mediastinoscopy," "Targeted Therapy for Non-Small Cell Lung Cancer," "What Causes Lung Cancer?"

American Lung Association: "What You Need to Know About Lung Cancer Testing."

Clinical Cancer Research: "Effects of Co-Occurring Genomic Alterations on Outcomes in Patients with KRAS-Mutant Non-Small Cell Lung Cancer."

Clinical and Translational Medicine: "Clinical Potential of Gene Mutations in Lung Cancer."

CytoJournal: "Next-Generation Sequencing in Non-Small Cell Lung Cancer Using a Customized, Targeted Sequencing Panel."

JCO Clinical Precision Oncology: "Clinicopathologic Features of Non-Small-Cell Lung Cancer Harboring NRTRK Gene Fusion."

Jorge Gomez, M.D., assistant professor, Mount Sinai School of Medicine; volunteer spokesperson, American Lung Association.

Journal of Clinical Oncology: "Clinical Features and Outcome of Patients with Non-Small-Cell Lung Cancer Who Harbor EML4-ALK."

Journal of the National Comprehensive Cancer Network: "What, When, and How of Biomarker Testing Non-Small Cell Lung Cancer."

Lung Cancer Foundation of America: "What are the Most Commonly Tested Mutations and Treatments?" "What Do I Need to Know About Genetic Mutation Testing?"

LUNGevity Foundation: "Biomarker Testing."

Memorial Sloan Kettering Cancer Center: "Lung Cancer Genomic Testing (EGFR, KRAS, ALK)."