A biomarker is defined by the National Cancer Institute as “a biological molecule found in blood, other bodily fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease.” Most often, biomarkers are proteins that can be tested to give information about a person’s particular disease.

In the case of lung cancer, especially the form of non-small cell lung cancer (NSCLC) called adenocarcinoma, biomarkers may be used to help doctors make cancer treatment plans. If a person’s tumor has certain genetic errors (mutations) or makes a specific protein, the person may be treated with specialized medicine that can target those biomarkers in particular.

Understanding Genetic Mutations and Biomarkers

Genes found in DNA provide the instructions for making proteins. When these genes are mutated, cells will make proteins that are also mutated; in some cases, the changes are so drastic that the protein cannot function properly.

Most genes that are mutated in lung cancer are known as oncogenes. Oncogenes are responsible for making proteins that help cells grow and divide, but when these proteins are mutated, the abnormal proteins cause uncontrollable growth and the formation of tumors. Driver mutations are the specific mutations (mostly in oncogenes) that cause cells to become cancerous.

Every tumor is different, and treatments will not work the same for everyone. However, identifying these genetic mutations and their proteins can help doctors better treat cancer. The U.S. Food and Drug Administration (FDA) has approved several targeted therapies that block specific mutated proteins found in lung cancer. There are also ongoing clinical trials for new drugs that may be able to block previously untreatable mutations.

Testing for Lung Cancer Biomarkers

Your doctor will typically take a biopsy to run biomarker testing (also known as molecular testing or genomic testing). Biomarker testing looks for genetic changes or the abnormal expression of certain cancer-related proteins.

Biopsies

First, a biopsy is performed to remove small pieces of tumor tissue for testing. Be sure to confirm with your doctor that enough tissue will be taken to run all of the biomarker tests. Biopsies can be done to collect tissue samples from primary tumors and those that have metastasized and spread to other places in the body.

In some cases, a liquid biopsy (blood sample biopsy) can be done to look for genetic mutations. When tumor cells die, they are broken down and release their DNA into the bloodstream. This circulating tumor DNA, or ctDNA, can be collected in a blood sample and analyzed.

Biomarker Testing

Once the tissue and blood samples have been collected, the samples are sent to a laboratory to be processed and analyzed by a pathologist. In most cases, a biomarker test looks for mutations that are commonly found in lung cancer and that have FDA-approved treatments.

Biomarker testing is done using next-generation sequencing, a process that looks closely at the DNA for any mutations. Some common types of mutations that occur in genes that can cause lung cancer include:

• Gene rearrangements or fusions — One part of a gene fuses with another gene, creating an abnormal protein that leads to uncontrolled cell growth.
• Gene amplification — There are more copies of a gene than normal, causing it to be overexpressed and leading to overactive proteins and uncontrolled cell growth.
• Gene deletions — Part or all of a gene is missing, so little to no protein is made, leading to uncontrolled cell growth.

If you have NSCLC, ask your doctor about getting a comprehensive biomarker test. This test will look for several genetic mutations and abnormal proteins that are known to play a role in lung cancer.

A procedure known as immunohistochemistry (IHC) can also be used to look for different biomarkers. In this test, antibodies that are attached to special dyes are put onto a tissue sample. The antibodies will only bind to the biomarker protein that is being tested for. When they bind to the protein, the dye is activated and can be seen under a microscope.

Types of Lung Cancer Biomarkers

Lung cancer biomarkers are mainly driver mutations that result in mutated proteins. If these biomarkers are identified, a type of targeted therapy called tyrosine kinase inhibitors (TKIs) can be used to help shrink tumors. Biomarkers can include receptor tyrosine kinases, signaling proteins, and immune checkpoint inhibitors.

Receptor Tyrosine Kinases

Driver mutations generally make special proteins known as receptor tyrosine kinases (RTKs). RTKs are responsible for transmitting growth signals from the outside of a cell to the inside. RTK mutations include ALK, EGFR, MET, RET, ROS1, and NTRK.

ALK

ALK mutations can occur when the ALK gene is fused with other genes, the most common being EML4. This mutation creates an abnormal protein that constantly sends growth signals to the cell, even when there is no real signal. As a result, the cell grows and divides uncontrollably and eventually becomes cancerous. Roughly 5 percent of NSCLC cases have an ALK gene fusion.

If the ALK biomarker is found, several TKIs can be used to stop the ALK protein from sending growth signals. These TKIs include:

• Alecensa (alectinib)
• Alunbrig (brigatinib)
• Lorbrena (lorlatinib)
• Xalkori (crizotinib)
• Zykadia (ceritinib)

EGFR

EGFR mutations are found in 10 percent to 15 percent of lung cancer cases. The most common type of mutation is the point mutation L858R. This means that the mutation changed the amino acid lysine into arginine, which changes the shape of the EGFR protein and makes it send growth signals constantly. Other mutations include deletions and the insertion of other genes into the EGFR gene.

Depending on the EGFR biomarker found in testing, several TKIs can be used, including:

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

MET

MET biomarkers in lung cancer involve gene amplification and exon 14 skipping.

MET gene amplification means that there are too many copies of the MET gene in the DNA. This excess of gene copies means that excess proteins are also made. All of these proteins then send growth signals, which cause the cancer cells to grow and divide rapidly.

Exons are pieces of genes that are responsible for giving the instructions to make proteins. In some cases of lung cancer, the MET gene is missing exon 14. Normally, the MET protein will bind to another protein, CBL, to be broken down. However, when exon 14 is missing, CBL cannot bind to MET. This means the protein isn’t broken down and can continue sending growth signals to the cell, leading to uncontrolled growth.

The FDA has approved two MET inhibitors to block these proteins: Tabrecta (capmatinib) and Tepmetko (tepotinib).

RET

The most common mutation that can occur in RET in lung cancer is a gene fusion. These fusions are found in 1 percent to 2 percent of lung cancer cases, most often in adenocarcinomas.

The most common RET fusion is with the gene KIF5b, and the second-most common is with CCDC6. The abnormal proteins made from these gene fusions constantly send growth signals, leading to uncontrolled cell growth.

There are two FDA-approved inhibitors that block the RET protein: Retevmo (selpercatinib) and Gavreto (pralsetinib).

ROS1

ROS1 gene fusions are found in 1 percent to 2 percent of lung cancer cases, generally in adenocarcinomas. The most common fusion partner is the CD74 gene. This fusion creates an RTK protein that constantly sends growth signals.

There are four FDA-approved ROS1 inhibitors, including:

• Lorbrena (lorlatinib)
• Rozlytrek (entrectinib)
• Xalkori (crizotinib)
• Zykadia (ceritinib)

NTRK

In lung cancer, NTRK mutations are caused by gene fusions. The mutations are rare, occurring in less than 1 percent of cases. Three different NTRK genes — NTRK1, NTRK2, and NTRK3 — can all fuse with other genes to create abnormal proteins. These proteins will send constant growth signals, leading to the development of cancer cells.

There are two FDA-approved NTRK inhibitors: Rozlytrek (entrectinib) and Vitrakvi (larotrectinib).

Signaling Proteins

In addition to RTKs, there are other signaling proteins that play a role in lung cancer, including KRAS and BRAF proteins.

KRAS

KRAS is a protein inside the cell involved in sending growth signals. In 13 percent of NSCLC cases, there is a mutation in the KRAS gene known as G12C. This means that the amino acid glycine has been changed to a cysteine. When this change occurs, the KRAS enzyme is in a permanent “activated” state and helps send constant growth signals.

Recently, the drug Lumakras (sotorasib) was developed to block the KRAS protein.

BRAF

BRAF is another protein involved in sending growth signals inside of cells. The BRAF gene can acquire a mutation known as V600E. This means the amino acid valine has been changed to glutamic acid. The mutation changes the shape of the BRAF protein so it constantly sends growth signals.

Tafinlar (dabrafenib) is an FDA-approved BRAF inhibitor used to treat NSCLC cases with this biomarker.

Immune Checkpoint Inhibitors

To find out if you are a good candidate for a type of treatment called immunotherapy, your doctor will look for the presence of the biomarker proteins PD-1 and PD-L1 in and around your tumor. The more PD-1 and PD-L1 that is expressed, the more likely you are to respond to immunotherapy treatment. A pathologist will use IHC on your tumor tissue sample to look for this biomarker.

Several immunotherapies are approved for treating lung cancer, including:

• Imfinzi (durvalumab)
• Keytruda (pembrolizumab)
• Libtayo (cemiplimab-rwlc)
• Opdivo (nivolumab)
• Tecentriq (atezolizumab)

Talk With Others Who Understand

MyLungCancerTeam is the social network for people with lung cancer and their loved ones. On MyLungCancer, members come together to ask questions, give advice, and share their stories with others who understand life with lung cancer.

Have you had biomarker testing done? Share your experience in the comments below, or start a conversation by posting on MyLungCancerTeam.