Lung Cancer

MOLECULAR TESTING

BIOMARKERS IN IMMUNOTHERAPY FOR LUNG CANCER

Cancer is caused by mutations in your genes, which are pieces of DNA. Research has found several specific genetic mutations that lead to lung cancer. Doctors can test for these mutations as part of the diagnostic process by looking for biomarkers, which are the molecules produced by the cancer cells or other cells in the body in response to cancer. Testing for biomarkers is known as molecular testing. It may include testing for specific genes, proteins or molecules of the tumor and can be measured in the blood, plasma, urine, cerebrospinal fluid or other body fluids or tissues. Biomarkers are also known as tumor markers, molecular markers, biological markers or serum markers.

 Most molecular testing for lung cancer looks for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions, for which several targeted therapies have been developed. Researchers have identified other biomarkers that are involved in some types of lung cancers. National guidelines currently recommend the following genes be tested if lung cancer is suspected: ALK, BRAF, EGFR, MET, ERBB2 (HER2), NTRK, RET and ROS1.

Next-generation sequencing (NGS) is used to test these genes. This technique is capable of processing multiple DNA sequences simultaneously with more speed and accuracy. NGS can be done on both tumor tissue and blood and, at present, can detect abnormalities associated with specific therapies.

To find out if you are a candidate for immunotherapy, your doctor may also look for the following factors along with molecular testing:

  • PD-L1 expression may be tested to determine if the tumor cells or immune cells in the tumor’s microenvironment contain a higher level, which may mean you could be a good candidate for immune checkpoint inhibitors.

Index

  • Tumor mutational burden (TMB) is an assessment of the number of genetic mutations in a tumor. It can also help doctors determine if you will respond to immunotherapy. It is believed that the higher the TMB level is, the more likely you will be to respond.
  • Microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) may be tested to determine if the cancer is caused by genes that have problems repairing themselves. MSI-H describes cancer cells that have a greater than normal number of genetic markers called microsatellites, which are short, repeated sequences of DNA. Every time a cell reproduces itself, it makes a copy of its genes and DNA. During the process, errors in duplication can be made, much like a misspelled word. The body normally corrects the error, but sometimes it isn’t caught and fixed. It then becomes a mutation that is reproduced in later versions of the cell. Cancer cells that have large numbers of microsatellites may have defects in the ability to correct mistakes that occur when DNA is copied. Cancers with MSI-H features appear to respond better to immunotherapy.

Research has shown that people with a high level of PD-L1 expression also typically respond better to immunotherapy. In addition, the level of expression will help your doctor determine whether to give immunotherapy alone or in combination with chemotherapy. People who have tumors with 50 percent or more PD-L1 expression are usually considered good candidates for immunotherapy as a single treatment. If the amount is less than 50 percent, people may be treated with a combination of one or two types of chemotherapy along with an immunotherapy. However, not everyone with a high PD-L1 expression should be given immunotherapy, especially someone with an active EGFR mutation.

Not all people who receive immunotherapy respond. In some cases, people with high expressions of PD-L1 do not respond to immunotherapy. Some people with a low PD-L1 expression do respond but less often. Researchers are not sure why this happens and more research is needed so immunotherapy is not given to someone who may not respond to it.

Inform your doctor if you have an autoimmune disorder, such as Crohn’s disease, ulcerative colitis or lupus. An autoimmune condition means you have an overactive immune system, and introducing immunotherapy may increase potential safety risks and life-threatening toxicities. Also let your doctor know if you've received immunotherapy before because previous treatments may affect your doctor’s treatment decisions.