Molecular Testing & Biomarkers
Precision medicine has become an important part of treating non-small cell lung cancer (NSCLC). It involves doctors learning specific information about a person’s tumor. These findings can be used to make a diagnosis, plan treatment, find out how well treatment is working, make a prognosis, and monitor for progression or recurrence. Precision medicine is possible because of molecular testing.
What is Molecular Testing?
Molecular testing uses samples of blood or tissue to identify a tumor’s genetic mutations (changes) that could indicate the cancer’s behavior, how aggressive it might be and if it will metastasize (spread). It is typically first performed along with other diagnostic tests before treatment begins to determine whether the tumor’s mutations qualify it for specific treatments, such as targeted therapy or immunotherapy.
Understanding the types of mutations your tumor has will help you make better decisions with your doctor about your treatment options. It offers the possibility of treating the cancer more effectively without damaging healthy cells and may spare you from aggressive treatments that may have many side effects.
Molecular testing uses specific tests to examine tumor tissue and sometimes blood to find possible mutations in genes, chromosomes, proteins, enzymes or other molecules, and to look for biomarkers. Biomarkers are molecules produced or shed by cancer or other cells as a response to cancer and are a sign that cancer is present.
This testing is recommended specifically for NSCLC patients – especially if the cancer is advanced – because starting treatment right away offers the best chance for a positive outcome. It may also be done during treatment for monitoring purposes.
Tissue testing is most commonly used for these tests, but liquid biopsies are increasingly being used in some hospitals because of the ease and convenience of taking a blood sample versus a tissue sample. Liquid biopsies are used to test for mutations by looking for circulating cancer cells shed from the tumor or pieces of DNA from the tumor.
If certain mutations or biomarkers are found, you may be eligible for precision medicine in the form of targeted therapy and immunotherapy.
Targeted therapies are designed to block the action of certain enzymes, proteins or other molecules involved in the growth and spread of cancer cells. These therapies are designed to target specific mutations or biomarkers and leave healthy cells alone, which can mean fewer side effects. Immunotherapies stimulate or suppress the immune system to help the body find cancer. Some types of immunotherapy only target certain cells of the immune system.
Biomarkers for Targeted Therapies
As part of diagnosis, most NSCLC patients will be tested for epidermal growth factor receptor (EGFR ) mutations and anaplastic lymphoma kinase ( ALK ) fusions, which are the two most common biomarkers in NSCLC for which targeted therapies have been created.
EGFR plays a role in regulating cell growth and survival. When EGFR is mutated, it drives abnormal cell growth so that the cancer grows unchecked.
The ALK gene is normally activated while a person is still in the womb but shuts off before the baby is born. In some people, it gets turned back on later in life and fuses with another gene. When this happens, it is known as an ALK fusion or ALK rearrangement, and the cancer is considered ALK -positive.
Other biomarkers that have been found in NSCLC include BRAF , KRAS , MET , ERBB2 ( HER2 ), NTRK , RET and ROS1 . Although not everyone with NSCLC will have a biomarker that can be treated with a specific targeted therapy, research is ongoing to find more mutations and therapies to treat them.
The tests commonly used for determining EGFR and ALK status include immunohistochemistry and fluorescence in situ hybridization (FISH). If your doctor wants to check for multiple possible biomarkers, next-generation sequencing (NGS) is used. This technique enables the processing of multiple DNA sequences simultaneously with more speed and accuracy than single-gene tests. NGS can be done on both tumor tissue and blood, and at present can detect abnormalities that may be treated with specific therapies.
Qualifying for Immunotherapy
Molecular testing may also be used to look for other abnormalities that may make you eligible for immunotherapy. Your doctor may look for any of the following factors.
PD-L1 expression may be tested to determine whether 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 a type of immunotherapy known as immune checkpoint inhibitors. Research has shown that people with a high level of PD-L1 expression sometimes 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.
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, 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.
When cells lose the ability to correct errors, it is known as deficient mismatch repair (dMMR). 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 and dMMR features appear to respond better to immunotherapy, though this is rare in lung cancer.