If you’ve been diagnosed with non-small cell lung cancer (NSCLC), one of the first conversations to have with your clinician should be about testing your tumor tissue for cancer biomarkers. Biomarkers can be gene changes or high levels of proteins that are known to cause cancer. They can give your clinician important information about your cancer, including how it might respond to treatment.
“According to National Comprehensive Cancer Network guidelines, everyone with a stage 2 or higher lung cancer should undergo molecular testing,” said David Tom Cooke, M.D., chief of general thoracic surgery at UC Davis Health. “There are FDA-approved regimens that tackle the major genetic mutations involved in lung cancer and have been shown to improve disease-free survival.”
Cooke noted that not all people with lung cancer receive initial biomarker testing as soon as they’re diagnosed, despite the guidelines being clear. “Don’t be afraid to ask your doctor for testing before any treatment begins,” he said. “Just politely say, ‘I would like to have my tumor undergo biomarker testing or next-generation sequencing.’”
Biomarker testing requires only small sample
Lung cancer is diagnosed with a bronchoscopy, a minimally invasive procedure that lets your clinician look inside your lungs. The clinician will use a thin tube with a light and camera on it. If they see a mass of cells in your lungs, they will use tiny tools to take a piece of the tumor to send to the lab.
To do biomarker testing for lung cancer, clinicians in the hospital lab will run tests on the tumor sample removed during your bronchoscopy. Ideally, your clinician will order next-generation sequencing, which uses one sample to test for many genetic mutations.
If your clinician wasn’t able to perform a lung biopsy to remove tumor cells, some biomarkers can also be identified with a blood test, called a liquid biopsy. Your clinician will explain more about what they need to complete your biomarker testing.
Lung cancer biomarkers
Genetic biomarkers often occur as mutations on one or more of these genes:
- EGFR – The epidermal growth factor receptor (EGFR) protein helps cells grow. Changes, or mutations, in the EGFR gene, most commonly EGFR exon 19 deletions or EGFR L858R mutations, can lead to lung cancer. These mutations tell clinicians what type of change in the DNA occurred. EGFR mutations account for 10%–15% of cases of lung cancer in the U.S. People who develop EGFR-positive lung cancer are most likely to be younger never-smokers. Asian people are also more likely to have EGFR mutations.
- ALK – The anaplastic lymphoma kinase (ALK) gene is active in humans while they’re still in the womb, then usually shuts off before birth. In some people, the ALK gene turns on again later in life and fuses with another gene, which can lead to cancer. ALK mutations account for about 4% of lung cancers in the U.S.
- ROS1 – In ROS1-positive lung cancer, the ROS1 gene has fused with another gene, most often CD74, to cause the cancer. ROS1 gene changes occur in about 1%–2% of patients with lung cancer and generally occur in adenocarcinomas.
- BRAF V600E – In this mutation of the BRAF gene, one amino acid gets switched out for another. BRAF V600E-mutated cancers are most often seen in melanoma but can also occur in lung adenocarcinomas.
- NTRK – In a cancer that tests positive for an NTRK (pronounced “en-trek”) gene fusion, a piece of the NTRK gene fused with a piece of another gene. This mutation is relatively rare in lung cancer. NTRK fusions are also seen in breast and colorectal tumors, as well as 20+ other tumor types.
- MET – Currently, two possible changes to the MET gene can cause lung cancer. In MET exon 14 skipping, a mutation causes a specific part of the gene to be removed. In MET gene amplification, there are too many copies of the gene.
- RET – The most common mutation of the RET gene in lung cancer is a fusion with another gene. This type of mutation is also called RET rearrangement.
- KRAS – The KRAS (pronounced “kay-ras”) gene helps control communication between cells. A G12C mutation of the KRAS gene is a frequent cause of lung cancer.
- HER2 – Human epidermal growth factor receptor 2 (HER2) acts like an on/off switch for cells, much like EGFR. When HER2 is broken, it gets stuck in the “on” position and allows cancer cells to grow. In lung cancer, the HER2 gene can either have a mutation or too many copies. Your clinician may also refer to HER2 as ERBB2. HER2 gene mutations also play a role in other types of cancer, including breast cancer.
- NRG1 – This mutation occurs when two parts of a gene fuse together, leading to abnormal cell growth and, sometimes, cancer. NRG1 gene fusions are often found in a subtype of NSCLC called invasive mucinous adenocarcinoma.
Protein biomarkers can help provide information on whether the cancer cells will respond to immunotherapy. Immunotherapy works by training the immune system to recognize and attack cancer cells.
- PD-L1 – PD-L1 is protein that is found on the surface of some cells. When cancer cells have high levels of PD-L1, they turn off immune cells that exist to fight diseases, including cancer. PD-L1 blocks immunotherapy, but drugs known as PD-L1 inhibitors prevent that from happening, enabling the immune system to destroy cancer cells.
- TMB – Tumor mutational burden measures the number of mutations inside a tumor. The mutations lead to production of abnormal proteins by the cancer cells. Immunotherapy may work if your tumor has at least one abnormal protein that the immune system can recognize.
Therapies for lung cancer
Currently, at least one targeted therapy exists to treat each of these genetic mutations. “Targeted therapies” are called that because they target only the specific cancer-causing protein in each tumor.
One of the most common class of targeted therapy drugs for lung cancer are called tyrosine kinase inhibitors (TKIs). Your clinician will choose the right TKI for your tumor type, mutation, disease stage and any prior treatments.
Targeted therapies won’t work on people who don’t have the specific mutation each drug is designed to treat. But people with lung cancer who don’t have any actionable genetic mutations may receive chemotherapy and/or immunotherapy. Immune checkpoint inhibitors, a type of immunotherapy, often can be used to treat people whose tumors express high levels of PD-L1 or high TMB.
Lung cancer remains a serious diagnosis, but your clinician is more likely than ever before to have information about your tumor that they can use to develop the treatment that is most likely to treat your cancer. And, when it comes to lung cancer, knowledge — and personalized medicine thanks to today’s latest biomarkers — can make all the difference.
This educational resource was created with support from Daiichi.
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