Navigating Biomarker Testing: Frequently Asked Questions

Not all lung cancers are the same. When scientists look at tissue from a person’s lung cancer tumor under a microscope they can tell what type (non-small cell, small cell or carcinoid) and subtype the lung cancer is.

Now there is a way to get more detailed information about the makeup of the tumor. It involves testing tumor tissue for abnormalities in its DNA and levels of specific proteins in the tumor. These tests are sometimes called biomarker, molecular, or genomic testing.  If doctors know exactly what causes the tumor to grow, a patient may be able to go on a "targeted" therapy that can slow tumor growth or shrink the tumor. Testing can also show levels of an important protein called PD-L1 which may help predict if a patient would benefit from immunotherapy.

Currently, biomarkers with approved targeted treatments are most common in patients with a subtype of non-small cell lung cancer (NSCLC) called adenocarcinoma. While other types of lung cancer may occasionally have these biomarkers, tumor testing is generally not performed for squamous cell or small cell lung cancers unless the patient does not have a smoking history. If that is the case, then biomarker testing should be performed on these cell types. Not everyone with lung cancer will have biomarkers that can be treated with targeted therapies. While lung cancer biomarker testing is a promising field, it does not guarantee a cure. All patients should have their PD-L1 levels tested to determine if they may be candidates for immunotherapy.

If your doctor doesn't recommend biomarker testing for you, you can ask why. Biomarker testing may not be right for every person. If you have questions about whether or not your tumor should be tested, you may want to seek a second opinion. It is important to work closely with your doctor to discuss all your treatment options at every step of your journey.

The best time to talk to your doctor about tumor testing is before a biopsy is done. This helps ensure that your doctor removes enough tissue during the biopsy to perform comprehensive biomarker testing. It is also important to talk about additional biomarker testing if your cancer continues to grow after you have been on a targeted therapy.

When you speak with your doctor, mention that you want to discuss comprehensive biomarker testing, also called next generation sequencing (NGS). NGS testing is strongly recommended for all patients with non-small cell lung cancer, including those at advanced stages, in order to capture a full genomic profile—especially because missing any actionable mutations could limit treatment options.

Liquid biopsy results take about 5-7 days. Tissue biopsy results take about 2-4 weeks (depending on if it is done in house or needs to be sent out). Ideally, patients (particularly patients with limited or no smoking history) should not be started on immunotherapy before test results come back. If necessary, patients can start on chemotherapy.

The answer to this shows just how important it is to participate in research if you have the opportunity! It used to be that testing was only relevant for patients whose disease had spread outside the lung, or metastatic disease. But now, researchers have learned that some patients who have early-stage disease should receive a targeted therapy after surgery whereas others should receive immunotherapy. If neoadjuvant therapy is being considered, biomarker testing should be done before surgery. This is one example of why it is important for patients to know if they have any biomarkers before making any treatment decisions. 

If you've already has a tissue biopsy but your tumor was not tested for biomarkers, you may want to ask your doctor if comprehensive biomarker testing is right for you and if there is any leftover tissue from the biopsy that can be tested. If there isn't enough tissue, your doctor might consider doing another tissue biopsy or performing a liquid biopsy, or blood test. Liquid biopsies can quickly identify several types of important biomarkers and serve as a complementary tool to tissue biopsy, helping guide treatment decisions. They are also used in initial testing if tissue is unavailable and can be used for monitoring after treatment to check for resistance or recurrence. Lung cancer treatment can sometimes change the makeup of a tumor, so your doctor may recommend another tissue or liquid biopsy if your tumor has become resistant to treatment. This allows doctors to get the most accurate and timely information available about your tumor.

Sometimes treatment can cause a tumor makeup to change or the tumor to become resistant to targeted therapy. Ask your doctor about re-testing your tumor after your first treatment.

If you have non-small cell lung cancer, it is important to discuss comprehensive biomarker testing with your doctor. This type of testing looks for several genetic mutations, alterations and proteins in all the genes known to be associated with lung cancer. This gives doctors a full picture or "genomic profile" of your tumor. Test results will show if you have a biomarker that can be treated with an FDA-approved targeted therapy, or if you are likely to benefit from immunotherapy. Testing results will also provide information about markers that are possibly being studied in clinical trials. This helps doctors make better-informed treatment recommendations to customize your treatment plan.

Your tissue may be tested at the hospital or clinic where you are being treated or sent to a certified company and laboratory. Your oncologist should order these tests and work with the pathology department in your hospital or clinic to arrange for your tissue to be sent to the right place. Results from this testing usually take one to two weeks. Biomarker testing is not always covered by insurance. Your doctor, nurse navigator or financial support team may be able to help with understanding your insurance coverage. Still, it is important to ask about any out-of-pocket costs associated with biomarker testing.

If your tumor wasn't tested before you started treatment, it might not be too late. Ask your doctor about testing leftover tissue or doing a liquid biopsy (blood draw).

Patients may hear other patients and medical professionals use the phrase “full battery of genomic testing,” or something similar. There are many different genomic/biomarker tests and each one is slightly different. However, the ideal test would be next generation sequencing (NGS). NGS tests for the following biomarkers:

• EGFR mutations
• ALK rearrangements
• ROS1 rearrangements
• RET rearrangements
• NTRK rearrangements
• MET exon 14-skipping mutations
• MET gene amplification
• BRAF mutations
• HER2 mutations
• KRAS mutations
• NRG1 fusions

To round out the data, your doctor should test your tumor’s PD-L1 level, which is not included in an NGS test but provides information about whether or not you might benefit from immunotherapy. There are other relevant markers that may provide important information to your doctor, however all of the major NGS companies and all of the NGS testing that goes on in hospitals includes the important markers.

Ideally, the patient should not have to choose the biomarker test. Hospitals adept at treating lung cancer patients either have next-generation sequencing (NGS) tests in-house or contract with an outside company. Even though in-house hospital NGS may not look for as many markers as a commercial outside company, they look for all of the relevant markers for lung cancer and both are equally reliable. If your hospital has done NGS on your lung tissue, you do not need to repeat the test with another company. If you do find yourself in the position of deciding on a biomarker test, look for a commercial vendor that does DNA and RNA sequencing. RNA sequencing helps detect fusions (also called rearrangements) like ALK and ROS1, which can be hard to detect in DNA sequencing. Cheaper tests are not less reliable. Sometimes newer tests can cost more, but if a test has been around longer it can be offered at a cheaper rate.

Liquid biopsies are highly specific but not as sensitive as tissue biopsies. That means, if a biomarker appears in a liquid biopsy, the physician is pretty confident the patient has that biomarker. However, if something doesn’t show up on a liquid biopsy, it doesn’t mean it’s not there. Kind of like if you looked in your closet for a shirt and saw it, you would know it is there. But if you didn’t see it, it doesn’t mean it’s not in the closet. It could have been hidden in the back or fallen on the floor.

There are a few situations that make liquid biopsies less likely to pick up results. Liquid biopsies work by looking at DNA that has been shed into the bloodstream by cancer cells. If a patient is responding well to treatment or if there is not a lot of disease in the body, there is less circulating tumor DNA, which might mean the liquid biopsy misses something.

In general, liquid biopsies are very accurate at finding point mutations like mutations in EGFR. They are slightly less accurate when finding more complex alterations such as gene fusions lor extra copies of a gene (referred to as amplification). Liquid biopsies are not able to detect histology changes like when some patients’ lung cancers change from non-small cell to small cell after treatment. However, tests are improving rapidly.

Liquid biopsies do not diagnose lung cancer, but instead may provide more information important in treatment decision-making. Liquid biopsy results come back usually in a week or less, making it an important test that can provide valuable information about treatment options.

Watch this video to learn about the different types of biomarker tests. 

Results from biomarker testing show if there are certain abnormalities in the DNA of the tumor and levels of specific proteins present in the tumor. The abnormalities found in most tumors are not inherited; they are changes that happen to your DNA over time. This means you are unlikely to pass them down to your children. Abnormalities in lung cells can happen from exposure to environmental factors like cigarette smoke, radon, asbestos or other chemicals. Some gene changes in cancer may also be random or have no known specific cause.

The results of the test may show biomarkers that can help determine what treatment options would be best for you. Not all doctors order testing for the same set of biomarkers. The markers with current FDA-approved treatments are:

• Epidermal Growth Factor Receptor (EGFR) mutation 
• Anaplastic Lymphoma Kinase (ALK) gene rearrangement
• ROS1 rearrangement
• BRAF V600E mutation
• NTRK fusion
• MET amplification or MET exon 14 skipping
• RET rearrangements
• KRAS mutation
• HER2 mutations and overexpression
• NRG1 gene fusions
• PD-L1 level (a protein that may help determine your tumor's likelihood of responding well to certain immunotherapy drugs).

Your tumor may also be tested for other gene changes, such as STK11 mutations, that are either being studied in clinical trials, have drugs approved for treatment of other types of cancer or provide information about how you might respond to a certain treatment.

Talk to your doctor about receiving the most comprehensive biomarker testing possible. The more information you have about the makeup of your tumor, the better informed you and your doctor will be to make treatment decisions.

There are currently FDA-approved lung cancer treatments for tumors showing abnormalities in EGFR, ALK, ROS1, BRAFV600E, MET, RET, KRAS, HER2 and NTRK and NRG1 genes. Treatments for biomarkers are often called "targeted therapy" because they directly target what is causing the tumor to grow. PD-L1 levels are also used to help inform whether or not a patient may benefit from immunotherapy. 

Lung cancer research is moving at a rapid pace and there continues to be drug approvals for patients whose tumors grow after being on first-line therapy. If you do not test positive for a biomarker with an approved targeted therapy, your doctor may recommend immunotherapy with or without traditional chemotherapy. Surgery or radiation may also be recommended. It may also be appropriate to enroll in a clinical trial looking at treatments for other markers.

It is important to have a trusting relationship with your doctor. If you begin to ask questions about biomarker testing and are unsatisfied with the answers, it may be time to seek a second opinion. Some of the top questions to ask your doctor are:

• When should I get biomarker testing?
• Will you review the results with me when they are available?
• Will the testing need to be repeated?
• If I am not a candidate for biomarker testing, can you tell me why?
• Should I go on any treatment before my results come back? This last one is a bit of a trick question. It is very important for patients not to start immunotherapy before the results of biomarker testing come back because it could cause problems with starting on a targeted therapy. If a patient is highly symptomatic, a doctor may choose to start the patient on chemotherapy before the test results come back.