Lung cancer

A biomarker is any molecule that can be measured in tissues, blood, or other bodily fluids. Presence of a biomarker may be a sign of an abnormal bodily process or condition or a disease. A biomarker may also be called a molecular marker, genotype, or signature molecule.

Biomarkers can be used to:
Determine whether a disease or condition is present
Determine how aggressive the disease is
Predict how well the body will respond to a treatment for a disease or condition

Biomarker testing (also known as mutation, genomic, or molecular testing) is a way for the healthcare team to gather as much information as possible about a patient’s unique lung cancer. It uncovers whether the patient has a treatable driver mutation and establishes the patient’s PD-L1 protein expression level. The results of these tests help determine whether any of the European Medicines Agency (EMA)-approved lung cancer targeted therapies or a particular biomarker-driven immunotherapy drug is right as part of the patient’s treatment plan. Biomarker testing is used to plan these treatments for advanced-stage non-small cell lung cancers. (Note that biomarker testing may also be useful in some situations for early-stage lung cancers.)

Two types of biomarkers are currently used to help optimize a lung cancer patient’s treatment plan: driver mutations within the cancer’s DNA to determine whether a targeted therapy is appropriate and the level of expression of a particular protein in the patient’s tumor to determine whether an immunotherapy drug is appropriate.

Driver mutations

All the organs and tissues in our bodies are made up of cells, and each of these cells contains thousands of genes. Genes are made up of DNA, which is a specific code that is use to ultimately make proteins that have specific functions for the cell. It is essential for each gene to have the correct DNA code, or instructions, for making its protein. When the DNA is correct, the protein is able to perform the correct function.

When a gene has an error in its DNA, it is said to be mutated, or changed. Mutations can be:
Acquired: Also called somatic. Present only in the tumor and not passed on to children
Inherited: Present in all cells of the body and passed on to children

Virtually all of the biomarkers that are helpful to making treatment decisions in lung cancer are acquired. Inherited biomarkers are still being researched.
Mutations occur often, and normally the body can correct them. However, depending on where in a gene the change occurred, the small change may go undetected by the body and become part of the cell’s blueprint. Over time, an accumulation of mutations can result in the formation of a tumor. Mutations that cause cancer are called driver mutations.
Driver mutations are biomarkers that are used in biomarker testing in lung cancer; their presence may determine whether a patient will be prescribed one of several approved targeted therapies or be potentially eligible for a clinical trial for a targeted therapy still in development.

Right now, scientists have the most information about driver mutations in the subtype of NSCLC called lung adenocarcioma. The driver mutations in lung adenocarcinoma that currently have EMA-approved targeted therapy drugs available are EGFR, ALK, ROS1, BRAF V600, NTRK, and RET. Driver mutations in SCLC and other types of lung cancer are also being studied. There are as yet no targeted therapies that are EMA-approved for them.

Immunotherapy Biomarkers

There are several immunotherapy biomarkers; only one, PD-L1, is currently used in the clinic for lung cancer.

PD-L1: PD-L1 is a protein biomarker used to determine whether a lung cancer patient is likely to benefit from a treatment with a type of immunotherapy drug called an immune checkpoint inhibitor. Immune checkpoint inhibitors are drugs that help the patient’s own immune system fight the cancer. They do this by overriding the immune system’s fail-safe mechanisms, which are designed to suppress the immune response at appropriate times to minimize damage to healthy tissue. Patients who have a high level of PD-L1 are more likely to respond to immune checkpoint inhibitors. However, even those with tumors that do not express PD-L1 may respond.

Other immunotherapy biomarkers: While they are not yet used in the clinic for lung cancer, scientists are also studying types of immunotherapy biomarkers other than PD-L1, such as tumor mutational burden (TMB), CTLA-4 expression, and microsatellite instability.

Biomarker testing may be appropriate:

• When the doctors suspect lung cancer and have recommended a biopsy
• When a patient is already diagnosed with lung cancer
• When a patient’s lung cancer recurs (comes back) after treatment
• All patients with a lung cancer diagnosis should discuss biomarker testing with their healthcare team.

Biomarker testing can be done using either a sample of the tumor tissue or a blood sample; When a blood sample is used, the procedure is known as a liquid biopsy. Currently, tumor tissue testing is the most common procedure, and is discussed in this section. Liquid biopsies are discussed in the next section.

For biomarker testing with a sample of the tumor tissue, doctors most often obtain tumor tissue via a biopsy.

There are many different biopsy techniques that can be used to obtain the tumor tissue. The technique is determined by the location and size of the tumor, as well as the patient’s overall health. The patient’s healthcare team will discuss the best options with the patient as well as the risks and benefits of the procedures. Among the tissue collection techniques are bronchoscopy, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), transthoracic needle biopsy, thoracoscopy, thoracentesis, mediastinoscopy, and mediastinotomy. Regardless of how the tissue is collected, a patient should confirm with the doctors, before the tissue is removed, that adequate tissue will be collected so that all necessary biomarker tests can be performed. Tissue from the tumor is saved for a long time, so that additional testing, if necessary, can be done.

After the tumor tissue is collected, it is sent to a laboratory for testing. Ideally, comprehensive biomarker testing will be done. In comprehensive biomarker testing, driver mutations in multiple genes are tested for at the same time, rather than sequentially, including not only the ones with approved treatments, but also other known driver mutations. Some of the driver mutations currently without approved treatments may have treatments being tested now or in the near future in clinical trials to which a patient could be matched. An advantage of comprehensive biomarker testing is that when a new mutation target is discovered, it can easily be added to the set of mutations being tested for. Comprehensive biomarker testing is done via a process known as next-generation sequencing, or NGS.

A patient’s doctor may recommend additional biopsies and biomarker testing at several points in the treatment process. The ultimate decision to recommend another biopsy depends on the location of the cancer and the patient’s health status and lung function.

At the laboratory, the tissue sample collected during the biopsy procedure is tested and analyzed by a pathologist. Laboratory results from the biopsy are recorded in a report.

The initial report issued by the pathologist, which includes the diagnosis of lung cancer, its histological type, and its stage, is called the pathology report. (In some cases, limited information about the presence or not of several common biomarkers, including most likely EGFR and ALK, may also be included.)

Most often, however, a separate report from a pathologist with information about a more extensive set of biomarker testing results will follow the initial, pathology report. This report is typically called a biomarker testing report (but may also be referred to as a molecular testing report or a genomic testing results report). The biomarker testing report is based on the biomarker testing that occurs after the patient’s initial diagnosis of lung cancer. The report contains critical information about a patient’s cancer. Specifically, the biomarker testing report indicates whether a patient has biomarkers—either driver mutations or a high level of PD-L1 protein expression—that indicate that a patient may respond to a particular targeted therapy or to an immunotherapy drug, either approved or in clinical development.

The biomarker testing report may take up to more than 4 weeks to be processed. Patients should request a copy of the report for their medical records. Sometimes, the report is also available in a patient’s electronic health records, which are accessible through a hospital’s patient portal. The biomarker testing report may be helpful for discussions with the patient’s healthcare team, to pursue a second opinion about the diagnosis and/or the recommended treatment plan, or to pursue a clinical trial. (Note: The tissue samples will also be needed for a second opinion; as mentioned earlier, these are kept for a long time so will be available.)

Based on conversations with several pathologists, below are the top two things to look for in a biomarker testing report

Biomarker (mutation or PD-L1 status): This information is on the first page. After the name of each mutation tested for, the report indicates whether or not the mutation is present. In some cases, the report may say “no actionable mutation identified” to indicate that testing did not reveal that the patient has a mutation with an EMA-approved targeted therapy. Likewise, the patient’s PD-L1 protein expression level can be found here.

Appropriate drug for biomarker: Typically, next to the location of the biomarker status, the report notes the drug or drugs (if multiple options are available) that may be effective for a patient with this particular mutation.

If an advanced-stage lung cancer patient’s tests are positive for the EGFR, ALK, ROS1, BRAF V600, NTRK, RET, or mutation, there are EMA-approved targeted therapies for each that may be prescribed. For details about each treatment: what it is, who is eligible for it, how it is administered.

In addition, a certain level of the PD-L1 biomarker will help the healthcare team determine whether a patient is likely to benefit from an immunotherapy drug. For details about each immunotherapy treatment: what it is, who is eligible for it, how it is administered, etc.

What are you trying to find with biomarker tests?
Have I already had any biomarker tests? Which ones?
Who performs these tests?
How are the tests performed?
Are there any complications from these tests?
How long will it take to get the test results?
Where can I get more information about biomarker testing?
Are there any limitations of biomarker testing?
Will insurance pay for these tests?

After getting biomarker testing:

What tests were done?
What are the results of these tests?
How will the results affect my treatment?
The test results are negative: should I be retested?
The test results are not clear: should I be retested?
Are there any medications that target my type of lung cancer?
Will I need these tests again? If so, why? When?
Are there any clinical trials open to me based on these results?
How can I get a copy of my biomarker testing report?