Biomarkers and Molecular Testing
Targeted Therapy and Immunotherapy
Biomarkers and Molecular Testing
A biomarker is a distinct substance produced by a tumor that helps doctors diagnose cancer and determine how a patient will respond to different kinds of treatment. Biomarkers are found in a patient’s tumors and sometimes in blood or other body fluids; they can indicate the presence, severity, or type of cancer. There are many different types of biomarkers and they may appear in particular combinations in melanoma patients.
Biomarkers can be detected using a variety of laboratory tests, which are often performed on the same tumor tissue specimen (biopsy) that is used for diagnosis. The specific genetic mutations in a tumor’s DNA affect which specific biomarkers are found in tumor cells.
Knowing your tumor’s biomarker fingerprint can help doctors decide how to treat your cancer. Frequently, biomarker molecules are proteins that are made from mutated genes in a patient’s tumor and that drive development of tumors. These mutations/biomarkers can be directly targeted with specialized drugs to reduce tumor growth. So-called targeted drugs attack and deactivate specific, cancer-promoting biomarkers.
Researchers have identified many biomarkers associated with melanoma. People with advanced melanoma may be able to narrow down treatment choices based on molecular tests for these six major biomarkers: BRAF, NRAS, KIT, GNA11/GNAQ, CDK4, and MEK1.
Testing for biomarkers is generally recommended for patients with stage III or IV melanoma. Almost all people with melanoma test positive for one of the six major biomarkers. If your oncologist is not familiar with molecular testing, it is acceptable and advisable to get a second opinion about your treatment options.
Please see our resources list for providers of molecular testing. The Melanoma Research Foundation (MRF) can also give you personal guidance on molecular testing for biomarkers.
If you have tested negative for all major melanoma biomarkers that can help guide treatment decisions, there are still many potential treatment options, including immunotherapy. You may also be able to enroll in a clinical trial. You and your care team will work together to figure out the best approach for you. We highly recommend that you also seek second and third opinions as part of the decision-making process. The various resources provided by the Melanoma Research Foundation can also help you navigate your melanoma diagnosis and treatment.
Targeted Therapy and Immunotherapy
Targeted therapy is a term that describes a type of melanoma treatment that uses drugs to identify and attack specific mutant proteins in cancer cells. These mutant proteins are present only in cancers, but not in normal tissues. Therefore, they are good targets for drugs that act like “guided missiles” to attack only these “mutant” or abnormal proteins. Targeted therapies can sometimes be used in different combinations depending on a tumor’s distinct combination of biomarkers. They can also be combined with chemotherapy or immunotherapies (see below). Although targeted therapies have side effects, they are generally better tolerated than chemotherapy.
Because the genetic mutations in each tumor are different, the treatments for each mutation will be different. These personalized treatments recognize that, what works for one type of melanoma, may not work for another. Targeted therapies are a relatively new line of research. If your oncologist is not familiar with molecular testing and targeted therapies, it is acceptable and advisable to get a second opinion about your treatment options.
Like other cancer therapies, a targeted therapy may stop working over time. This is because a tumor may develop resistance to the treatment. A tumor that initially shrinks in response to a targeted therapy may subsequently undergo additional genetic changes (mutations) that enable it to withstand further treatment. When this happens, your doctor will decide on another treatment strategy. Many ongoing clinical trials are exploring different strategies to avoid and/or overcome resistance to targeted therapies. Often, these strategies involve combining different kinds of targeted therapies, or combining targeted therapies with chemotherapy or immunotherapy (see below).
Targeted therapies are different from traditional chemotherapies because they attack specific targets in tumor cells that are not present in normal cells. Chemotherapy drugs work by stopping cell division and growth throughout the body. While this allows chemotherapies to shrink tumors, it means they attack healthy cells as well. This is why chemotherapy treatment is often accompanied by harsh side effects. However, recent studies have shown that combining targeted therapies with chemotherapies can prove particularly beneficial for some cancer patients.
Like targeted therapy, immunotherapy is a relatively new strategy for cancer treatment. Immunotherapies help the body’s own immune system attack tumors. There are many different approaches to immunotherapy. Some immunotherapy treatments strengthen the immune system as a whole, enabling it to more effectively deal with a tumor. Another approach is to weaken signals that tumors send out to stop the immune system from fighting them. Yet another approach involves taking immune cells from tumors or the blood and growing them in a lab in special conditions that make them more active. The strengthened cells are then returned to the patient’s body, where they actively kill tumor cells.
Many researchers believe that some of the best cancer treatments in the near future will combine targeted therapies and immunotherapies. There are many ongoing clinical trials exploring such combinations.
A clinical trial is a research study that has progressed from a scientific question through laboratory testing and is now ready for human volunteers. Clinical trials are critical to the development of new melanoma treatments, ways to ease the symptoms of melanoma treatments, and collect tumor or blood samples for research. These new treatments may include drugs, surgical procedures, and new ways to manage side effects. The clinical trials process is overseen by the U.S. Food and Drug Administration (FDA), a local institutional review board (also known as an ethics committee), and a physician specifically trained to manage clinical trials.
A clinical trial may be referred to as a “research study,” “study,” or “trial.” The team that manages the clinical trial is often referred to as the “clinical trials team,” “research staff,” or “study staff.” Do not let the names confuse you as they all mean the same thing.
In order for a new drug to be approved by the U.S. Food and Drug Administration (FDA) for use in humans, it must pass through a rigorous testing process. This testing process is called a clinical trial and is composed of four different phases usually referred to as phases I through IV.
Phase I trials are the first level in which the researchers evaluate safety, determine a safe amount of drug, and identify side effects that might occur with the treatment. Before this phase, the treatment has already been researched at length in the lab and on animals and the drug has been determined to be ready for use in humans. The research team will adjust the amount of the treatment you receive at different intervals in the trial while monitoring the treatment’s side effects. Typically, there may be only 20 to 80 people selected to participate in a phase I clinical trial. Usually these are patients with advanced stages of disease.
Phase II trials begin after a treatment has been found to be safe in phase I trials. During phase II, the research team will use a specific treatment, or combination of treatments, to determine the effectiveness for a specific type of cancer. A phase II clinical trial may include 100 to 300 people.
Phase III trials will be done when a treatment is found to be effective in phase II trials. During this phase, the treatment will be tested on a large number of patients comparing standard treatments (treatment you receive outside of the clinical trial) with the new treatment. If you participate in a phase III clinical trial, you may be randomly assigned to a control or test group. If you are assigned to the control group, you will receive the standard treatment for your specific type and stage of melanoma. If you are assigned to the test group, you will receive the new treatment. Results from the two groups will be closely monitored by the research team to determine which treatment is most effective and the side effects of the treatment. Phase III trials include up to 3,000 patients.
Phase IV trials begin after the treatment has been approved by the FDA. In phase IV clinical trials, the treatment will be given to a much larger group of patients. In this phase, additional information will be gathered about effectiveness, side effects that might not have been previously identified, and safety issues that can only be identified in a larger group of participants.
Participating in a clinical trial may have several potential benefits for you. By participating in the trial, you will:
- Play an active role in determining the direction of your health care
- Have access to new treatments before they are widely available
- Receive expert medical care at leading health care facilities
- Help others by contributing to medical research
Before you agree to participate in a clinical trial, you should talk to your oncologist and the doctor in charge of the trial to make sure you understand the possible risks. You should understand that the treatment being used may not be better and side effects may be worse than the standard treatment. Because the treatment is new, your health care team may not know all of the side effects that you will experience. A clinical trial may require more time and attention from your health care team and from you than would a nonclinical trial treatment regimen. This extra time may include trips to the cancer center, more treatments, hospital stays, and complex dosage requirements.
In a study done in 1999, the American Society of Clinical Oncologists found that only 3% of adults with cancer participate in clinical trials. This low level of participation in clinical trials means that advances in cancer care do not happen as quickly as they might. Your participation in clinical trials can help to develop new cancer treatments for all cancer patients.
Any time you are facing a treatment decision, you should ask about clinical trials that might be appropriate for you. Clinical trials are not just for advanced stage melanoma– clinical trials are available for all stages of melanoma. Ideally, your entire health care team will be available to talk to you about new treatments that may be available. For example, your oncologist, radiologist, and surgeon may each have access to information about different clinical trials. Once you know about clinical trials that might be appropriate, you should discuss the options with your entire team who can help you understand the benefits and risks based on your specific melanoma and health status.
There are thousands of clinical trials in the U.S. available to the cancer community; however, not all clinical trials will be available in your area. Clinical trials may be open at only one cancer center; others may be open in hundreds of cancer centers across the country. The number of participating centers depends on the disease being studied, the phase of the clinical trial, and the complexity of the clinical trial.
If you are interested in participating in a clinical trial, there are many sources of information. Here are a few:
- Your health care team (eg, oncologist, radiologist, pulmonologist) –ask your health care team if a clinical trial is appropriate for you at this time and what clinical trials are available at your center. If no trials are available at your center, ask your oncologist which investigation drugs or procedures might be right for you. With this information, you can search the government database for clinical trials in your area.
- Cancer Commons’ Clinical Trial Finder. We have selected trials we believe are most likely to benefit the patients who enroll in them. You can search for trials based on your particular type of melanoma, your stage, your location, and the results of any molecular tests you have had.
- The U.S. National Institutes of Health (NIH) list of clinical trials, which lists both federally funded and privately supported clinical trials. There are many other Internet sites with information on clinical trials, but they are generally built on information from the NIH.
The NIH clinical trial list includes over 136,000 clinical trials available worldwide, not just in the U.S. When you access the Web site, you should search for a clinical trial using the most specific information you have. For example, if your diagnosis is uveal melanoma, search for “uveal melanoma in the U.S.” A list will open showing all of the studies that are in the database. In the listing, you will be able to tell the status of the clinical trial (eg, Completed, Recruiting, Not yet recruiting, Active). The list will include what conditions are being targeted in the trial and what treatments are actually being tested (eg, drug, radiation therapy). Clicking on the name of the study will open a new window that shows extensive information about the specific study, including how long the trial is expected to last, eligibility requirements, how outcomes will be measured, and contacts for the trial. If you find clinical trials that may be applicable to you, it is critical that you discuss them with your health care team.
Searching for clinical trials may be very confusing, since the resulting list may contain hundreds of possibilities. The Melanoma Research Foundation (MRF) can help with identifying clinical trials in your area that may be of interest to you.
Please note: Much of this content is modified from the Lung Cancer Foundation‘s Navigating Lung Cancer handbook. Molecular testing, targeted therapy, and clinical trials are important considerations for both lung cancer and melanoma.