Biomarkers: What They Are, Why They Matter, and Where They are Going
The melanoma treatment field has been rewarded recently with an abundance of riches, including several targeted therapies, checkpoint immunotherapies, and many more experimental treatments in the pipeline. But all these exciting new treatment options for patients can also create complexity and confusion about which treatments patients should receive first, when combination treatment is necessary, when to stop therapy and when to switch to a new treatment altogether. Fortunately, help is on the way in the form of biomarkers — molecular or cellular indicators for whether a patient is likely to respond or is currently responding to their therapy, or whether they are likely to have a recurrence of their cancer.
What are Biomarkers?
At the most basic level, biomarkers are objective and measurable signs that something is or is not taking
place within the body. The term is literally a mashup of ‘biological’ and ‘marker’ and is used constantly in modern medicine. Put in a different way, doctors use various biomarkers to determine if your liver is working correctly, to determine if your body is responding appropriately to a medication, or a surgery is successful.
When it comes to melanoma biomarkers, we are often referring to the expression of certain proteins by tumor cells themselves or other cells in the tumor microenvironment, the presence or a specific genetic mutation, or even clinical metrics such as the size of the tumor(s) and location. But relevant biomarkers aren’t only in the tumor or tumor-environment — they can also be found in other parts of the body including cell-free snippets of DNA found in the blood, or the composition of the gut microbiota. Many of these biomarkers are showing promise for aiding treatment decisions for melanoma patients, but only one, BRAF mutation status, is currently approved by the Food and Drug Administration (FDA) to distinguish melanoma patients likely to respond to therapies targeting the BRAFV600E mutation in this gene.
How are Biomarkers Measured?
Some biomarkers, such as the size or location of a tumor are easy to measure, but others require the development of sophisticated tests that are able to measure tiny changes in the body, from specific mutations driving a tumor (such as tests designed to measure BRAF status), to the diversity of bacteria in the gut’s microbiome. Keeping the development of new biomarker tests in lockstep with the advancement of new treatment options is important to help guide the use of new therapies.
For example, targeted therapies are currently FDA approved in the treatment of patients with BRAF mutant melanoma. This is great for the half of all patients with cutaneous melanoma who have the mutation, but what of the other half? What if we had no way of knowing who fit into this category without treating everyone — and then simply prayed it would work? Fortunately, researchers developed accurate and reproducible biomarker tests to determine who is likely to benefit from this treatment approach, saving patients without the BRAF mutation from a treatment that isn’t likely to ever work for them.
Developing biomarker tests is important because it gives clinicians information they need to make strategic treatment recommendations for their patients.
What are the Current Challenges and Where are Biomarker Tests Heading?
First and foremost, it isn’t always clear what can be objectively measured — for all patients — to answer some of the most pressing questions faced by clinicians. Second, these tests must be rigorously evaluated in clinical trials before they can be widely adopted.
Current research suggests that a combination of biomarkers may be more informative than measuring a single biomarker such as BRAF status. For example, one pretreatment biomarker panel that relies on six biomarkers for tumor and immune cell features was found to be a much more powerful predictor of risk of melanoma recurrence than its individual components.
One of the more comprehensive approaches to discerning biomarkers is to do a complete genetic analysis of a patient’s tumor via a process called next-generation sequencing (NGS), which is likely to be more informative than a simple genetic test, as multiple genes are now known to play major roles in melanoma. Researchers think that NGS can be useful for melanoma patients because some mutations identified with this technology may be “actionable.” That is, there are approved drugs that may be aligned with specific mutations, often used to treat other forms of cancer, that may be effective in treating melanomas with these mutations.
Clinicians also face the conundrum of whether to treat patients beyond surgery, as the drugs originally approved for unresectable metastatic melanoma are now approved to treat some stage 3 patients, in what is known as the adjuvant setting. Clinical trials are also looking at treating patients with even earlier stages of the disease. Physicians are treating some patients at high risk of having a melanoma recurrence before or shortly after their surgical removal of their tumor with immune and other cancer therapies, in an effort to have “no tumor left behind” even though many of those patients are likely to be cured by surgery alone. To help navigate these challenges, clinicians need a better understanding of which patients are most likely to have a recurrence of their melanoma and thus should be subjected to the risks of the drug treatments.
“We have the challenge of colliding multiple biomarkers for multiple therapies,” noted Keith Flaherty of Massachusetts General Hospital. Janis Taube, a dermatopathologist at Johns Hopkins University added, “There are a lot of exciting biomarkers in melanoma, but we’re now looking at the gap between discovery and clinical practice.” Taube and Flaherty were two of about two dozen representatives from industry, the FDA, and academia that the MRA brought together as part of its 2021 Scientific Retreat for a lively roundtable discussion on how to move biomarker development forward and into clinical practice so that more melanoma patients can benefit.
Taube suggested biomarkers currently in the discovery and development stages need to be tested in large clinical trials. The results of such trials can refine the guidelines for how these biomarkers are interpreted, as well as validate their reproducibility and accuracy, and their efficiency, in terms of cost and time. She pointed out unity is lacking in terms of how current biomarkers are used, with cutoff levels for specific biomarkers varying according to the institution at which they are done. She suggested developing more universal guidelines for biomarkers.
MRA’s Chief Science Officer Marc Hurlbert asked whether more extensive NGS analyses should be reserved for melanoma patients not served well by current treatments. Jason Luke of the University of Pittsburgh responded “Everyone agrees that patients with advanced melanoma should have NGS and not just BRAF and that would open up greater space for these patients to participate in clinical trials.” Luke suggested MRA advocate for NGS as part of the standard care for patients with advanced melanoma as a way to inspire insurers to pay for such analyses. Deborah Norton of Novartis agreed that there needs to be clarification of which melanoma patients should have NGS and when. “I think all melanoma patients need it but there is resistance to this from insurers, so a call to action on this would be helpful,” she said. “Is NGS testing ready for prime time is a key point,” Flaherty stressed.
What is Needed to Move the Field Forward?
Before taking new steps to move the field forward, it’s important to make sure that no patients are being left behind. David Solit of Memorial Sloan Kettering Cancer Center suggested that MRA could advocate for the creation of a tiered list of biomarkers seen as standard of care for patients with melanoma, versus those used only in the framework of a clinical trial. Solit noted that insurers based their reimbursement policies on expert statements about when certain treatments or diagnostic tests should be performed, and there is a lack of an expert organization for cancer biomarkers that can make those recommendations. Norton suggested tapping the National Comprehensive Cancer Network (NCCN) to work with for expert biomarker recommendations. NCCN is a non- profit network of 30 Comprehensive Cancer Centers in the United States that publishes treatment guidelines and insurers often follow those guidelines in determining what is covered.
Taube noted there is great academic interest in developing tests that could simultaneously measure multiple biomarkers in a tumor utilizing a single technique such
as histrochemistry, thus reducing the tumor sample size needed, but she is disappointed by how these innovative tests are not moving forward and into clinical practice. “How best can we partner with industry and the FDA for them?” she asked. Luke suggested MRA could consider advocating for such multiplex tests as part of standard of care for melanoma patients. Steven Lemery of the FDA added MRA could help establish standards for when patients should be re-biopsied or have blood samples to assess for biomarkers for treatment effectiveness, so as to clarify when insurers should reimburse such procedures.
“Every year biomarkers become more relevant. We have to stop talking about them and do something to drive their use in practice,” Norton stressed.