Biomarkers for Melanoma Prognosis and Treatment Response

Biomarkers can help describe melanoma, estimate the risk of its progression and inform discussions about treatment. Their role is growing in European melanoma research, but no single result can reliably predict an individual patient’s outcome or replace clinical judgement.

Some tests, such as determining whether a tumour has a BRAF mutation, can identify a treatment option. Others, including PD-L1 expression, tumour mutational burden (TMB) and circulating tumour DNA (ctDNA), are being studied for how well they help predict or monitor response. Understanding what each result can and cannot show is essential.

What melanoma biomarkers can—and cannot—tell us

A melanoma biomarker is a measurable feature of a tumour, blood sample or other biological material that provides information about the disease. Prognostic biomarkers relate to the likely course or outcome of melanoma, while predictive biomarkers indicate whether a particular treatment may be more or less likely to work.

The distinction depends on the question being asked. A prognostic marker may be associated with outcomes regardless of treatment. A predictive marker concerns the relationship between a marker and the effect of a specific therapy. Some biomarkers may be investigated for both roles, but evidence for one does not automatically establish the other.

Biomarkers can include DNA changes, patterns of gene activity, proteins expressed by tumour or immune cells, and tumour material detected in blood. Their meaning depends on factors such as melanoma stage, the sample tested, the treatment under consideration and the quality of evidence supporting the test.

A biomarker provides a piece of the clinical picture, not a guaranteed forecast. Results need to be interpreted alongside the patient’s health, disease characteristics, previous treatments and preferences.

Genetic biomarkers and targeted treatment

Genetic biomarkers can identify changes that make a melanoma eligible for certain targeted treatments. In advanced melanoma, testing for BRAF mutations is clinically important because BRAF V600 alterations can help determine whether BRAF- and MEK-inhibitor therapy is an option.

BRAF is part of a cell-signalling pathway that can drive tumour growth when altered. When a relevant mutation is found, clinicians may discuss targeted therapy, which acts on proteins in this pathway. The result helps define a treatment option; it does not, on its own, decide that treatment is best or predict how long it will control the disease.

Targeted therapy and immunotherapy work differently and have different potential benefits, side effects and patterns of response. Treatment choice may depend on disease burden and pace, symptoms, other medical conditions, previous treatment, and the wider clinical context. A negative BRAF result also does not mean that no treatment is available.

Testing should use an appropriate tumour sample and a validated laboratory method. If a sample is small, old or contains little tumour tissue, the result may be limited; the care team can explain whether another sample or test is appropriate.

Biomarkers studied in immunotherapy

PD-L1 expression and tumour mutational burden are studied as potential clues to response to immunotherapy, but neither is a definitive guide for every person with melanoma. Immunotherapy decisions cannot be reduced to a single biomarker result.

PD-L1 is a protein that can be expressed by tumour cells and some immune cells. Because it can interact with immune checkpoint pathways, researchers have examined whether its presence in a tumour sample is associated with response to checkpoint-inhibitor immunotherapy. Results can vary with the test method, the threshold used and the tissue sample. A low or absent result does not necessarily rule out benefit.

TMB describes the number of mutations detected in a tumour’s DNA under a particular testing approach. The biological idea is that some mutations may produce abnormal proteins that the immune system can recognise. However, TMB values can differ by assay and tumour sample, and a higher value does not guarantee response. Its clinical role in melanoma depends on the question and the evidence for the specific setting.

These markers are useful research tools and may contribute to a broader assessment, but their limitations matter. Tumours can differ between sites and change over time, while a biopsy captures only one part of that biology. Clinical trials continue to assess how biomarkers, disease features and treatment history can be considered together.

Blood-based biomarkers and treatment monitoring

Circulating tumour DNA (ctDNA) is tumour-derived DNA found in the bloodstream, and researchers are investigating whether changes in its level can help track melanoma over time. A blood test may offer a way to sample tumour activity without taking a new tissue biopsy, but ctDNA monitoring is not a universal substitute for imaging or clinical assessment.

In principle, a detectable ctDNA signal may provide information about tumour burden, and a change during treatment may be associated with a change in disease activity. Yet the amount of ctDNA released into blood can vary. Some melanomas may release very little, so a negative result cannot always exclude active disease. Test sensitivity also depends on the assay and the genetic features being tracked.

Researchers are studying ctDNA for several possible uses: assessing disease after surgery, identifying molecular changes during treatment, and detecting early signs of progression or response. These are active areas of investigation, and the clinical meaning of a result depends on the setting and validated evidence for the test used.

For now, treatment monitoring generally draws on the full clinical picture, including symptoms, examination and imaging where appropriate. A ctDNA result should be interpreted by the treating team rather than used alone to start, stop or change therapy.

Applying biomarker results in clinical care

Biomarker results inform care when clinicians match the test to a clear clinical question and interpret it alongside the patient’s circumstances. Before testing, it helps to know what the result could change, which sample will be analysed and whether the test is established for that purpose or still being evaluated.

In practice, the process often involves these steps:

• Define the question: Is testing intended to identify an actionable mutation, estimate prognosis or explore a possible treatment-response marker?
• Check the sample: Confirm that the tumour tissue or blood sample is suitable for the assay and represents the clinical situation as well as possible.
• Interpret the result in context: Consider the melanoma’s stage and features, treatment history, overall health and available options.
• Discuss uncertainty: Clarify whether the evidence supports routine decision-making, adds one piece of information or remains mainly research-based.

A common pitfall is treating a positive biomarker as a promise of treatment success. A marker can identify a potential option without guaranteeing response, its duration or tolerability. The opposite error is assuming that a negative result rules out all benefit from a treatment class; this is especially risky where the marker is not a reliable exclusion test.

In European melanoma research, collaborative clinical studies help evaluate biomarkers across patient groups and treatment settings. Research findings can take time to become routine practice, so clinicians distinguish validated tests from promising results that still need confirmation.

Research priorities and remaining challenges

Melanoma biomarker research aims to make prognosis and treatment selection more precise while confirming that tests improve decisions in real clinical settings. Key challenges include tumour diversity, changes in cancer over time, differences between laboratory assays and the need to validate findings in independent clinical studies.

A biopsy samples one location at one point in time. If separate tumour deposits have different molecular features, a single tissue result may not represent every cancer cell. Blood-based approaches such as ctDNA could help address this limitation in some cases, but they also have technical and biological constraints.

Research also needs to show that adding a biomarker to care offers useful information beyond established clinical factors. A marker may correlate with outcome yet still fail to improve treatment decisions. Reliable evaluation therefore considers how a test was performed, which patients were studied, what outcome was measured and whether the result can be reproduced.

European research groups, including the European Organisation for Research and Treatment of Cancer (EORTC), contribute to collaborative studies that assess melanoma treatments and patient outcomes. As evidence develops, the aim is to define where biomarkers can support care, where they remain uncertain and how best to explain that uncertainty to patients.

Frequently asked questions about melanoma biomarkers

What is the difference between a prognostic and predictive biomarker?

A prognostic biomarker is associated with the likely course or outcome of melanoma. A predictive biomarker helps indicate whether a particular treatment may be more likely to work. The same marker may be studied for both purposes, but each use needs its own evidence.

Does a BRAF mutation determine which melanoma treatment is appropriate?

No. A relevant BRAF mutation can identify targeted therapy as a possible option, but it does not determine the best treatment by itself. Clinicians consider other disease and patient factors, as well as the benefits and risks of available treatments.

Can biomarkers reliably predict response to immunotherapy?

No single biomarker reliably predicts immunotherapy response for every person with melanoma. PD-L1 expression and TMB may provide information in some contexts, but results have limitations and should not be treated as guarantees or used in isolation.

Can a blood test monitor melanoma treatment response?

ctDNA blood tests are being investigated as a way to monitor melanoma and treatment response over time. Their usefulness depends on the amount of tumour DNA in the blood and the test method, so they do not replace other clinical assessments in every case.