Personalised Medicine At A Glance: Metastatic Melanoma

For patients, policy makers and other non-medical professionals

This text was prepared by ESMO for the European Alliance for Personalised Medicine – January 2015

Melanoma is a cancer arising from specialised cells found in the skin called melanocytes. These cells produce the dark melanin pigment responsible for skin colour. Exposure to ultraviolet light (eg from the sun) increases production of melanin, giving the DNA of skin cells some protection against the adverse effects of this form of radiation and darkening skin colour. But overexposure can lead melanocytes themselves to become malignant.

Advanced melanoma has been very difficult to treat, but progress in understanding the biological basis of the disease has led to more effective and personalised therapy.

In Europe in 2012, there were over one hundred thousand new cases of melanoma of the skin and more than twenty thousand deaths from the disease. Although still infrequent compared with cancers of the lung, colon, breast and prostate, melanoma is an increasing problem.

Types of treatment

As with all tumours, initial treatment is tailored to the patient’s individual circumstances and the size and spread of the cancer. Surgical removal of melanomas that are small and confined to one site on the skin usually resolves the problem. The cancer is cut out along with a surrounding margin of healthy tissue, with the width of the margin depending on the diameter of the melanoma. But melanomas that are large or penetrate deep within the skin, and those that are ulcerated, are more likely to recur. Radiotherapy sometimes has a place in treating extensive but still localised disease.

Melanoma that has spread to other parts of the body and its internal organs (i.e. metastatic disease) generally cannot be cured. Cytotoxic chemotherapy, using drugs such as dacarbazine, has been tried but with disappointing results. But this does not mean that all treatments are ineffective. Advances in two areas of targeted therapy are particularly promising. The first is immune modulation.

Immuno and targeted therapy

Although the response is generally too weak to overcome the disease, melanoma does activate our immune systems. One new treatment option is an antibody drug called ipilimumab which strengthens this natural response. Its effect has been described as taking the brakes off the immune system. Ipilimumab inactivates a protein (CTLA-4) which inhibits the activity of T lymphocytes. Once released from inhibition, the T lymphocytes are better able to recognise and destroy melanoma cells.

The second and probably more important advance is the development of new drugs targeted at molecular abnormalities that are found in many melanomas. These genetic defects – which vary from one patient to another – seem the key to more effective treatment. Increased understanding of their role underpins current progress in personalised medicine. Uncontrolled cell division is the essence of cancer. Blocking the abnormal growth signalling that causes uncontrolled proliferation is the essence of targeted treatment.

Gene mutations

Particularly important to melanoma was the discovery of the MAPK (mitogen-activated protein kinase) pathway which transmits a growth signal from a receptor on the surface of a cell to its nucleus. Among the messenger molecules are RAS, RAF and MEK. If a mutation arises in a gene responsible for producing one of the proteins involved in this signalling cascade, the pathway may become overactive. Growth messages are transmitted when they are not appropriate, causing excessively high rates of cell division.

Gene mutations that activate BRAF (a subtype of the RAF component of the MAPK pathway) are found in about 50% of melanomas. The second most common abnormalities are activating mutations in NRAS (a subtype of the RAS element of the pathway) which are found in roughly 20%. If individual patients have one type of mutation, they are unlikely to have the other.

By identifying the mutations that have caused a particular patient’s cancer, it should be possible to provide personalised treatment. Drugs that target NRAS mutations are still under investigation. But drugs that target BRAF are already in routine use in patients whose tumours show relevant mutations.

BRAF inhibitors and how to oversome resistance

Two specific gene mutations (V600E and V600K) account for the majority of BRAF abnormalities in melanoma. Patients whose cancers have either of these mutations are now treated with the BRAF inhibitors vemurafenib or dabrafenib. These drugs combat abnormal activation of the MAPK pathway and melanomas are likely to shrink. However, cancer cells eventually develop ways of bypassing these BRAF growth inhibitors. The MAPK pathway starts to function abnormally again, and growth of the melanoma resumes.

This process can be delayed by using a combination of drugs. Recent clinical trial evidence shows that combining the BRAF inhibitor dabrafenib with another drug, trametinib, postpones the return of cancer progression. Trametinib inhibits a different signalling molecule, MEK, which acts downstream from RAF in the signalling cascade. Use of the new drug combination increases survival time in patients with previously untreated metastatic melanoma while not causing any overall worsening of side effects.

Worthwhile progress is therefore being made in melanoma patients who have BRAF mutations. It is clear that additional drugs will be needed to bring the abnormal MAPK pathway under long-term control. For those patients whose melanomas arise from gene abnormalities in other signalling pathways, the search for effective interventions is still at an early stage. But at least we know that the principle of personalising treatment can be made to work in practice.