What’s new in research and treatment of melanoma skin cancer?
Causes, prevention, and early detection
Sunlight and ultraviolet (UV) radiation
Recent studies suggest there may be 2 general ways that UV exposure is linked to melanoma, but there is likely some overlap.
The first link is to sun exposure to as a child and teenager. People with melanoma often have an early history of sunburns or other intense sun exposures, although not everyone does. This early sun exposure may cause changes in the DNA of skin cells (melanocytes) that starts them on a path to becoming melanoma cells many years later. Some doctors think this might help explain why melanomas often occur on the legs and trunk, areas that generally aren’t exposed to the sun as much in adulthood.
The second link is to melanomas that occur on the arms, neck, and face. These areas are chronically exposed to sun, particularly in men.
Tanning booths may encourage either kind of melanoma to develop.
Researchers are looking to see if melanomas that develop from these types of UV exposure have different gene changes that might require them to be treated differently.
Most skin cancers can be prevented. The best way to reduce the number of skin cancers and the pain and loss of life from this disease is to educate the public, especially parents, about skin cancer risk factors and warning signs. It is important for health care professionals and skin cancer survivors to remind everyone about the dangers of excess UV exposure (both from the sun and from man-made sources such as tanning beds) and about how easy it can be to protect your skin against too much UV radiation.
Melanoma can often be detected early, when it is most likely to be cured. Monthly skin self-exams and awareness of the warning signs of melanomas may be helpful in finding most melanomas when they are at an early, curable stage.
The American Academy of Dermatology (AAD) sponsors annual free skin cancer screenings throughout the country. Many local American Cancer Society offices work closely with the AAD to provide volunteers for registration, coordination, and education efforts related to these free screenings. Look for information in your area about these screenings or call the American Academy of Dermatology for more information. Their telephone number and website are listed in the “Additional resources” section.
Along with recommending staying in the shade, the American Cancer Society uses a slogan popularized in Australia as part of its skin cancer prevention message in the United States. “Slip! Slop! Slap! and Wrap” is a catchy way to remember when going outdoors to slip on a shirt, slop on sunscreen, slap on a hat, and wrap on sunglasses to protect your eyes and the sensitive skin around them.
Melanoma DNA research
Scientists have made a great deal of progress during the past few years in understanding how UV light damages DNA and how changes in DNA can cause normal skin cells to become cancerous.
Some people, though, may inherit mutated (damaged) genes from their parents. For example, changes in the CDKN2A (p16) gene cause some melanomas to run in certain families. People who have a strong family history of melanoma should speak with a cancer genetic counselor or a doctor experienced in cancer genetics to discuss the possible benefits, limits, and downsides of testing for changes in this gene.
Advances in melanoma DNA research are also being applied to molecular staging. In ordinary staging, a lymph node removed from a patient is looked at under a microscope to see if melanoma cells have spread to the lymph node.
In molecular staging, RNA (a chemical related to DNA), is extracted from cells in the lymph node. Certain types of RNA are made by melanoma cells but not by normal lymph node cells. A sophisticated test called reverse transcription polymerase chain reaction (RT-PCR) is used to detect these types of RNA.
Early studies have found that RT-PCR is better than routine microscopic testing at detecting the spread of melanoma to lymph nodes. This test could eventually help identify some patients who might benefit from more treatment such as immunotherapy after surgery. However, some doctors are concerned that this test may lead to unnecessary treatment for some patients, which is why this test is not currently recommended. Studies are now in progress to learn more about how results should influence choice of treatment.
While early-stage melanomas can often be cured with surgery, more advanced melanomas can be much harder to treat because standard cancer treatments such as chemotherapy are not very effective. But in recent years, newer types of immunotherapy and targeted therapies have changed the treatment of this disease, and many new treatments have shown a great deal of promise in treating advanced melanomas.
This type of treatment helps the body’s immune system attack melanoma cells more effectively. Some forms of immune therapy, such as ipilimumab (Yervoy), cytokines (interferon-alfa and interleukin-2), and the BCG vaccine are already used to treat some melanomas (see “Immunotherapy for melanoma skin cancer”).
Drugs that block CTLA-4: Ipilimumab targets CTLA-4, a protein that normally suppresses the T-cell immune response, which might help melanoma cells survive. Ipilimumab has been shown to help some people with advanced melanomas live longer, and is already being used to treat some people with advanced melanoma.
A recent early study found that combining ipilimumab with another immunotherapy drug known as GM-CSF helped patients with advanced melanoma live longer than those who got just ipilimumab alone. The people who got the combination also seemed to have fewer serious side effects. Further clinical trials are testing ipilimumab combined with this or other drugs.
Drugs that block PD-1 or PD-L1: Melanoma cells also use other natural pathways in the body to help avoid being detected and destroyed by the immune system. For example, they often have a protein called PD-L1 on their surface that helps them evade the immune system.
New drugs that block the PD-L1 protein, or the corresponding PD-1 protein on immune cells called T cells, can help the immune system recognize the melanoma cells and attack them. One of these, pembrolizumab (Keytruda), a drug that blocks PD-1, is now approved to treat advanced melanoma. In early studies, This and other drugs that block these proteins, such as nivolumab, have shrunk tumors in about one quarter to one-third of people with melanoma, which is better than most results seen with ipilimumab. These drugs appear to have fewer serious side effects as well, and many of the tumor responses have been long-lasting so far. Larger studies of these new drugs are now being done, including some that use one of these drugs with ipilimumab to see if the combination might work even better.
Melanoma vaccines: Vaccines directed at melanoma are being studied in clinical trials. These are experimental therapies that have not yet been proven to be helpful.
These vaccines are, in some ways, similar to the vaccines used to prevent diseases such as polio, measles, and mumps that are caused by viruses. Such vaccines usually contain weakened viruses or parts of a virus that cannot cause the disease. The vaccine stimulates the body’s immune system to destroy the more harmful type of virus.
In the same way, killed melanoma cells or parts of cells (antigens) can be injected into a patient as a vaccine to try to stimulate the body’s immune system to destroy other melanoma cells in the body. Usually, the cells or antigens are mixed with other substances that help boost the body’s immune system as a whole. But unlike vaccines that are meant to prevent infections, these vaccines are meant to treat an existing disease.
Making an effective vaccine against melanoma has proven to be harder than making a vaccine to fight a virus. The results of studies using vaccines to treat melanoma have been mixed so far, but many newer vaccines are now being studied and may hold more promise.
Other immunotherapies: Other forms of immunotherapy are also being studied. Some early studies have shown that treating patients with high doses of chemotherapy and radiation therapy and then giving them tumor-infiltrating lymphocytes (TILs), which are immune system cells found in tumors, can shrink melanoma tumors and possibly prolong life as well. Newer studies are looking at changing certain genes in the TILs before they are given to see if this can make them more effective at fighting the cancer. This approach has looked promising in early studies, but it is complex and is only being tested in a few centers.
Many studies are now looking to combine different types of immunotherapy, which may be more effective than any single treatment for advanced melanoma.
As doctors have discovered some of the gene changes in melanoma cells, they have developed drugs that attack these changes. These targeted drugs work differently from standard chemotherapy drugs. They may work in some cases when chemotherapy doesn’t. They may also have less severe side effects.
Drugs that target cells with changes in the BRAF gene: As noted in the section “Targeted therapy for melanoma skin cancer,” about half of all melanomas have changes in the BRAF gene, which helps the cells grow. Drugs that target the BRAF protein, such as vemurafenib (Zelboraf) and dabrafenib (Tafinlar), as well as drugs that target the related MEK proteins, such as trametinib (Mekinist), have been shown to shrink many of these tumors. These drugs are now often used in melanomas that test positive for this gene change.
One of the drawbacks of these drugs is that they seem to work for only a limited time before the cancer starts growing again. A new approach now being studied is to combine a BRAF inhibitor with a MEK inhibitor. Early results have been promising, showing that combining the drugs results in longer response times and that some side effects (such as the development of other skin cancers) might actually be less common with the combination.
Drugs that target cells with changes in the C-KIT gene: A small number of melanomas have changes in the C-KIT gene. This is more likely in melanomas that start on the palms of the hands, soles of the feet, under fingernails, or in certain other places.
Clinical trials are now testing drugs such as imatinib (Gleevec) and nilotinib (Tasigna), which are known to target cells with changes in C-KIT.
Drugs that target other gene or protein changes: Several drugs that target other abnormal genes or proteins, such as sorafenib (Nexavar), bevacizumab (Avastin), pazopanib (Votrient), and everolimus (Afinitor), are now being studied in clinical trials as well.
Researchers are also looking at combining some of these targeted drugs with other types of treatments, such as chemotherapy or immunotherapy.
Last Medical Review: 10/29/2013
Last Revised: 09/05/2014