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New research indicates that cutaneous melanoma is the most mutation-driven form of all cancers. While research has determined that there is more than one form of cutaneous melanoma, forms with more mutations may respond better to immunotherapies that have been approved by the Federal Drug Administration (FDA) since 2011. Learn more
Dermatologists have long known that the majority of melanomas arising from the skin are associated with exposure to ultraviolet light, but a presentation at the summer meeting of the American Academy of Dermatology (August 2015, New York) allowed clinicians to deepen their knowledge, and provided a framework on the current understanding of the disease.
“We have long known that cutaneous melanoma is different from other forms, such as those that arise from the acral sites, uveal tract or the mucous membranes. One study found 171 mutations per sun-exposed tumor, compared with nine mutations per sun-shielded tumor,” says Julide Tok Celebi, M.D., professor in the departments of dermatology and pathology at the Icahn School of Medicine, Mount Sinai, New York.
Scientists have recently learned that cutaneous melanoma has the highest mutational load among all cancers.
“With prostate cancer, we find 10 or 12 mutations per megabase,” she says. “Childhood cancers such as acute myeloid leukemia harbor a very low mutational burden. Melanoma is the highest with 100 to 120 mutations per megabase.”
Lung cancer carries the second-highest mutational burden. It’s important to note that melanoma and lung carcinoma are both associated with environmental carcinogens (ultraviolet radiation and smoking, respectively), which implicates significant DNA damage, Dr. Celebi says.
“We’ve learned over the past few years through advances in next generation sequencing that mutational load in cutaneous melanoma correlates with sun-exposure signatures at the molecular level,” Dr. Celebi says.
The knowledge has clinical significance, too. “Researchers found that melanomas with more than 100 mutations did better with an anti-CTLA4 monoclonal antibody,” an immunotherapy which has become clinically available since 2011, she adds.
“We are hoping that we are getting closer to personalized medicine in melanoma. Immunotherapy works and can be durable. Patients with stage-4 disease are not relapsing right away. We have patients that are surviving three, four, or five years beyond diagnosis, but not everyone, and a subset of patients are not responding at all. Ten years ago, five-year survival was 15%, and now some patients are living more than five years with no disease. We never had such an exciting momentum in the treatment of metastatic melanoma before,” notes Celebi.
“One could look at the tumor through the eyes of a clinician, and classify it based on the tumor’s anatomic location. Another way of characterizing the disease in an unbiased fashion is looking at the genomic and genetic characteristics in melanomas.
Genetic characteristics are highly relevant to most cutaneous melanomas, as 50% have a DNA variant called a BRAFV600 mutation, Dr. Celebi says.
“When a BRAF mutant melanoma is diagnosed, we have drugs targeting the mutation; that plus MEK inhibition is quite effective, and the disease survival is prolonged by 10 to 12 months. This was very exciting four years ago, and led to FDA-approval of these drugs. Unfortunately, about seven to 12 months later, the disease recurs. At the moment, with these inhibitors, we’re not curing patients, but the survival is prolonged,” she says.
There are four subtypes of genomic classification methods based on mutations in the DNA: In addition to BRAF, there are RAS mutant melanomas and NF1 mutant melanomas.
“There are also what are referred to as triple negatives,” she adds.
In addition to BRAF, about 30% of patients have RAS mutant melanoma, and 14% have NF1 mutant melanomas.
“Unfortunately, we don’t have a drug that is used routinely at the moment for these other forms, but that’s a major initiative,” she says.
Dr. Celebi also discussed another oncogene called KIT.
“If you look at KIT mutations among any cutaneous melanoma, you will only see a mutation frequency of 3%, but if you’re looking at an acral or mucosal melanoma, there is about a 15 to 20% mutation and/or amplification frequency. Mutations in this gene are common in leukemia, and also gastro-intestinal stromal tumors. The clinical relevance is that we have a drug targeting the mutant KIT tumor, which is first line therapy in some of these other malignancies,” she explains.
We are interested in figuring out which patients will respond to immunotherapy. The presence of tumor infiltrating lymphocytes within the tumor and such patients having better survival rates is a well-known observation. Cytotoxic T-cells get recruited to the tumor microenvironment, however an inhibitory system [upregulation of inhibitory checkpoint molecules] do not allow them to reject the tumor. Current immunotherapy approaches unleash the inhibitory systems that allow T-cell killing. Scientists will dissect further and determine which of these patients will respond to immunotherapy. Even better, they will develop biomarkers that can predict response to treatment.
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“The immune subclass does very well in terms of survival. We would predict these immune-high or TIL positive patients might benefit from immunotherapy better, but we don’t know that yet. We don’t know which patients will respond to, say, anti-CTLA4 therapy, or anti-PD1 or anti-PL1 drugs,” she explains.
Dr. Celebi says that, along with the expansion of knowledge, have come molecular tests, which provide scientists and doctors with more information.
“These tests which are being developed are somewhat in their infancy, and have come out within the last year or so.
For example, Icahn School of Medicine at Mount Sinai uses a 50-hotspot gene panel approved by the New York State, which tests for genes associated with melanoma (such as BRAF, NRAS, KIT), as well as colon and breast cancer, she explains.
“The panels are applied on formalin-fixed paraffin-embedded sections, so you don’t have to re-biopsy,” Dr. Celebi says. “At the moment, we’re only using testing if it has clinical relevance, if a treatment is available. I’d like to see the prices reduce, and to order the relevant tests at the time of diagnosis."
“Aside from testing for BRAF, NRAS, or KIT mutations, we don’t have great markers at the moment,” Dr. Celebi explains. Scientists know that tumors with 100 or more mutations respond well to anti-CTLA4 therapy, she notes.
“So this could be one marker we could use,” she says. “Other than that, we don’t know which patients will respond to which therapy.”
Dr. Celebi said that she hopes new biomarkers for immunotherapy will be available next year, along with a number of new immunotherapy drugs.
“Unfortunately, there is still no cure for the majority of stage-4 melanoma cases, because patients will exhibit either intrinsic resistance to the drugs, in which case there is no response, or acquired resistance after treatment. However, we have high hopes for developing even better treatment strategies than we have developed so far,” she says.
 Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189-99.