Biomarker Testing of Rare Melanomas to Help Select Personalized Treatment

The most common type of melanoma is cutaneous melanoma. To help select the right treatments for melanoma, doctors may look for biomarkers, which are features in the tumor cells or the body (for example, cholesterol as a biomarker for risk of heart disease) that can be measured and give information about a person’s health and help predict a person’s response to treatment. One way to understand more about an individual person’s cutaneous melanoma is by performing a type of biomarker testing called genomic testing of tumor samples. This type of biomarker testing looks for changes in DNA (called mutations) and other DNA alterations that are found only in cancer cells and not normal, otherwise healthy cells throughout the body. These mutations in tumor cells produce abnormal proteins that cause or contribute to development or growth of the cancer.

The results of biomarker testing can be helpful to patients with cutaneous melanoma in several ways:

• Biomarker testing can identify tumors that are likely to respond to drugs such as BRAF inhibitors like dabrafenib and MEK inhibitors like trametinib that target these growth-promoting mutations.
• This type of testing can also find biomarkers that may predict response to other types of therapy including possibly immunotherapy.¹ This is an active area of research.
• Biomarker testing of tumor tissue DNA is also being investigated as a possible way to determine if the cancer is likely to come back and can therefore help decide how closely a patient should be monitored after treatment.

There are also other types of melanoma that are much more rare: acral, mucosal, and uveal melanoma. These melanomas occur on non-sun-exposed skin such as the soles of the feet, palms of the hands, and underneath the nail beds (acral); in mucous membranes such as the mouth, nasal cavity, GI tract, and reproductive tract (mucosal); and eyes (uveal). Less is known about these rare melanomas, and fewer specific treatments for them have been developed.

Some rare melanomas can share some of the tumor mutations found in cutaneous melanoma (for example, mutations in BRAF, NRAS, or NF1), but they can also have different mutations. Although about half of cutaneous melanomas have BRAF mutations, fewer acral melanomas do, meaning that fewer patients with acral melanoma are helped by BRAF inhibitors.²,³ In addition to mutations, biomarker testing of rare melanomas has identified other types of DNA abnormalities. For example, acral melanomas often have rearrangements of large segments of DNA. Biomarker testing of rare melanomas has the potential to identify other DNA changes that could help with selection of personalized treatments.

MRA-funded investigators are leading the way in characterizing similarities and differences among cutaneous, acral, mucosal, and uveal melanomas. MRA has supported biomarker identification in rare melanomas that was performed by Maryam Asgari, MD, MPH, Boris Bastian, MD, PhD, Jeffrey Sosman, MD, Nicholas Hayward, PhD, and their colleagues.

MRA-funded biomarker analysis of acral melanomas by Drs. Bastian, Asgari, and Sosman has found mutations and other DNA alterations that are unique or more common in acral compared to cutaneous melanomas. For some of these, targeted drugs are already approved, and for others, development of new therapies is anticipated.²,³ Multiple clinical trials investigating drugs that target these mutations in rare melanomas are in progress. Ongoing work by Dr. Hayward on rare melanomas seeks to comprehensively understand the role of individual genes on cancer cell growth.

The mutations identified in rare melanomas can serve as biomarkers for tumor vulnerabilities that physicians can target with medicines, using either drugs that are already available or newly developed experimental treatments that target a particular mutation. These biomarkers further differentiate and classify the many types of melanomas and lead to the best precision medicine opportunities. In this way, if a particular biomarker is identified in a patient, that patient may be able to receive personalized treatment for their melanoma.

MRA is also gathering more information on biomarkers identified in rare melanomas through the RARE Registry. People with acral or mucosal melanoma are invited to join the RARE Registry where they can provide information about their quality of life and treatments by answering surveys and providing medical records. People with cutaneous melanoma are also invited to participate for comparison. RARE Registry participants receive clinical trial alerts that may include trials testing therapies that target identified DNA alterations. Future plans for the RARE Registry include the ability of registry participants to provide tumor tissue for additional analyses. Increasing the number of tissue samples in the RARE Registry biobank will help scientists find even more similarities and differences in these tumors.

Biomarker analysis of rare melanomas is an active area of investigation. Researchers anticipate that more clinical trials will open as a result of identification of tumor biomarkers that can be targeted with existing therapies or newly developed drugs.

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