Sylvester Researchers Study Size and Gene Expression to Classify Uveal Melanomas

A team of researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine has conducted two new studies that may help guide prognosis and treatment of uveal melanomas.

Building on key discoveries made in recent years, the research team, led by J. William Harbour, M.D., an eye cancer expert at Sylvester, factored tumor size and mutations into a patient’s prognosis. The findings from their studies were recently published as separate articles in JAMA Ophthalmology.

Uveal melanoma, the most common primary eye tumor, is very different from melanoma found in the skin. For example, uveal tumors are more difficult to access: a needle biopsy versus a relatively easy skin sample. This difficulty continues after the cancer has spread. While skin melanomas tend to invade lymph nodes, uveal cancers often go to the liver, where they might remain dormant for years before flaring up.

Treatments vary, as well. Since surgery would be a last resort, uveal melanomas are generally treated with a form of radiation called brachytherapy, in which radioactive iodine is placed near the tumor. If the tumor gets too big, the eye may need to be removed.

In one study, the team looked at the metastatic risk associated with tumor diameter. They found that tumors 12 millimeters or larger indicate a 70 percent risk of metastasis over five years. If the tumor is less than 12 millimeters, five-year risk declines to around 10 percent.

Researchers don’t quite understand why 12 is the magic number. It’s possible the smaller tumors are getting treated early enough to prevent metastasis, a characteristic that could help refine care.

“This diameter study suggests we should treat class 2 tumors when they’re smaller,” said Harbour. “We’re gearing up to validate these findings in a large, prospective multicenter trial.”

Uveal tumors also differ genetically from other melanomas, which is why the researchers studied mutations as well as tumor size. Their findings could ultimately help physicians personalize treatments.

Once clinicians have taken a biopsy, the next step is to determine whether the tumor is likely to spread or metastasize.

“We’ve made a lot of progress,” said Harbour. “Gene expression profiling is pretty accurate, stratifying patients into class 1 or class 2, which are much more likely to metastasize.”

In the second study, Harbour’s group looked at five genes that might be driving the disease. They found three that have a definite impact on prognosis: BAP1, SF3B1, and EIF1AX.

“Uveal melanoma needs one of these three drivers for cancer to progress,” said Harbour. “These three mutations are clearly associated with metastatic risk.”

Normally, BAP1 is a cancer suppressor, but the mutated version loses that ability, allowing uveal melanomas to proceed. The gene is almost always associated with class 2 tumors and is also mutated in mesothelioma and other cancers. In addition, BAP1 patients aren’t good candidates for checkpoint inhibitors, the immunotherapies that can be highly effective in certain patients.

The other two mutations are linked to class 1 disease. SF3B1 patients are more amenable to immune therapies. EIF1AX patients have much lower risk of metastasis.

“The gist was to show that these three mutations can be used in association with the gene expression panel to improve prognostication,” said Harbour.

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