Combining Genetic Tests Offers Superior Risk Prediction in Uveal Melanoma

A recent study led by Dr. J. William Harbour of UT Southwestern Medical Center marks a shift in how doctors predict the spread of uveal melanoma (UM). Published in Nature Communications, the COOG2 study confirms that combining the DecisionDx-UM gene expression profile with PRAME testing provides a more accurate roadmap for patient care than traditional DNA mutation analysis alone.

While standard sequencing looks only at tumor DNA, DecisionDx-UM captures the microenvironment, including how immune cells interact with the cancer. This allows for superior prediction of metastasis-free and overall survival.

Harbour, a Professor and Chair of the Department of Ophthalmology at UT Southwestern Medical Center, sat down for an interview with CURE to discuss these findings and what they mean for patients.

Transcript

The study highlights that combining the DecisionDx-UM test with PRAME expression is superior to standard mutation analysis. And for a patient who's just been diagnosed with uveal melanoma, what does this superiority mean for their day-to-day care and peace of mind?

it means that we have a very accurate prediction of what their risk is in the future of that melanoma in the eye, which will be treated promptly, but what's the chance that some of it got out and got into the body and we just can't find it yet with a CT scan, but it's going to show up later. So, if you're in a low-risk group, that can be very reassuring. We'll still do some scans of your body from time to time to just to be on the safe side, because no test is perfect, and even in low risk things can happen from time to time.

And then, those that are at high risk, we no longer have to just say, “I'm sorry, you have a high-risk tumor.” There are a number of things that we can do to look ahead and try to do things to improve their survival. So, for example, No. 1 is we adjust their surveillance scans. So if you're in a low-risk group, we may just scan your liver once a year and maybe check your lungs once a year. If you're in the high-risk group, let's say class 2, PRAME-positive, we're going to want to scan your liver every three or four months, at least for the first five years, and probably scan your chest with a chest CT at least once a year.

No, 2, we have therapies now that are available in the adjuvant setting, meaning in the preventative setting. We've diagnosed the primary tumor in the eye. We've biopsied it. We see that it's class 2, it's high risk. We've treated the primary tumor, let's say, with radiation. Now that tumor is dead, mortally wounded, so it can't spread anymore, but we know that there's a significant chance that some of it got out and it's hiding in the body somewhere. So, we can put patients on clinical trials, and there are several of those available already. One of them is based on work out of my lab using a drug called quisinostat, which we have shown in a number of different experiments in the laboratory to reverse many of the effects of losing BAP1 in the cancer cell, so it can kind of revert the cancer cell from class 2 back to class 1 — in theory, that's what it's doing.

So, we have a clinical trial of quisinostat for class 2 patients that has already opened at University of Miami Sylvester Cancer Center, where I was before, and the principal investigator is my long term colleague, Dr Jose Lutzky, and we're opening a center here, another site for the clinical trial here at UT Southwestern in Dallas, and several other sites around the country, so patients will have access to this quisinostat trial. It's an oral agent, so you don't have to have an infusion. It's well tolerated in most patients. So that's a great option for somebody who wants to not just sit back and hope for the best, but actually wants to take some action and try to improve their outcome. Now this is a clinical trial, meaning that we don't have proof that it works. We have to do the trial to know that it works. We have a lot of reasons to think that it will help, but we have to do the trial to know.

There are other trials. This is more in the arm of what you would call molecular targeted therapy, where we're targeting a specific protein that becomes abnormal in class 2 uveal melanomas. The other type of therapy is immunotherapy. So there is an approved immunotherapy for UVA melanoma called Kimmtrak (tebentafusp-tebn), and that has shown benefit in the metastatic setting, and so that is now being looked at in the adjuvant setting. Now that one does require an infusion from time to time, and it requires a certain blood type, an HLA type, that you have to be matched to. So it's a little bit more restrictive, but that's another option for patients. So increasingly, it's of value to know, even if you have a high-risk tumor — yeah, that's something you didn't want to hear, but you have information now that you can act on to try to improve your outcome and for us to learn how to take better care of patients.

References

1. “Landmark Study Shows Combination of Castle Biosciences' DecisionDx®-UM and PRAME Outperforms Gene Mutation Analysis in Predicting Survival Outcomes in Uveal Melanoma,” news release; https://ir.castlebiosciences.com/news/news-details/2025/Landmark-Study-Shows-Combination-of-Castle-Biosciences-DecisionDx-UM-and-PRAME-Outperforms-Gene-Mutation-Analysis-in-Predicting-Survival-Outcomes-in-Uveal-Melanoma/default.aspx

Transcript has been edited for clarity and conciseness.

For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here.