The Use of Aqueous Humor Liquid Biopsy in Patients With Uveal Melanoma

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In this video, Jesse L. Berry, MD, discusses her team's study that examined the use of aqueous humor liquid biopsy to determine metastatic risk in patients with uveal melanoma (UM). Dr Berry talks about how this method of biopsy impacts the clinical care of patients with UM, what knowledge gaps currently exist, and the future of this area of research.

Additional Resource:

  • Peng CC, Sirivolu S, Pike S, et al. Diagnostic aqueous humor proteome predicts metastatic potential in uveal melanoma. Int J Mol Sci. Published online April 6, 2023. doi:10.3390/ijms24076825

Jesse Berry

Jesse L. Berry, MD, is the director of ocular oncology at the University of Southern California (USC) Roski Eye Institute and the Children's Hospital Los Angeles, Keck School of Medicine of USC (Los Angeles, California).



Jesse L. Berry, MD: Hi everyone. I'm Jess Berry. I am the director of ocular oncology at the USC Roski Eye Institute and Children's Hospital Los Angeles, which are both part of Keck School of Medicine of USC.

Consultant360: How did this research question come about?

Dr Berry: My main body of research focuses on use of the aqueous as a liquid biopsy for ocular tumors, and I started with the pediatric tumor retinoblastoma, and the reason is that you cannot directly biopsy that tumor. So there was a huge lack of information at the molecular level about these tumors because you couldn't access tissue at all.

And so we started this research at, again, USC back in ... Well, I guess we really started it probably in about 2012, but our first publication was in 2017 and it started aqueous humor liquid biopsy research throughout the US and really around the world, again with an initial focus on retinoblastoma, which is a retinal-based tumor. But the other main tumor that I treat is a uveal melanoma or choroidal melanoma, which is a tumor that is much more likely to form in adults and forms in one of the layers under the retina, the choroid. That tumor can be biopsied. So we do have a lot of molecular information about that tumor. It doesn't have the same gap as it does for retinoblastoma. However, not all tumors in uveal melanoma can be biopsied. It may be in a difficult location or not infrequently the tumor is very thin, and so the risks of doing a biopsy are higher in those settings.

Additionally, biopsy does still require a needle into the back of the eye into a structure that may bleed or cause retinal detachment while infrequent that does happen. So in order to break down some of those barriers, we looked at applying this body of research—aqueous humor liquid biopsy—to our adult patients in the uveal melanoma setting.

C360: How do your results impact testing patients with uveal melanoma for potential metastasis?

Dr Berry: Right now, everything remains in the research realm. By that I mean if you want to do a clinical test for a patient to determine what kind of risk of metastatic disease they have, that currently requires a tumor biopsy, and then that sample needs to be sent out either for chromosomal analysis or, very, commonly gene expression profiling is done with a company called Castle Biosciences. However, what we hope will happen in the future is that either in addition to a tumor biopsy or as a standalone test, the aqueous humor can be used to provide similar information, not exact, but similar.

The benefits of the aqueous humor are, as I said, you can take all comers, so it doesn't matter the size of the tumor, you'd be able to access the aqueous in nearly all patients. That actually could be done in clinic if needed. So right now, a tissue biopsy is usually done in the operating room, and it's done at the time of other definitive treatment such as plaque brachytherapy, but the aqueous could be taken in clinic, I've done that before, and that sample can be taken safely while the adult is awake, they're just at the slit lamp the same way that you do a normal eye exam. And we hope that we'll be able to assay this fluid to get information that predicts the risk of metastatic disease.

Now, this might help with some treatment decisions. There are small tumors that patients currently don't want to move forward with treatment on them unless they're known to otherwise be high risk. I could spend hours going over that, so I'll leave that statement as it is. It's a complex statement, but we may be able to provide some information regarding the risk of the tumor to those reluctant patients. And it's possible, we're not there yet, but it's possible that it might also be able to give a validated and confirmed molecular diagnosis for melanoma where right now the diagnosis is done based on clinical imaging and clinical features that we see in the eye.

C360: Are there any other knowledge gaps that exist in this area of research and if so, what are they?

Dr Berry: Yeah, there are a lot. One of the knowledge gaps that I hope we'll be able to help with again, is understanding the molecular features of these smaller tumors, the ones that are difficult to biopsy. Now, these smaller tumors also, generally, we know shed less DNA into the aqueous humor, and DNA is one of the main analytes we look at in a liquid biopsy setting. So we're looking for chromosomal alterations or we're looking for mutations in certain genes. That being said, as we showed in our recent work, the proteins do seem to be secreted even in small tumors and we were able to detect a signal in those patients. And so it's possible that by investigating this different analyte, looking at proteins, we'll be able to better understand the protein signature of high-risk and low-risk melanoma.

And I hope that, as I mentioned, it may even be able to help us with diagnosis so that if we have a suspicious lesion but we're not entirely sure if it's a melanoma or not, or if we have a small tumor that we couldn't biopsy, we'd be able to get some important and impactful information regarding prognosis from those patients.

C360: What is the next step in research in testing patients with uveal melanoma for metastasis?

Dr Berry: As it relates to our body of research, particularly using the aqueous as a liquid biopsy, it's about samples. And so we want to get in as many patients as we possibly can. Uveal melanoma is a rare diagnosis, only about six per million people in the US will be diagnosed with this disease. And of course, I don't see all of them. And so we are definitely trying to broaden our reach so that patients who would be willing to participate in this research study would be able to send their samples from other centers. We already have a couple of centers who do collaborate with us and share samples. And this allows us to have a broader population of patients and a more diverse population than I see just in my single center so that we can validate and better understand these results.

As this moves forward, our goal would be, of course, to have a clinical test. We've already done that for retinoblastoma. There is now a clinical liquid biopsy test that's available that's through Children's Hospital Los Angeles, and actually, we did include some of the melanoma mutations in there. So for certain patients, we'd be able to look at the aqueous for that in a clinically-validated way. But as it relates to our recent work on proteins, that still does need to be validated before we can offer it as a clinical test. So more to come on that. That's definitely a main goal of the future of our program.

C360: What is the overall take-home message from your study?

Dr Berry: The take-home, I would say is that we are able to rethink the way we approach biopsy now in patients with uveal melanoma, that the aqueous humor harbors information from ocular tumors is now sort of resoundingly clear. And that's true both for the pediatric cancer retinoblastoma, but as well as melanoma. And it's been clear from research outside of my lab in other cancers such as lymphoma of the eye. So that the aqueous is going to play a role as a liquid biopsy, I think is quite clear what that role is, is still an area of active research, and I'm really excited about it. I invite doctors at other centers to collaborate with us, and I think the more that we work together, the more likely it is that we'll be able to get this information into the clinical sphere so that it can help our patients, which is ultimately what we're all here for.

C360: In your opinion, how do you hope your research impacts the future of care for patients with uveal melanoma?

Dr Berry: I hope that by using the aqueous, we will be able to include all patients. So like I said, there's lots of patients I say, "Your tumor's only 1.5 millimeters. That's a little too small for me to biopsy." In the future, I hope I never have to say that. I hope I can say, "We have a liquid biopsy option available for you so that you can get information about your tumor even though it's small." And I also mentioned this, but I hope that it will help us diagnose patients that have these sort of high risk but questionable lesions and that this would be something we'd be able to easily take a sample in clinic while the patient is there with just a tiny drop of anesthesia and get some really impactful data to help us decide what to do for these patients.

Dr Berry: Thank you all so much for inviting me to be here today to share our exciting research. I hope this will be the first of many. This is a growing field, and I really expect in the next couple of years for this to make impactful changes in the way we care for our patients with these rare ocular cancers. So it's a delight that you all are interested in it, and thank you for the invite.