What Role May ctDNA Have in Melanoma Management?

Circulating tumor DNA (ctDNA) negativity has been associated with prolonged response to treatment with immune checkpoint inhibitors (ICIs), researchers have found. While it is still too early for ctDNA to play a role in clinical practice, experts expressed enthusiasm for the future.

ctDNA, as explained by the National Cancer Institute, is a term used to refer to small pieces of DNA that are released into a patient’s blood by tumor cells.

Researchers published their findings in Nature Communications; they drew on data from 87 patients with advanced melanoma who were treated with ICIs and received a combined 321 liquid biopsies. ctDNA was detected in 76.9% of postsurgical patients with relapse (10 of 13 patients), and all nine patients without progression remained ctDNA negative.

“In summary, the results of this study confirm the prognostic relevance of ctDNA in patients with advanced melanoma treated with ICI,” researchers wrote in Nature Communications.

CURE spoke with Dr. Michael K. Wong and Dr. Diwakar Davar about the study, its findings and the potential role of ctDNA in melanoma management in the future.

“Right now, today, there isn't enough data to say yay or nay, it's not going to be used clinically. But stay tuned, because without a doubt, this is where the whole field is going,” said Wong.

Wong, a member of CURE’s advisory board, is the physician in chief at Roswell Park Comprehensive Cancer Center in Buffalo, New York, and Davar is an associate professor of medicine at the University of Pittsburgh.

Transcript:

Wong: The bottom line is, can you measure in blood a signal about the behavior of a patient's tumor just by looking at blood, so no need for biopsy and so on and so forth? And No. 2, will this new methodology, which is convenient for the patient because you don't need to do scans or anything, will that give us enough information to act on it? This paper is only on 97 patients, which in oncology, that's a very small number. It's basically a proof of concept like, "Hey, look, there's a trend here. Let's go and study this more." Because if you didn't get a trend, you would be like, "Forget it. Not worth it."

But this certainly did show a trend. And the trend is that in those patients where the variant went up, there was a hint that these had a higher likelihood of having recurrence, or in those patients where the variant didn't go down under treatment, it means that they had persistent tumor; it didn't go down. And you say, "Well, who cares? I can just do a scan." That's correct. But the idea is that you don't have to do a scan, No. 1, and No. 2, this may be more sensitive than a scan, right? You pick it up earlier.

Davar: When you look at the number of people who had circulating tumor DNA that was firstly not low. So, in melanoma, there's this idea that melanoma is a tumor that doesn't shed, as opposed to, say, colorectal cancer or lung cancer. But melanoma, in this case, was associated with detectable ctDNA. So that's one sort of very important point. The reason that's important is that if you're a circulating tumor DNA company, and you weren't certain that melanoma was an area to study before this, because of this prevailing idea that it doesn't shed, now you're like, "You know what? In the context of a prospectively done study at an academic medical center, this is clearly detectable."

Then the second thing is the pattern, which is to say that one, it's detectable. Two, it very clearly mirrors what you expect to see in patients, which is that the vast majority of the time, people who benefit from therapy have a rapid and clear decline in circulating tumor DNA. That's great, and that's very, very, very helpful. And there are some exceptions to this. There are people whose circulating tumor DNA levels are sort of extraordinarily high, who don't appear to necessarily come down, and that usually is associated with having sort of extensive disease in a PET scan. But outside of that, in the vast majority of cases, this is associated with a very good result.

Wong: Right now, today, there isn't enough data to say yay or nay; it's not going to be used clinically. But stay tuned, because without a doubt, this is where the whole field is going. There are other publications using technology backed by big companies. There's lots of funding.

An example is Natera, who just published a paper in Merkel cell carcinoma. You see "Merkel cell carcinoma, who cares? It's a rare tumor?" Exactly. But the thing is that Merkel is famous for having a very distinctive genetic signature. So, it all relies on picking up a signature, right? And so that also means that some tumors are more apt to be reliable than others. Melanoma and Merkel are skin cancers, and when I talk to you about getting radiation damage to your skin, those are famous for having high TMB, tumor mutational burden, in other words, lots of mutations. Other cancers, like some of the sarcomas, have very low mutations, and you could expect the number of variants is low. Now they didn't test sarcomas, not surprisingly, because it's not a high variant tumor.

So what I'm saying, to translate in plain English, is that this technology, likely, even in its best form, is not going to be used for all cancers because some cancers simply won't have enough variance to go on.

Transcript has been edited for clarity and conciseness.

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