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TGen Team Hopes $2M Study Will Help Lay Path for Liquid Biopsy Monitoring in Metastatic Melanoma

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NEW YORK (GenomeWeb) – Led by a team from the Translational Genomics Research Institute, researchers are pushing forward to test whether circulating DNA mutations might be a better way to monitor the disease progress and drug responses of metastatic melanoma patients than current imaging tools.

The investigation, funded by a recently awarded $2 million grant, is part of an ongoing swell of interest in liquid biopsy: non-invasive cancer testing that relies on detection of tumor DNA and other nucleic acid fragments that float freely in the blood and body fluids.

According to Muhammed Murtaza, co-director of TGen's Center for Noninvasive Diagnostics and the study's principal investigator, metastatic melanoma is a fitting choice for studying how liquid biopsy could be used for monitoring, because clinicians in this field are already interested in tracking the progress of their patients' disease using radiological imaging — usually CT scans — in order to try to stay a step ahead of a particularly aggressive form of cancer.

Drugs may work for a time on the disease, but doctors are eager to catch the moment they stop being effective so that patients can be switched to alternative therapies. Monitoring can also be essential in the application of new immunotherapy drugs, which sometimes cause a phenomenon called pseudoprogression in which patients look like they are doing worse before they begin doing better.

Having a way to track patients using blood samples instead of imaging scans would save patients time, reduce their exposure to radiation, and ideally decrease costs.

Despite this potential, Murtaza said that there has been little data collected so far on circulating DNA monitoring in melanoma, even while other disease areas have started to become test cases for a similar approach.

Notable examples include studies showing that serial ctDNA testing can pick up signs of a recurrence in colorectal, lung, breast, and other solid tumors that have been surgically removed, and that these DNA signals can also help predict whether patients will respond well to a particular drug based on patterns in their liquid biopsy results during the first few weeks of treatment.

Murtaza's new five-year TGen effort, which also involves collaborators at Yale University and the University of California, Los Angeles, will attempt to look at some of these same questions more comprehensively in melanoma.

The team is confident based on other studies that DNA mutations do circulate in the blood of metastatic melanoma patients, but they hope now to identify the patterns involved: at what point during treatment, and by how much, ctDNA levels change, and exactly how those changes correlate to treatment response, and importantly, to overall outcomes.

The group is studying about 100 patients in total from three existing cohorts, Murtaza said. One is a group treated with immune checkpoint inhibitors in a clinical study being conducted at UCLA. The other is a set of patients given standard-of-care therapy at the Mayo Clinic in Arizona. And a third is from a TGen-led Stand Up to Cancer genomics-enabled melanoma study that recruited patients with wild-type BRAF mutations who received targeted therapies guided by their exome sequencing results.

Investigators will examine blood samples from multiple timepoints during these patients' treatments and will try to develop quantitative thresholds for monitoring, which they then plan to validate in another 50 or so individuals

There are three main questions the team will focus on, Murtaza added. One is whether circulating DNA signals can help provide clarity in cases of ambiguous immunotherapy responses that imaging can't resolve. "With the number of mixed responses you see on imaging – especially early on in immunotherapy, there is a clear rationale [to trying to see if] circulating markers can help us tell apart a true lack of response or true progression from pseudoprogression," Murtaza said.

A second primary question for the team will be whether they can show that ctDNA can help disentangle responders and non-responders earlier in the treatment cycle, "at one or two weeks in instead of a two to three months when the first scan is usually performed."

Similarly, the investigators will study whether the ability to examine ctDNA more often appears to suggest a benefit to patients over scans that can only be applied every few months.

Finally, Murtaza said, the group will be looking at a relatively new phenomenon in the disease — borne of the introduction immunotherapies — cases of complete response, meaning patients whose imaging scans show a total disappearance of their tumors.

"It's a big question for the field," Murtaza said, "how long we should continue to treat a patient with this kind of complete response. So, we are hoping that this [study] may provide answers [about] whether cfDNA signals persist or clear in these patients."

Murtaza said that he and his team are expecting to publish on their DNA detection methodology in the scientific press and so couldn't provide many details about the techniques they'll use to measure mutations in patients' blood.

He did say, though, that the approach is similar to strategies employed in earlier studies of colorectal cancer patients (or to the platform now being commercialized by Natera), in which comprehensive sequencing results from an individual's tumor tissue are used to pick out a bespoke set of mutations that can be tracked in the blood using simpler, more targeted technology.

Similar approaches continue to be explored in a range of cancer types, and other recent announcements include a study by the Fox Chase Cancer Center evaluating Natera's ctDNA technology in monitoring kidney cancer recurrence; an effort by UCSD Moores Cancer Center using Biocept's Target Selector assays to try to predict cancer recurrence and treatment response in breast, colorectal, and lung cancer patients; and a project at the Addario Lung Cancer Medical Institute and Washington University School of Medicine testing Inivata's InVision liquid biopsy platform for minimal residual disease detection and recurrence monitoring in lung cancer patients post-surgery.

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