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NYU Team to Validate ddPCR Liquid Biopsy for Monitoring Metastatic Melanoma Recurrence

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NEW YORK (GenomeWeb) – Unlike other cancers, there are not yet molecular assays that can give early signs of recurrence for metastatic melanoma. Serum lactate dehydrogenase, or LDH, is sometimes measured, but has low sensitivity and specificity. But, also unlike other cancers, melanomas tend to have an abbreviated playbook of possible mutations.

Stepping in to fill the unmet need for molecular melanoma monitoring, David Polsky, a dermatologist and researcher at New York University, was awarded funds this week from the National Cancer Institute to transform a set of seven biomarkers into a digital PCR-based assay to track melanoma recurrence.

"What we want to be able to do is detect ctDNA at low abundance, in patients who may be clinically disease free," Polsky said in an interview with GenomeWeb. Elevated levels could indicate disease recurrence, which could then guide therapies for patients.

The award, which totals $211,875 for the first year, is structured such that results from two years of validation can be parlayed into an additional three years for a clinical assessment.

Polsky said his group is collaborating with Bio-Rad and MolecularMD on the droplet digital PCR assays, and that the test is expected to become part of a clinical trial with Bristol-Meyers Squibb comparing adjuvant ipilimumab to nivolumab.

Prior to the commercial availability of ddPCR, Polsky's group had developed an allele-specific real-time PCR in collaboration with MolecularMD which that firm subsequently licensed from NYU.

But the researchers ultimately did a pilot study comparing ddPCR to the real-time PCR method, finding that ddPCR showed superior sensitivity and precision.

Melanoma happens to have "hotspot" mutations, such that approximately 50 percent of patients have a mutation in the BRAF gene, with 90 percent of those being either V600E or V600K. The NRAS gene is mutated in about 20 percent of patients, most commonly in Q61R, Q61L, and Q61K.

"We were fortunate that Bio-Rad had research-use only assays already developed for those five targets," Polsky said.

The list of biomarkers also includes two mutations in the telomerase reverse-transcriptase gene, or TERT. Among patients who do not carry the BRAF or NRAS mutations, "a good portion of them have a TERT mutation, and these mutations are in the promoter region of the TERT gene," Polsky explained.

The NYU group is now developing the TERT assays in collaboration with Bio-Rad on the ddPCR system. Bio-Rad has been focusing on oncology by adding to its newly launched line of Droplet Digital PCR Multiplex Mutation Screening Kits, and ddPCR was used recently in a clinical validation of liquid biopsy of non-small cell lung cancer.  

Ultimately, the paradigm for initial therapy is to find out what mutation is in a patient's metastatic tumor and then choose the ddPCR target based on that, Polsky said.

"We're hoping this test can get into the hands of the practicing oncologist," he said.

In a patient who is metastatic but surgically disease-free and is on adjuvant immunotherapy, an early indication of disease relapse or progression might allow a doctor to put them on some kind of active treatment, like a BRAF/MEK inhibitor combination, for example.

"If you have to wait until you start to see it on the CAT scan, or even worse when the patient has symptoms, they may have a larger burden of disease and be less amenable to treatment," Polsky said.

And in patients who are being actively treated, progression, indicated by higher ctDNA levels, could guide a physician to switch treatments. "If you can switch them when the disease burden is low then they may have a better survival — this needs to be tested in a clinical trial setting, but we want to have the tools to be able to address that," he said.

The correlation between a rise in cell-free circulating tumor DNA and recurrence of disease is a subject of ongoing research and is more established in other cancers, such as colon and breast cancer. Polsky co-authored a study in Molecular Oncology earlier this year showing the same thing happens in melanoma. This retrospective analysis of prospectively accrued patient data also showed BRAF and NRAS mutant ctDNA levels measured via ddPCR were superior to LDH at detecting disease progression.

However, melanoma might ultimately be easier to design assays for, since only five mutations can cover about 60 percent of patients, Polsky said, while colon cancer and breast cancer have such variability that they require either large panels or sequencing to personalize treatment.

Polsky said the first two years of the grant will consist of analytical validation to get the assays ready to be used in a CLIA lab. After that there will be three years to analyze patient samples from the clinical trial in which plasma will be collected at standardized intervals.

The group is working with MolecularMD, for which Polsky also does consulting, and that firm is interested in running clinical trial support, he said. This would require a CLIA environment, but it remains to be determined whether the test will be run at NYU specifically. Bio-Rad is jointly developing the TERT assays and assisting with validation and sample analysis, and the collaborators have an agreement covering intellectual property.   

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