David Polsky, MD, PhD, the Alfred W. Kopf, MD, Professor of Dermatologic Oncology, Ronald O. Perelman Department of Dermatology Professor in the Department of Pathology, and director of the Pigmented Lesion Service at NYU Langone Health’s Perlmutter Cancer Center, on the association between circulating tumor (ct)DNA and survival in melanoma.

ctDNA is the fraction of DNA in the plasma that comes from the tumor and it is identified by identifying mutations that stem from the tumor, explains Polsky. For example, in 

-mutated DNA can be found in the plasma and measured.

Some studies have shown that the level of circulating 

-mutated DNA prior to treatment with BRAF/MEK therapies, such as dabrafenib (Tafinlar) and trametinib (Mekinist), was shown to be associated with survival. If patients had low ctDNA, they had a better survival compared with if they had high ctDNA.

Investigators also examined what would happen at 4 weeks on treatment and found that patients whose ctDNA became undetectable had a doubling in progression-free survival and overall survival. Those findings were observed in patients with a high tumor burden as assessed by lactate dehydrogenase, which is a standard surrogate blood marker for tumor burden, concludes Polsky.

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David Polsky, MD, PhD, on the association between circulating tumor DNA and survival in melanoma.

Dr. Polsky on the Association Between ctDNA and Survival in Melanoma

David Polsky, MD, PhD, the Alfred W. Kopf, MD, Professor of Dermatologic Oncology, Ronald O. Perelman Department of Dermatology Professor, Department of Pathology, and director of the Pigmented Lesion Service, NYU Langone Health’s Perlmutter Cancer Center, discusses the use of circulating tumor DNA (ctDNA) in the COMBI-d trial on melanoma.

NYU Langone Health’s Perlmutter Cancer Center uses droplet digital polymerase chain reaction in their laboratories, which is known to be a highly sensitive and specific method to detect ctDNA, says Polsky. Data from the COMBI-d trial presented at the 2019 ASCO Annual Meeting showed that ctDNA monitoring is clinically valid in predicting whether patients with unresectable, metastatic 

-mutant melanoma will benefit from dabrafenib (Tafinlar) alone or in combination with trametinib (Mekinist).

Investigators saw a very high detection rate of 93% in these patients, says Polsky; this means that investigators were able to detect the 

 mutation in the patient’s tumor prior to treatment in 93% of patients, which is the highest percentage reported to date, according to Polsky.

Although other sequencing-based assays have advantages over ctDNA and are able to detect multiple mutations at the same time, the sensitivity of ctDNA is thought to be the highest when looking at a single molecule target at a time, concludes Polsky.

David Polsky, MD, PhD, discusses the use of circulating tumor DNA (ctDNA) in the COMBI-d trial on melanoma.

Dr. Polsky on the Clinical Validity of ctDNA in BRAF-Mutant Melanoma

David Polsky, MD, PhD, the Alfred W. Kopf, MD, Professor of Dermatologic Oncology, Ronald O. Perelman Department of Dermatology Professor, Department of Pathology, and director of the Pigmented Lesion Service, NYU Langone Health’s Perlmutter Cancer Center, discusses the unmet need of clinical utility in liquid biopsy.

There is a need for physicians to keep working on clinical utility studies and to find the appropriate setting for these tests, says Polsky. These tests also need to be performed in the Clinical Laboratory Improvement Amendments (CLIA)—certified laboratories because currently they are being performed within research laboratories in the United States. Additionally, these tests have to be moved to clinical laboratories where they are conducted with oversight for any blood test.

Once clinical utility is shown in a research study and the assays are being performed in CLIA certified laboratories then I could see them being adopted in melanoma, Polsky adds. There are commercial companies that are developing liquid biopsy but it is mostly in other tumors and it has not made it to the melanoma space yet, concludes Polsky.

David Polsky, MD, PhD, discusses the unmet need of clinical utility in liquid biopsy.
 
 

Dr. Polsky on the Unmet Need of Clinical Utility in Liquid Biopsy

David Polsky, MD, PhD, the Alfred W. Kopf, MD, Professor of Dermatologic Oncology, Ronald O. Perelman Department of Dermatology Professor, Department of Pathology, and director of the Pigmented Lesion Service, NYU Langone Health’s Perlmutter Cancer Center, discusses the exploration of blood-based biomarkers in melanoma.

Many groups are analyzing tissue samples to identify measurable biomarkers, including proteins, RNA, or DNA mutations that are prognostic and may be associated with poorer outcomes, explains Polsky. From there, these biomarkers move into the predictive space where they might be able to act as predictors for patient response on a follow-up therapy.

Research at NYU Langone Health focuses on blood-based biomarkers, particularly circulating tumor DNA, says Polsky. On an international level, multiple labs, according to Polsky, are also investigating the role of ctDNA in melanoma as well as other cancers.

David Polsky, MD, PhD, discusses the exploration of blood-based biomarkers in melanoma.

Dr. Polsky on the Exploration of Blood-Based Biomarkers in Melanoma

David Polsky, MD, PhD, Alfred W. Kopf, MD Professor of Dermatologic Oncology, Ronald O. Perelman Department of Dermatology, professor, Department of Pathology, and director, Pigmented Lesion Service, NYU Langone’s Perlmutter Cancer Center, discusses potential applications of circulating tumor DNA (ctDNA) as a biomarker in melanoma. 

Polsky and researchers studied the ctDNA of 345 patients with unresectable or metastatic melanoma who were treated with dabrafenib (Tafinlar) or dabrafenib plus trametinib (Mekinist) in the randomized phase III COMBI-d trial. 

Based on the findings, ctDNA could be used in conjunction with CT imaging to shed light on indeterminate radiographic findings in patients. says Polsky.

In 2018, a paper published by investigators at Johns Hopkins University suggested that incorporating ctDNA assessment into clinical practice could influence treatment decisions, clarify radiographic interpretations, and ultimately impact outcomes.

David Polsky, MD, PhD, discusses potential applications of circulating tumor DNA as a biomarker in melanoma. 
 

Dr. Polsky on Potential Applications of ctDNA in Melanoma

David Polsky, MD, PhD, Alfred W. Kopf, MD Professor of Dermatologic Oncology, Ronald O. Perelman Department of Dermatology, professor, Department of Pathology, and director, Pigmented Lesion Service, NYU Langone’s Perlmutter Cancer Center, discusses the next steps that have to be taken to validate the clinical utility of circulating tumor DNA (ctDNA) as a biomarker in 

A study led by Polsky demonstrated the clinical validity of ctDNA monitoring in predicting whether patients with advanced 

-mutant melanoma would benefit from either dabrafenib (Tafinlar) alone or in combination with trametinib (Mekinist). Investigators need to evaluate additional timepoints as they only had week 4 samples for the first analysis. Further analysis could show better predictive value on which to base a survival model, says Polsky.  

If additional follow-up reveals consistent findings, investigators would like to launch a clinical trial randomizing patients to a prespecified second-line therapy. At the time of progression, patients would switch to another agent and then could be randomized to receive therapy based on a rise in their ctDNA versus radiographic progression, which is the standard of care. That type of a design would demonstrate whether the marker has clinical utility, not just clinical validity, concludes Polsky.

David Polsky, MD, PhD, Alfred W. Kopf, MD Professor of Dermatologic Oncology, Ronald O. Perelman Department of Dermatology, professor, Department of Pathology, and director, Pigmented Lesion Service, NYU Langone’s Perlmutter Cancer Center, discusses the next steps that have to be taken to validate the clinical utility of circulating tumor DNA (ctDNA) as a biomarker in BRAF-mutant melanoma.

Dr. Polsky on Validating ctDNA as a Biomarker in BRAF-Mutant Melanoma

David Polsky, MD, PhD, Alfred W. Kopf, MD Professor of Dermatologic Oncology, Ronald O. Perelman Department of Dermatology, professor, Department of Pathology, and director, Pigmented Lesion Service, NYU Langone’s Perlmutter Cancer Center, discusses the predictive value of circulating tumor DNA (ctDNA) in 

In an analysis led by Polsky, ctDNA monitoring was found to be clinically valid in predicting whether patients with unresectable, metastatic 

-mutant melanoma would benefit from either dabrafenib (Tafinlar) alone or in combination with trametinib (Mekinist). At baseline, the amount of ctDNA was predictive of survival.

This is the first study to show the predictive value of ctDNA, as prior studies have only been able to detect its presence or lack thereof, explains Polsky. Moreover, there was a high sensitivity rate of 93% of patients who had a 

 V600E mutation in their plasma. With this platform, investigators were able to quantify these levels with outcomes.

For example, the samples that were collected at week 4 were predictive of survival benefit. If patients had no detectable ctDNA at week 4, they had a progression-free survival and overall survival that was approximately double that of those who had persistent ctDNA detected at week 4.

Further follow-up may indicate that ctDNA could become a monitoring tool that could direct treatment. For example, if patients have positive ctDNA for a prolonged period of time after starting treatment, adding an additional treatment might be considered, explains Polsky. On the other hand, if patients have no evidence of ctDNA during treatment, they might not require additional therapy. However, this hypothesis will have be validated in future studies before it can be applied to practice.

David Polsky, MD, PhD, Alfred W. Kopf, MD Professor of Dermatologic Oncology, Ronald O. Perelman Department of Dermatology, professor, Department of Pathology, and director, Pigmented Lesion Service, NYU Langone’s Perlmutter Cancer Center, discusses the predictive value of circulating tumor DNA (ctDNA) in BRAF-mutant melanoma.

Dr. Polsky on the Predictive Value of ctDNA in BRAF-Mutant Melanoma

David Polsky, MD, PhD, professor of dermatologic oncology, Ronald O. Perelman Department of Dermatology, NYU Langone’s Perlmutter Cancer Center, discusses using circulating tumor DNA (ctDNA) kinetics as a biomarker to predict survival and monitor disease activity in patients with unresectable or metastatic melanoma.

Polsky and researchers studied patients who are part of the randomized phase III COMBI-d trial, which evaluated dabrafenib (Tafinlar) versus dabrafenib plus trametinib (Mekinist) in patients with unresectable or metastatic melanoma. In this analysis, researchers examined the ctDNA enrolled 345 patients at the baseline.

 V600E/K ctDNA at baseline and week 4 in plasma samples. Mutation-specific droplet digital PCR assays were used to measure, according to Polsky. The ctDNA results were categorized as positive/negative using an analytically validated detection threshold of 0.25 copies/mL. The primary goals of the study were to examine progression-free survival and overall survival.

David Polsky, MD, PhD, discusses using circulating tumor DNA kinetics as a biomarker to predict survival and monitor disease activity in patients with unresectable or metastatic melanoma.

David Polsky, MD, PhD

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