Higher ctDNA Serves as Early Warning for Melanoma Recurrence Risk
David Polsky, MD, discussed a study showing ctDNA levels before melanoma treatment strongly predict recurrence and its speed, potentially guiding future therapy decisions.
Extreme close-up of a melanoma: © mavis - stock.adobe.com
A new study published in The Lancet and led by NYU Langone Health researchers indicates that the presence of circulating tumor DNA (ctDNA) in stage 3 melanoma patients before treatment is a strong predictor of cancer recurrence.
The study found that approximately 80% of patients with detectable ctDNA experienced recurrence, and their disease returned more than four times faster than those without detectable ctDNA. Higher ctDNA levels were also associated with quicker recurrence. Researchers suggest that ctDNA tests could help identify patients most likely to respond to therapy and guide future treatment decisions. They also found that the appearance of ctDNA during treatment strongly suggests worsening disease. This method, which detects mutated DNA fragments in the blood, proved as good as or better than other experimental tests in predicting recurrence. While promising, the researchers plan to improve the test's sensitivity and explore its clinical utility in improving patient outcomes.
In an interview with Targeted OncologyTM, David Polsky, professor of dermatology and pathology; Alfred W. Kopf, MD, professor of dermatologic oncology; director, Pigmented Lesion Section; vice chair for research, Ronald O. Perelman Department of Dermatology at Laura and Isaac Perlmutter Cancer Center, NYU Langone Health; and study senior author discussed this study and its implications for clinical practice.
Targeted OncologyTM: What was the primary motivation behind investigating ctDNA in the adjuvant setting for melanoma? What gap in current management were you hoping to address?
Polsky: We know that patients with resected stage III melanoma have highly variable survival outcomes. Some patients are cured by their surgical resection; others will recur. In melanoma, we don’t have a blood test to measure minimal residual disease [MRD]. Because ctDNA is a direct indicator of MRD, measuring levels in the adjuvant setting was an excellent test of whether ctDNA monitoring could identify patients who would recur.
David Polsky, MD
In your opinion, what is the most important finding of this study for clinicians treating melanoma?
We show that the quantity of ctDNA detected was important. The higher the level of ctDNA the greater the risk for recurrence. Secondly, we demonstrated the potential value of monitoring ctDNA levels over time. Although the test is not yet sensitive enough to identify all patients who will recur, in some patients the test was initially negative, but then became positive while on treatment. We called this molecular relapse, which is a term used in the management of liquid tumors. We found that the patients with molecular relapse inevitably recurred.
These results are important because the test may eventually be used to assist medical oncologists in managing patients. For example, in a patient with a positive ctDNA test, the physician may choose to accelerate the schedule for a follow up CT scan or get a PET-CT scan, or they may choose to escalate the patient’s treatment regimen based on a combination of the blood test results and scan results.
It’s also important to note that our test is not yet available for clinical use. However, there are other ctDNA tests are beginning to be used. Whether their use improves patient outcomes in melanoma is not yet proven. This is an important question and needs to be tested in a clinical trial where doctors compare using the blood test result to manage their patient, to not using it and following the current standard of care. If the blood test result demonstrates a benefit, it’s called “clinical utility”. This is being done in colon cancer. We’re not yet there in melanoma.
How do the findings of this study compare to the utility of ctDNA in other cancer types for minimal residual disease detection and prognosis? Are there any unique aspects to melanoma in this context?
As I mentioned, the use of ctDNA guided treatment is most advanced in colon cancer. In the recently reported DYNAMIC trial, the use of adjuvant therapy in stage II colon cancer was reduced without compromising survival outcomes, based on ctDNA-guided management. I’m not a colon cancer expert, but from what I understand, the liver and peritoneum are common sites of recurrence and multiple lesions may be present. These may be sites from which shedding of ctDNA is common making it a bit easier to detect recurrence.
In melanoma, recurrences can occur in the liver, as well as skin, lymph nodes, lungs, and brain, which are sites from which less DNA is less frequently detected. Som we need to conduct studies such as DYNAMIC in both stage II and III melanoma where adjuvant therapy is given to see if we observe similar results. Such study designs could also test whether watching and waiting for a positive ctDNA test or a positive CT scan to begin treatment results in better or worse overall survival compared to adjuvant therapy. Such a study could help resolve the debate regarding the overall survival benefits of adjuvant therapy, which have not been definitively demonstrated yet in melanoma.
What were the limitations of this study that should be considered when interpreting the results?
Among the limitations, we had fewer samples available for the longitudinal analysis compared with the baseline analysis so our results regarding the ability of the ctDNA test to identify recurrence during the follow-up period would have been more precise if we had more samples. Also, the longitudinal collections were not planned beyond 12 months. This restricted our ability to detect the increasing amounts of microscopic melanoma before clinical recurrence after 12 months. Analysis after 12 months would have been particularly valuable for patients in the active treatment group (compared with the placebo group) because they mostly had recurrence after the planned treatment cessation. A limitation of our assay was that it was not able to detect recurrence in all patients.
What are the next critical research questions that need to be addressed based on these findings? Are there plans for prospective studies using ctDNA to guide treatment decisions?
We are in discussions to conduct prospective studies using ctDNA to guide treatment decisions. An important next step is to make the test available in a clinical molecular pathology laboratory where it can be used in those clinical trials to determine whether using the test results to change patient management (e.g. delay treatment until the test or a CT scan is positive) actually improves patient outcomes compared to not using the test results (i.e. treating all patients). Another trial design could be to measure ctDNA in patients on adjuvant therapy using one drug and then randomize patients with a positive ctDNA result to another drug vs continuing the current treatment; or adding a second drug compared to continuing monotherapy.
