New research demonstrates that monitoring circulating tumor DNA (ctDNA) after surgical resection can effectively identify melanoma patients at high risk for early disease recurrence, potentially transforming post-surgical surveillance and treatment planning.
A comprehensive analysis of 870 patients with resected stage III BRAFV600-positive melanoma from the phase 3 COMBI-AD trial revealed that droplet digital polymerase chain reaction (ddPCR) testing could detect minimal residual disease (MRD) through ctDNA in 13% of patients who appeared disease-free by radiographic measures.
Predictive Power of ctDNA Detection
The study, recently published in The Lancet Oncology, represents the largest analysis of its kind for melanoma and demonstrates that ctDNA positivity strongly correlates with increased recurrence risk. Patients with detectable ctDNA showed significantly shorter recurrence-free survival compared to those without detectable ctDNA.
Among patients receiving placebo, ctDNA-positive individuals had a median recurrence-free survival of just 3.71 months compared to 24.41 months for ctDNA-negative patients. Similarly, in the targeted therapy group receiving dabrafenib plus trametinib, median recurrence-free survival was 16.59 months for ctDNA-positive patients versus 68.11 months for those who were ctDNA-negative.
"Many patients with measurable ctDNA, especially in the placebo group, quickly developed clinically or radiographically detectable recurrence compared with those with undetectable ctDNA," the researchers noted in their publication.
Superior Prognostic Value
At the 5-year follow-up, multivariate analyses revealed that ctDNA concentrations were more reliable predictors of survival than established prognostic indicators, including tumor substage, interferon gamma expression, and tumor mutational burden.
Dr. David Polsky, study author and professor at NYU Grossman School of Medicine, explained: "The blood test measures whether there is still melanoma in the patient. Although the test is not able to identify the presence of melanoma in all patients who have it, our data showed that when the test was positive during the follow-up period of the study, nearly 100% of patients recurred."
Implications for Clinical Practice
The findings suggest potential applications for ctDNA monitoring in clinical practice. For patients with detectable ctDNA during follow-up, who have a high likelihood of clinical recurrence, physicians might consider increasing the frequency or intensity of radiographic surveillance, such as switching from CT to PET-CT scans.
Conversely, for patients with undetectable ctDNA, clinicians might delay immediate systemic therapy initiation and instead opt for close ctDNA monitoring.
"We're envisioning the test being used to monitor patients over time, perhaps every month or couple of months in the first 1 to 3 years after surgery, for an early indication that their melanoma is recurring," Dr. Polsky stated.
Treatment Response Insights
The study also provided insights into treatment efficacy. Among patients receiving targeted therapy, the majority with detectable baseline ctDNA did not experience recurrence until more than three months after treatment discontinuation.
"This suggests that targeted therapy was effective at suppressing but not eliminating MRD in some patients," the researchers observed, highlighting the potential for ctDNA monitoring to inform treatment duration decisions.
Addressing Current Limitations
Despite promising results, the researchers acknowledge certain limitations. Not all patients with recurrence had detectable ctDNA, indicating room for improvement in test sensitivity. Dr. Polsky noted that future developments might include tests that simultaneously measure multiple mutations to increase detection probability.
Additionally, clinical utility studies are still needed to determine whether using ctDNA test results improves patient outcomes compared to standard approaches.
Future Directions
The researchers believe ctDNA monitoring could be particularly valuable for patients uncertain about undergoing adjuvant therapy, potentially allowing a watch-and-wait approach with more frequent blood testing than imaging scans.
"Together, the published results and data from the current study provide substantial support for evaluating the clinical use of baseline and longitudinal ctDNA monitoring to guide treatment modifications in future clinical trials," the researchers concluded.
As technology advances and additional validation studies emerge, ctDNA monitoring may become an integral component of melanoma management, offering a minimally invasive method to detect recurrence earlier and guide more personalized treatment decisions.
