ctDNA Monitoring Can Predict Early Melanoma Recurrence Following Resection

Checking for sparse levels of disease through circulating tumor DNA (ctDNA) after surgery can help identify a high risk of skin cancer recurrence, according to data on patients enrolled in a late-stage study.1 The insights were recently published in Lancet Oncology, showing that using droplet digital polymerase chain reaction (ddPCR) to identify minimal residual disease (MRD) prior to adjuvant targeted therapy can reliably predict a high risk of early recurrence. 

ctDNA has been established as a reliable identifier of MRD in various cancer types, and monitoring ctDNA has shown value for planning adjuvant treatment escalation or de-escalation, though comparable data in melanoma remain limited. These new findings, the researchers explained, come from the largest analysis of its kind and complement those from previous published studies on other solid tumors.

The risk of recurrence was significantly higher for patients who were positive for ctDNA, whether they received a placebo or targeted therapy. | Image credit: vladimircaribb - stock.adobe.com

“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,” they wrote. “For example, patients with detectable ctDNA during follow-up have a high likelihood of clinical recurrence, so a positive test result might translate into a consequential change in patient management, such as increasing the frequency or intensity of radiographic surveillance scans (e.g., PET-CT vs CT).”

Meanwhile, for patients with undetectable ctDNA, a decision may be made to prolong immediate initiation of systemic therapy and instead closely monitor ctDNA levels.

In this latest analysis, the researchers assessed levels of ctDNA among 870 patients with resected stage 3 BRAFV600-positive melanoma. Patients were enrolled in the phase 3 randomized COMBI-AD trial (NCT01682083), which split up patients to receive either combination targeted treatment with dabrafenib plus trametinib or a placebo. Previously described results of the trial were published in 2024, and the majority of the patients were non-Hispanic White, in line with the real-world melanoma patient population across the globe.2

Prior to treatment initiation, ddPCR testing identified residual disease via ctDNA in 13% of patients, all of whom were considered disease-free by radiographic measure. These patients were considered to have a high risk of early disease recurrence, with increased risk accompanying increasing levels of ctDNA. Median follow-up for analyses was approximately 5 years.1

“Many patients with measurable ctDNA, especially in the placebo group, quickly developed clinically or radiographically detectable recurrence compared with those with undetectable ctDNA,” wrote the researchers. “Interestingly, among patients in the combination therapy group, the majority of those with detectable ctDNA at baseline did not have recurrence until more than 3 months after treatment discontinuation, suggesting that targeted therapy was effective at suppressing but not eliminating MRD in some patients.”

Among patients receiving placebo, those who were ctDNA positive had a median recurrence-free survival of 3.71 months (95% CI, 2.39-6.89) vs 24.41 months (95% CI, 17.28-43.13) among patients who were ctDNA negative. For patients receiving the targeted therapy combination, median recurrence-free survival was 16.59 months (95% CI, 12.02-26.80) for those who were ctDNA positive and was 68.11 months (95% CI, 50.36-not reached).

The risk of recurrence was significantly higher for patients who were positive for ctDNA, whether they received a placebo (HR, 2.91; 95% CI, 1.99-4.25; P < .0001) or targeted therapy (HR, 2.98; 95% CI, 1.95-4.54; P < .0001).

At 5 years of follow-up, multivariate analyses identified ctCNA concentrations as a more reliable predictor of survival than tumor substage or tissue-based measures known as prognostic indicators for patient stratification, including interferon gamma expression and tumor mutational burden. The researchers warned of potential limitations to this comparison based on insufficient statistical power to determine clinical prognostic significance stemming from smaller numbers included in those analyses.

References

1. Syeda MM, Long GV, Garrett J, et al. Clinical validation of droplet digital PCR assays in detecting BRAFV600-mutant circulating tumour DNA as a prognostic biomarker in patients with resected stage III melanoma receiving adjuvant therapy (COMBI-AD): a biomarker analysis from a double-blind, randomised phase 3 trial. Lancet Oncol. Published online April 15, 2025. doi:10.1016/S1470-2045(25)00139-1
2. Long GV, Hauschild A, Santinami M, et al. Final results for adjuvant dabrafenib plus trametinib in stage II melanoma. New Engl J Med. 2024;391:1709-1720.