Circulating tumour DNA (ctDNA) is more sensitive than established serum biomarkers for identifying recurrence risk in patients with melanoma, with detectable ctDNA often preceding clinical disease progression by up to six months. This is according to a recent single-centre retrospective study conducted in Germany.

As adjuvant therapies become increasingly important in melanoma, clinicians face the challenge of identifying patients most likely to benefit from treatment while avoiding unnecessary toxicity in those at lower risk of relapse.

Traditional surveillance tools, including imaging, and the serum biomarkers S100 and lactate dehydrogenase (LDH), have limited sensitivity for detecting minimal residual disease and early recurrence.

Researchers at the University Hospital Schleswig-Holstein in Kiel, Germany, therefore evaluated whether ctDNA could improve risk stratification in patients with early-stage melanoma. The findings were published in the Journal of Cancer Research and Clinical Oncology.

The retrospective study included 61 patients with stage 1-3 melanoma who subsequently experienced disease progression. The investigators analysed 185 archived serum samples collected during follow-up, focusing on tumour-specific mutations including BRAF V600E/K, NRAS Q61K/L/R and TERT promoter mutations.

After excluding eight patients in whom no tumour-specific ctDNA mutations were identified, 53 patients remained in the primary analysis. Detectable ctDNA was identified in at least one sample from 43 patients.

Earlier detection of recurrence

In stage 2 disease, ctDNA was significantly more sensitive than LDH, while in stage III disease, it significantly outperformed both S100 and LDH. When stages 1-3 were analysed together, ctDNA remained superior to both biomarkers.

ctDNA concentrations increased progressively during the six months preceding clinically confirmed recurrence, often becoming detectable before disease progression was identified through routine imaging or clinical assessment.

Similarly, the proportion of ctDNA-positive samples remained consistently higher than that of S100- or LDH-positive samples throughout the year before recurrence.

The highest average levels were observed in patients progressing from stage 3 to stage 4 disease (24.25 copies/µL) and in those progressing within stage 3 disease (12.42 copies/µL).

Detectable ctDNA and poorer outcomes

Lower concentrations were observed as the disease progressed from localised to regional. However, ctDNA appeared less sensitive for detecting isolated intracranial disease, consistent with previous observations that central nervous system metastases may shed relatively little tumour DNA into the circulation.

Patients with detectable ctDNA also tended to experience poorer outcomes than those without. Median overall survival among ctDNA-positive patients was 57 months, with a hazard ratio for death of 2.56 compared with ctDNA-negative patients.

However, this association did not reach statistical significance. Detectable ctDNA was similarly associated with shorter progression-free survival, although this relationship was also not statistically significant.

The authors noted that the relatively small cohort may have limited the ability to detect significant differences in survival. They also emphasised that challenges remain before routine implementation, including the need to standardise testing methods, limited sensitivity for intracranial disease and the absence of prospective trials demonstrating improved outcomes when treatment decisions are guided by ctDNA results.

Overall, the findings suggested that ctDNA could represent a useful adjunct to current surveillance strategies for early-stage melanoma, providing earlier and more sensitive detection of disease recurrence than established serum biomarkers.

Reference
Bohne AS et al. Sensitivity and prognostic significance of circulating tumor DNA (ctDNA) in stage I to III malignant melanoma. J Cancer Res Clin Oncol 2026;152:106.