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. 2025 Apr 8:8:100295.
doi: 10.1016/j.jlb.2025.100295. eCollection 2025 Jun.

Circulating tumor DNA monitoring in advanced mutated melanoma (LIQUID-MEL)

Martines Gianmarco  1 , Palazzi Carolina  1 , Monica Gregorio  2 , Verzè Michela  1   2 , Pluchino Monica  1   2 , Giudice Giulia Claire  3 , Maffezzoli Michele  2   4 , Mazzaschi Giulia  1   2 , Manuguerra Roberta  5 , Azzoni Cinzia  5 , Bottarelli Lorena  5 , Tiseo Marcello  1   2 , Perrone Fabiana  1 , Minari Roberta  1
Affiliations

Circulating tumor DNA monitoring in advanced mutated melanoma (LIQUID-MEL)

Martines Gianmarco et al. J Liq Biopsy. .

Abstract

Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic melanoma, but a percentage of patients did not show benefit. Circulating tumor DNA (ctDNA) has emerged as a potential non-invasive tool for monitoring disease evolution and treatment response. The present study aimed to evaluate the clinical utility of ctDNA dynamics in patients with metastatic melanoma receiving ICIs, while exploring its role in the oncological course.

Materials and methods: The LIQUID-MEL study is a prospective, single-centre pilot study including patients with BRAF/NRAS-mutant metastatic melanoma. ctDNA was quantified using digital droplet PCR (ddPCR) at four different time points. Uni- and multivariable Cox regression models were used to assess the correlation between shedding and progression-free survival (PFS), and overall survival (OS).

Results: Overall, 23 patients were included. At baseline, ctDNA was detectable in 5/23 (21.7 %) cases. Baseline ctDNA shedding was associated with shorter PFS (3.88 months vs. 0.69 months, p=0.012). A strong numerical trend was observed also in OS (12.66 months vs. 2.53 months, p=0.287). Shedding at baseline did not demonstrate independent prognostic or predictive value in the uni- and multivariable analysis. The longitudinal analysis revealed intriguing patterns of ctDNA shedding in individual patients.

Conclusion: ctDNA detectability and its dynamic changes during treatment may have potential clinical utility in patients with metastatic melanoma, offering a valuable non-invasive tool for monitoring disease and treatment response. The small sample size limited the statistical power of the analysis. Further studies with larger cohorts are needed to validate its role in routine clinical practice.

Keywords: Immune checkpoint inhibitors; Liquid biopsy; Melanoma; Monitoring; Prognosis; ctDNA.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Representative Kaplan-Meier survival curve illustrating the impact of shedding on progression-free survival.
Fig. 2
Fig. 2
Representative Kaplan-Meier survival curve illustrating the impact of shedding on overall survival.
Fig. 3
Fig. 3
Dynamic changes of ctDNA for representative patients. T0, start of systemic treatment; T1, before second cycle (3–4 weeks); T2, first radiological reassessment (2–3 months); TPD, radiological progression of disease (TPD in a cell denotes progression timepoint); D, death before or near the collection timepoint; (II), second-line treatment.
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