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. 2024 Nov 28;22(1):1074.
doi: 10.1186/s12967-024-05783-7.

Monitoring circulating tumor DNA liquid biopsy in stage III BRAF-mutant melanoma patients undergoing adjuvant treatment

Sara Marchisio #  1 , Alessia Andrea Ricci #  2 , Gabriele Roccuzzo  3 , Eleonora Bongiovanni  3 , Erika Ortolan  1 , Luca Bertero  2 , Enrico Berrino  4   5 , Valentina Pala  3 , Renata Ponti  6 , Paolo Fava  3 , Simona Osella-Abate  7 , Silvia Deaglio  4   8 , Caterina Marchiò  4   5 , Anna Sapino  4   5 , Rebecca Senetta  9 , Ada Funaro  1 , Simone Ribero  3 , Pietro Quaglino  10 , Paola Cassoni  11
Affiliations

Monitoring circulating tumor DNA liquid biopsy in stage III BRAF-mutant melanoma patients undergoing adjuvant treatment

Sara Marchisio et al. J Transl Med. .

Abstract

Background: The introduction of adjuvant therapies for patients with resected cutaneous melanoma (CM) has increased the need for sensitive biomarkers for risk stratification and disease monitoring. This study aims to investigate the utility of circulating tumor DNA (ctDNA) assessment in predicting and reflecting disease status during adjuvant therapy.

Methods: We enrolled 32 patients with resected BRAF-mutated stage III CM receiving adjuvant targeted therapy or immunotherapy. Plasma samples of patients were collected at the baseline (treatment initiation) and during the therapy, and BRAF-mutated ctDNA was quantified by droplet digital PCR (ddPCR).

Results: Baseline ctDNA was detected in 11/32 (34.4%) patients and predicted postoperative high risk of relapse [HR 3.79, 95% CI 1.20-12.00, p = 0.023]. The three-year overall survival (OS) rate was 54.6% (95% CI 22.9-77.9) versus 95% (95% CI 69.5-99.3) in ctDNA-positive and negative groups, respectively, with significantly worse OS for ctDNA-positive patients [HR 7.92, 95% CI 1.56-40.36, p = 0.013]. Among the baseline ctDNA-positive group (high-risk patients), longitudinal ctDNA detection during adjuvant therapy reflected the clinical outcomes. Only non-relapsing patients cleared their plasma ctDNA by the end of the treatment, while persistent ctDNA detection provided early evidence of disease recurrence.

Conclusions: ctDNA detection shows promising results in the post-operative setting for identifying cutaneous melanoma patients at the highest risk of relapse and for real-time monitoring of patients' clinical status and treatment response.

Keywords: Adjuvant therapy; Cutaneous melanoma; Disease monitoring; Liquid biopsy; ddPCR.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was approved by Comitato Etico Interaziendale AOU Città della Salute e della Scienza di Torino (TESEO − 0061280 - CE CS2/1306) and was conducted in accordance with the ethical standards of the University of Turin IRB and the principles of the declaration of Helsinki. Informed consent: Informed consent to surgical procedure and data collection was obtained from all subjects involved in the study. Competing interests: The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Relapse-Free Survival according to baseline ctDNA status. Kaplan-Meier analysis for relapse-free survival (RFS) in 32 CM patients stratified by baseline ctDNA detection
Fig. 2
Fig. 2
Overall Survival according to baseline ctDNA status. Kaplan-Meier analysis for overall survival (OS) in 32 CM patients stratified by baseline ctDNA detection
Fig. 3
Fig. 3
Plasma ctDNA monitoring during adjuvant therapy. a. Overview of plasma ctDNA assessment during adjuvant therapy (12 months) in CM patients with detectable baseline ctDNA (n = 11). Patients are grouped according to relapse and ctDNA clearance status. Squares indicate the plasma samples corresponding to the end of treatment, and red triangles indicate clinical relapse confirmed by imaging techniques. Empty and blue dots indicate absence and presence of ctDNA, respectively. Abbreviations: NC, non-cleared; TC, transiently cleared. b. Graphical representation of plasma ctDNA levels during adjuvant therapy. Each dot represents a plasma sample analyzed at the indicated time point. Dotted and plain lines depict patients who were disease-free or showed clinical relapse by the time of the analysis, respectively. * indicates the time-point overlapping with clinical evidence of disease relapse
Fig. 4
Fig. 4
Sequential ctDNA monitoring in patients showing tumor relapse during adjuvant therapy. Graphical representation of plasma ctDNA levels in three CM patients (a, b and c) with evidence of disease recurrence during adjuvant therapy. Each dot represents a plasma sample analyzed. At the indicated time-point the corresponding imaging outcomes are shown. Red arrows point to metastasis
See this image and copyright information in PMC

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