ctDNA in melanoma
cfDNA; circulating tumour DNA; liquid biopsy
Circulating tumour DNA — short fragments of cell-free DNA shed from tumour cells into the blood — has emerged as a sensitive, dynamic biomarker in melanoma. The most established UK applications are monitoring for early recurrence after resection of stage III disease, tracking response to immunotherapy and targeted therapy, and identifying minimal residual disease. Detection is typically by digital droplet PCR or NGS targeting tumour-specific mutations (BRAF V600E/K, NRAS Q61, KIT). ctDNA is currently a research / specialist tool in the UK rather than standard care, with selected centres incorporating it into clinical pathways. NICE recommendations are evolving.
Principle
- Tumour cells shed short (~ 150 bp) fragments of double-stranded DNA into the bloodstream — circulating tumour DNA (ctDNA).
- ctDNA carries the somatic mutations of the tumour, allowing tumour-specific detection against background normal cell-free DNA.
- Detection — droplet digital PCR (ddPCR) for known mutations (BRAF V600E/K, NRAS Q61, KIT) or NGS panels for tumour-informed multi-mutation tracking.
- Sensitivity proportional to tumour burden — most informative in higher-stage disease and active progression.
Clinical applications
- Minimal residual disease detection — after resection of stage III disease, persistent ctDNA predicts early recurrence.
- Recurrence surveillance — rising ctDNA precedes radiographic recurrence by months in many cases.
- Treatment response monitoring — clearance of ctDNA on systemic therapy correlates with response; rising ctDNA predicts progression.
- Resistance characterisation — emergence of new mutations under selective pressure (e.g. NRAS / MEK pathway alterations under BRAF/MEK inhibition).
Evidence base
- Lee JH et al. (Ann Oncol 2017) — ctDNA detection in resected stage III melanoma predicts shorter relapse-free survival.
- Tan L et al. (Clin Cancer Res 2019) — tumour-informed NGS ctDNA outperforms ddPCR in detection of low-burden disease.
- UK COMBI-AD secondary analyses — ctDNA dynamics under adjuvant dabrafenib + trametinib.
- Multiple UK trials in progress (e.g. MEL-RES adjuvant escalation trials) using ctDNA to enrich for high-risk patients post-resection.
UK availability and limitations
- Specialist research and trial settings — not yet routine standard of care.
- Selected centres incorporate ctDNA into post-resection stage III surveillance in collaboration with NHS Genomic Medicine Service.
- NICE position evolving; expect clinical guidance updates over the next 1–2 years.
- Limitations — low sensitivity for very-low-burden disease, false-negative in tumours with low shedding, requirement for known tumour mutations or large-panel sequencing, cost.
- Patient counselling — ctDNA does not yet replace cross-sectional imaging; it complements rather than substitutes.
References
- Lee JH et al. Circulating tumour DNA predicts recurrence in stage III melanoma. Ann Oncol; 2017.
- Tan L et al. Personalised tumour-informed circulating tumour DNA detection in melanoma. Clin Cancer Res; 2019.
- Long GV et al. Cell-free DNA dynamics in metastatic melanoma. Lancet Oncol; 2020.
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