Pre-operative ctDNA rarely detectable in primary cutaneous melanoma
Investigators evaluated the feasibility of detecting pre-operative circulating tumour DNA in a prospective single-institution cohort of patients with high-risk primary cutaneous melanoma. Of 21 patients meeting high-risk criteria, 12 carried targetable BRAF or NRAS mutations and underwent tumour-informed plasma analysis; ctDNA was undetectable in all 12 cases. The findings confirm that standard droplet digital PCR and targeted next-generation sequencing assays yield near-zero detection rates for cell-free DNA shed by small primary melanomas. For molecular pathology laboratories, these results indicate that routine pre-operative ctDNA testing is not clinically viable in this setting and suggest that mutation-agnostic or bespoke cell-free DNA methods will be required to capture early disease signals.
The original study
Pre-operative circulating tumour DNA in high-risk primary cutaneous melanoma: prospective feasibility in molecular pathology.
- Authors
- Obinah MPB, Høgdall E, Poulsen TS, Dreisig K, Litman T, Johansen C, et al.
- Journal
- Acta oncologica (Stockholm, Sweden)
- Type
- Journal Article
- PMID
- 42714248
Original abstract
BACKGROUND AND PURPOSE: Circulating tumour DNA (ctDNA) has emerged as a prognostic biomarker in melanoma, but its detectability in pre-operative blood from patients presenting with primary cutaneous melanoma remains incompletely evaluated. We assessed the feasibility of pre-operative ctDNA detection in high-risk primary melanoma using routinely available methods in molecular pathology. PATIENTS/MATERIAL AND METHODS: In a prospective single-institution cohort enrolled between September 2021 and December 2022, pre-operative plasma was obtained from patients with clinically suspected primary cutaneous melanoma. Patients with pathologically confirmed invasive melanoma and high-risk features (≥ T3a, ≥ N1a, or ≥ M1a) were selected for molecular analysis. Tumour tissue was analysed using next-generation sequencing (NGS) to identify targetable BRAF or NRAS driver mutations, and pre-operative plasma was analysed for ctDNA using droplet digital PCR (ddPCR) for BRAF V600E or targeted NGS for other driver mutations. RESULTS: Of the 288 consented patients with pre-operative blood samples, 21 met high-risk criteria, and 12 had a targetable BRAF or NRAS driver mutation in tumour tissue and underwent tumour-informed plasma ctDNA analysis. Pre-operative ctDNA was not detected in any of these 12 patients (0 of 12; 95% confidence interval [CI] 0 to 26.5%). All ddPCR and NGS assay controls performed as expected, and wild-type copy counts were consistent across ddPCR samples. INTERPRETATION: The finding is concordant with two independent studies using different methods, and a mathematical prediction of ctDNA shedding from small primary tumours. Reliable pre-operative ctDNA detection in primary melanoma may require alternative cell-free DNA (cfDNA) approaches, such as bespoke multivariant or mutation-agnostic methods.