Detection of cell-free tumor DNA in cerebrospinal fluid as a diagnostic biomarker for leptomeningeal melanoma metastasis: A case series

Pigment Cell Melanoma Res. 2024 Nov;37(6):822-830. doi: 10.1111/pcmr.13186. Epub 2024 Jul 11.

Abstract

Leptomeningeal melanoma metastases (LMM) are associated with poor survival. Diagnosis is based on clinical presentation, brain MRI and cerebrospinal fluid (CSF) analysis. Inconclusive findings at initial presentation can delay treatment. In this single-center case series, detection of BRAFV600- and NRASQ61-mutant cell-free tumor DNA (cfDNA) in CSF was evaluated as a complementary diagnostic biomarker. In 12 patients with clinical suspicion of LMM, a retrospective analysis of MRI, CSF cytology and cfDNA analysis on 1 mL of CSF using the Idylla® platform was carried out. Nine patients displayed MRI abnormalities suggesting LMM. CSF analysis identified malignant cells in three patients (including one without MRI abnormalities). BRAFV600- or NRASQ61-mutant cfDNA was detected in CSF of nine patients (eight with and one without MRI abnormalities; all patients with positive CSF cytology). Subsequent follow-up confirmed LMM in all patients with positive and in one patient with a negative CSF cfDNA analysis (sensitivity 81.8%; specificity 100%). Our findings suggest that analyzing BRAFV600- and NRASQ61-mutant cfDNA in CSF using the Idylla® platform holds promise as a sensitive and specific complementary diagnostic biomarker for LMM, particularly in case of inconsistency between imaging and CSF cytology. The 110-min analysis can facilitate urgent treatment decisions.

Keywords: biomarker; brain metastases; cell‐free tumor DNA; cerebrospinal fluid; leptomeningeal metastasis.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor* / cerebrospinal fluid
  • Biomarkers, Tumor* / genetics
  • Cell-Free Nucleic Acids / cerebrospinal fluid
  • Cell-Free Nucleic Acids / genetics
  • Circulating Tumor DNA* / blood
  • Circulating Tumor DNA* / cerebrospinal fluid
  • Circulating Tumor DNA* / genetics
  • Female
  • GTP Phosphohydrolases / genetics
  • Humans
  • Male
  • Melanoma* / cerebrospinal fluid
  • Melanoma* / diagnosis
  • Melanoma* / genetics
  • Melanoma* / pathology
  • Membrane Proteins / cerebrospinal fluid
  • Membrane Proteins / genetics
  • Meningeal Neoplasms* / cerebrospinal fluid
  • Meningeal Neoplasms* / diagnosis
  • Meningeal Neoplasms* / genetics
  • Meningeal Neoplasms* / pathology
  • Meningeal Neoplasms* / secondary
  • Middle Aged
  • Mutation
  • Proto-Oncogene Proteins B-raf / genetics
  • Retrospective Studies

Substances

  • Biomarkers, Tumor
  • Circulating Tumor DNA
  • Proto-Oncogene Proteins B-raf
  • NRAS protein, human
  • BRAF protein, human
  • GTP Phosphohydrolases
  • Cell-Free Nucleic Acids
  • Membrane Proteins