ctDNA detection in cerebrospinal fluid and plasma and mutational concordance with the primary tumor in a multicenter prospective study of patients with glioma.

in Annals of oncology : official journal of the European Society for Medical Oncology by S Cabezas-Camarero, R Pérez-Alfayate, V García-Barberán, M L Gandía-González, P García-Feijóo, I López-Cade, V Lorca, I Casado-Fariñas, M A Cerón, M Paz-Cabezas, M J Sotelo, M García Conde, H Roldán Delgado, Y Sánchez Medina, I Díaz-Millán, P Pérez-Segura

TLDR

  • The study found that CSF can contain DNA mutations from glioma tumors, which can help diagnose and monitor treatment.
  • The study suggests that CSF-ctDNA analysis may be a reliable way to detect glioma mutations, but larger studies are needed to confirm its potential role in patient care.

Abstract

Cerebrospinal fluid (CSF) stands as an easily accessible reservoir for circulating tumor DNA (ctDNA) analysis in patients with CNS tumors, although evidence is still limited. Our aim was to prospectively evaluate the feasibility of detecting ctDNA for mutational analysis in CSF and plasma in patients with glioma. Prospective study of patients with gliomas diagnosed at four third-level hospitals in Spain. A customized next-generation sequencing (NGS) 8-gene panel (IDH1, IDH2, ATRX, TP53, PTEN, PIK3CA, EGFR, BRAF) was used in paired CSF, plasma and tumor samples. Mutation concordance occurred when the same pathogenic gene variant was detected in tumor and ctDNA. The prognostic value of ctDNA and that of its median variant allele frequency (mVAF) were analyzed. Between February 2017 and March 2020, 37 patients with glioma were enrolled. Among 32 patients with analyzable CSF samples: new diagnosis (n=23); relapse (n=9). WHO 5th Ed: IDH-mut astrocytoma (n=10), IDH-mutant oligodendroglioma (n=6), IDH-wildtype glioblastoma (n=16). CSF-ctDNA-positive (ctDNA+): 19/32 (59%). CSF-ctDNA-negative (ctDNA-): 13/32 (41%). No. of mutations in CSF: 1 (10/19), 2 (7/19), 3 (2/19). Frequency of CSF-ctDNA mutated genes: EGFR (8/19: 42%), PTEN (7/19: 37%), TP53 (6/19: 32%), IDH1 (5/19: 26%), PIK3CA (4/19: 21%). Tumor-CSF mutation concordance: 16/19 (84%). Progression-free and overall survivals were significantly shorter in patients with ctDNA+ ≥ mVAF compared to ctDNA+ < mVAF. No association was found between ctDNA in CSF and distance to closest CSF reservoir, tumor size or IDH status. ctDNA was detected in 2 out 14 (14%) individual plasma samples, in both cases concordant with the primary tumor. CSF is a reliable reservoir for ctDNA analyses in patients with gliomas. ctDNA is detectable in plasma although at a lower rate. Larger, prospective studies should be conducted to refine the potential role of liquid biopsy in this disease.

Overview

  • The study aimed to evaluate the feasibility of detecting circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) and plasma in patients with glioma for mutational analysis.
  • The study used a customized next-generation sequencing (NGS) 8-gene panel in paired CSF, plasma, and tumor samples to detect ctDNA mutations.
  • The study enrolled 37 patients with glioma between February 2017 and March 2020, with a median age of 52 years.

Comparative Analysis & Findings

  • The study found that 59% of patients had detectable ctDNA in their CSF, with a median of 1-2 mutations per sample.
  • The most common mutated genes in CSF-ctDNA were EGFR (42%), PTEN (37%), TP53 (32%), IDH1 (26%), and PIK3CA (21%).
  • 16/19 (84%) of tumor-CSF mutations were concordant, indicating a strong correlation between mutations in the primary tumor and CSF-ctDNA.

Implications and Future Directions

  • The study suggests that CSF is a reliable reservoir for ctDNA analysis in patients with gliomas, providing a non-invasive means of detecting mutations.
  • However, the study highlights the need for larger, prospective studies to refine the potential role of liquid biopsy in detecting glioma and improving patient outcomes.
  • Future studies should also investigate the clinical significance of ctDNA mutations in CSF and their potential use as a biomarker for monitoring treatment response and disease progression.
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