CSF ctDNA MSK 2024

Overview

Comprehensive prospective cohort of circulating tumor DNA (ctDNA) profiled in cerebrospinal fluid (CSF) from 711 patients with central nervous system (CNS) tumors at Memorial Sloan Kettering Cancer Center, collected between November 2018 and November 2022. The study used IMPACT468 and IMPACT505 targeted sequencing panels on 1,007 CSF samples spanning over 90 distinct CNS tumor types (both primary brain tumors and solid tumor metastases to the CNS), with a subset compared against ACCESS129 plasma ctDNA PMID:39289779.

Composition

  • 711 patients (adult and pediatric), 1,007 CSF samples total; 150/711 patients (21.1%) had multiple CSF samples (median 2, range 2-12) PMID:39289779.
  • Over 90 distinct tumor types including NSCLC (n=188), BRCA (n=150), DIFG (n=148), MEL, GI cancers, embryonal tumors, and others PMID:39289779.
  • 85 negative-control CSF samples from patients without clinically documented CNS involvement PMID:39289779.
  • Median follow-up 240 days (IQR 112-483 days) PMID:39289779.

Assays / panels (linked)

Papers using this cohort

  • PMID:39289779 — Hickman et al., Acta Neuropathologica Communications 2024. Real-world experience with circulating tumor DNA in cerebrospinal fluid from patients with central nervous system tumors.

Notable findings derived from this cohort

  • ctDNA detected in 53.0% (489/922) of CSF samples from patients with clinically documented CNS tumors; 100% specificity (0/85 positive among patients without CNS tumors) PMID:39289779.
  • 7,110 somatic alterations detected across 489 ctDNA-positive samples (3,944 non-synonymous mutations, 2,980 copy number alterations, 186 structural rearrangements) PMID:39289779.
  • TP53 was the most frequently altered gene (n=242, 49% of ctDNA-positive samples) PMID:39289779.
  • 50.7% (248/489) of ctDNA-positive samples carried a level 1 OncoKB actionable alteration; lung carcinomas had the highest actionability rate PMID:39289779.
  • ctDNA positivity associated with three-fold increased risk of death (HR 3.23, 95% CI 2.58-4.05, p < 0.001); median OS 235 days vs. 1,089 days PMID:39289779.
  • In NSCLC, leptomeningeal involvement was a strong predictor of ctDNA positivity (OR 20.17, p < 0.0001). CSF ctDNA had greater sensitivity than positive cytology for leptomeningeal disease (85.4% vs. 61.7%) PMID:39289779.
  • CSF VAFs were significantly higher than plasma VAFs (median 36.4% vs. 2.3%, p < 0.01), demonstrating the superiority of CSF over plasma for CNS tumor monitoring PMID:39289779.
  • Resistance mechanisms detected in serial CSF ctDNA: EGFR gatekeeper mutations (p.T790M, p.C797S), ALK resistance mutations (p.G1202R, p.G1269A), and MET resistance mutation (p.Y1230N) PMID:39289779.
  • Key genes altered: EGFR, KRAS, BRAF, PIK3CA, ERBB2, IDH1, H3-3A, STK11, KEAP1 PMID:39289779.

Sources

  • cBioPortal study: https://www.cbioportal.org/study/summary?id=csf_msk_2024

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