Genomic Characterization of Cerebrospinal Fluid Tumor DNA in Patients with Suspected Leptomeningeal Carcinomatosis

Sunday, May 5, 2024

2:55 PM – 3:00 PM CT

Location: S403ab

Presenting Author(s)

Tej D. Azad, MD, MS

Resident
Department of Neurosurgery, The Johns Hopkins University School of Medicine
Baltimore, MD, US

Co-Author(s)

AA

Ash Alizadeh, MD, PhD

Professor
Stanford University, United States
MD

Maximilian Diehn, MD, PhD

Professor
Stanford University, United States
MH

Melanie Hayden Gephart, MD, PhD

Professor of Neurosurgery
Stanford University
Stanford, California, United States
Michael C. Jin, BA (he/him/his)

Medical Student
Stanford University
Santa Clara, California, United States
SN

Seema Nagpal, MD

Professor
Stanford University, United States
SN

Shigeki Nanjo, MD

Researcher
Kanazawa University Cancer Research Institute, United States

Disclosure(s):

Tej D. Azad, MD: No financial relationships to disclose

Introduction: Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring neoplastic processes of the central nervous system. We hypothesize that analysis of CSF-tDNA in patients with advanced lung cancer improves the sensitivity of leptomeningeal disease (LMD) diagnosis and enables central nervous system response monitoring.

Methods: We performed next-generation sequencing with a lung cancer-specific sequencing panel applied to 85 CSF, blood, and tissue samples from 25 patients with advanced lung cancer who underwent lumbar puncture (LP) for suspected LMD. A subset of the cohort (N = 12) participated in a prospective clinical trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment with.

Results: CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 30.3%; median ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman’s ρ, 0.45; P = 0.02). For LMD diagnosis, cytology was 82.6% sensitive and CSF-tDNA was 91.3% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.3; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009).

Conclusion : Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA may improve the sensitivity of LMD diagnosis, enable improved prognostication, and drive therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.