Quantification of Cerebrospinal Fluid Tumor DNA in Lung Cancer Patients with Suspected Leptomeningeal Carcinomatosis

IntroductionCerebrospinal 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. MethodsWe applied CAPP-Seq using a lung cancer-specific sequencing panel to 81 CSF, blood, and tissue samples from 24 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. ResultsCSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearmans {rho}, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; 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). ConclusionsDetection 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.