Biom-34. Genomic Analysis of CSF Ctdna in Lung Cancer-Related Leptomeningeal Metastases

INTRODUCTION CSF-based ctDNA analysis holds potential in refining molecular diagnoses and staging in LMD, providing prognostic information, and optimizing CSF-directed therapy. Herein we retrospectively evaluate the potential clinical utility of analyzing CSF for SNV/MNV/indels, MGMT promoter methylation, and aneuploidy in optimizing LMD from lung cancer (LC). METHODS We examined 31 CSF samples from 8 LC patients with LMD (7 with longitudinal sampling, 2-6 samples per patient) collected under our institutional multi-agent intraventricular chemotherapy (MAIVC) protocol. The SummitTM assay was used to identify mutations and aneuploidy in CSF ctDNA, while the VantageTM assay evaluated MGMT methylation status via quantitative PCR. Molecular data were compared with primary tumor profiles, overall survival (OS) from LMD diagnosis, and clinical parameters (cytology, MRI, and treatment status). RESULTS The median OS was 358 days. In one patient, concordant EGFRG719F mutations (exon 19 deletion) were found in both primary tumor and CSF, with reductions in variant allele frequency (VAF) and aneuploidy following therapy (OS: 317 days). Another patient showed a late increase in EGFRQ791H and KRASQ61H variants and aneuploidy in the final CSF sample, with death occurring 44 days later (OS: 336 days). In a third patient, CSF-specific GNASR201H and HRASQ61L variants emerged shortly after therapy initiation, with an OS of 73 days. Two patients lacking significant variants or aneuploidy had extended OS (448 and 667 days). Persistent aneuploidy was observed in two patients: the MGMT-methylated patient survived 379 days, while the unmethylated patient survived 36 days. In one patient with a KRASG12A variant and aneuploidy, both resolved after one MAIVC cycle, with an OS of 635 days. CONCLUSIONS Unique driver mutations and dynamic changes in ctDNA were detected. The potential prognostic value of MGMT methylation warrants further investigation. Incorporating fusion detection and the addition of complementary CSF proteomic analysis could enhance insights. Larger prospective studies are ongoing.