Work

Biom-05 Characterization of Tumor-derived Dna Mutations, Copy Number Changes, and Methylated Fragments Within Cerebrospinal Fluid and Plasma From Patients Undergoing Surgery for Lung Cancer Brain Metastasis

Year: 2025

Type: conference-abstract

Abstract: Surgical management of brain metastasis (BrM) improves outcomes in selected patients, yet predicting CNS progression following surgery remains challenging. To identify circulating tumor-(ct)DNA markers associated with disease progression, we collected patient-matched BrM tissue, cerebrospinal fluid (CSF), and/or plasma from 75 patients undergoing lung cancer BrM resection. CSF and plasma were also collected from patients who progressed to leptomeningeal disease (LMD). Cell-free DNA was extractable (>1ng) in 76% of CSF (38/50) and 100% of plasma samples (78/78). We assessed mutations by tissue-informed ultradeep sequencing via the PredicineBEACONTM MRD assay as well as genome-wide copy number variants (CNV) and differentially methylated fragments (DMFs) via the PredicineEPICTM DNA methylation assay. In patients undergoing craniotomy for non-small cell lung cancer, we identified ctDNA mutations, CNVs, and DMFs in 100%, 83%, and 100% of CSF and 79%, 23%, and 100% of plasma, respectively. In matched CSF:plasma pairs, all CSF mutant (p=.019) and CNV (p=.02) tumor fractions and 76% of CSF DMF counts were higher than plasma. Only 22% of CSF DMFs were concordant with matched plasma and 37% of the plasma DMFs were concordant with matched CSF, suggesting ctDNA methylation in the CNS may be related but distinct from the periphery. CSF shared 74% DMF concordance with matched BrM tissue whereas plasma shared 50%. Overall survival correlated with plasma mutant ctDNA (tumor fractions of >1% vs. <1% = HR: 2.2, CI: 1.1-4.4, p=.025) and DMFs (counts >5000 vs. <500= HR: 20.7, CI: 3.8 to 113, p=.0005), yet CSF ctDNA levels did not correlate with outcome. However, the number of unique DMF sites detected in CSF increased in patients with LMD versus parenchymal BrM (2716 vs. 442, p=.007). Furthermore, DMF counts were higher in lung adenocarcinoma BrMs that later progressed to LMD (p=.002), suggesting aberrant methylation may contribute to BrM-to-LMD progression.

Source: Neuro-Oncology Advances

DOI: 10.1093/noajnl/vdaf123.025