Genetic characteristics of cerebrospinal fluid-derived circulating tumor DNA in brain metastases of lung adenocarcinoma.

Abstract

e20503 Background: Brain metastases (BM), encompassing parenchymal metastases (PM) and leptomeningeal metastases (LM), are a common and fatal complication of advanced lung adenocarcinoma (LUAD). However, the genomic disparities between PM and LM, as determined by cerebrospinal fluid (CSF)-derived circulating tumor DNA (ctDNA), and its clinical utility as a liquid biopsy medium remain unclear. Methods: We conducted a retrospective study involving 33 patients diagnosed with BM from LUAD, comprising 16 cases with PM and 17 cases with LM, at Shandong Cancer Hospital between March 2018 and June 2021. CSF and matched peripheral blood lymphocyte samples were collected from all patients, and plasma samples were collected from 25 of them. Genomic profiles of CSF and plasma in patients with PM and LM were compared. CSF-ctDNA, plasma-ctDNA, and DNA from matched peripheral blood lymphocytes underwent next-generation sequencing (NGS) based on a 769 cancer-related gene panel. Results: A total of 363 mutations were detected in CSF-ctDNA, with 90.9% (30/33) of all LUAD patients with PM or LM showing mutations. EGFR mutations were the most common, occurring in PM samples from 56.3% (9/16) of patients and in LM samples from 76.5% (13/17) of patients, followed by other frequently mutated driver genes, including TP53 in 19 (57.6%) patients, MLH1 in 9 (27.3%) patients, and KMT2C in 8 (24.2%). Notably, EGFR 19del was more prevalent as a driver mutation in patients with LM compared to those with PM in our study, particularly the p.E746_A750del mutated subtype. Furthermore, the frequency of mutations in the mismatch repair (MMR) pathway was significantly higher in patients with LM than in those with PM. Additionally, CSF exhibited a more comprehensive profile of driver genomic mutations than matched plasma in patients with any form of BM, accompanied by a higher variation burden and detection of druggable mutations. Conclusions: CSF-ctDNA sequencing revealed distinct genomic patterns in patients with BM, particularly in LM, and could potentially enhance the management of BM patients compared to plasma.