Clinical utility and predictive value of cerebrospinal fluid cell-free DNA profiling in non-small cell lung cancer patients with leptomeningeal metastasis

• Published in: Neoplasia (New York, N.Y.) Vol. 60; p. 101113
• Main Authors: Liang, Sheng-Kai, Liao, Wei-Yu, Shih, Jin-Yuan, Hsu, Chia-Lin, Yang, Ching-Yao, Wu, Shang-Gin, Lin, Yen-Ting, Wen, Yueh-Feng, Chen, Lun-Che, Chen, Yen-Fu, Chen, Ya-Fang, Lin, Yen-Heng, Yu, Chong-Jen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2025; Neoplasia Press; Elsevier
• Subjects: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor - cerebrospinal fluid; Biomarkers, Tumor - genetics; Carcinoma, Non-Small-Cell Lung - cerebrospinal fluid; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell-free DNA (cfDNA); Cell-Free Nucleic Acids - cerebrospinal fluid; Cell-Free Nucleic Acids - genetics; Cerebrospinal fluid (CSF); ErbB Receptors - genetics; Female; High-Throughput Nucleotide Sequencing; Humans; Intrathecal pemetrexed; Leptomeningeal metastasis; Lung Neoplasms - cerebrospinal fluid; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Meningeal Carcinomatosis - cerebrospinal fluid; Meningeal Carcinomatosis - drug therapy; Meningeal Carcinomatosis - genetics; Meningeal Carcinomatosis - secondary; Meningeal Neoplasms - cerebrospinal fluid; Meningeal Neoplasms - drug therapy; Meningeal Neoplasms - genetics; Meningeal Neoplasms - secondary; Middle Aged; Mutation; Non-small cell lung cancer (NSCLC); Original Research; Predictive Value of Tests; Prognosis; LM; MSI; ITP; NSCLC; OS; MRI; TTD; CI; TMB; CNV; 19DEL; EGFR; Cerebrospinal fluid (CSF); Intrathecal pemetrexed; cfDNA; Non-small cell lung cancer (NSCLC); CSF; Leptomeningeal metastasis; ITC; Cell-free DNA (cfDNA); SNV; VAF; NGS
• DOI: 10.1016/j.neo.2024.101113
• ISSN: 1476-5586; 1522-8002

•CSF cfDNA sequencing reveals LM resistance mechanisms & treatment avenues in NSCLC.•ITP shows promise for post-targeted treatment NSCLC patients with LM.•MET copy number gain predicts beyond 6-month survival post-ITP in LM NSCLC cases. Leptomeningeal metastasis (LM) is a challenging complication of non-small cell lung cancer (NSCLC). Cerebrospinal fluid (CSF) cell-free DNA (cfDNA) analysis using next-generation sequencing (NGS) offers insights into resistance mechanisms and potential treatment strategies. We conducted a study from February 2022 to April 2023 involving patients from five hospitals in Taiwan who had recurrent or advanced NSCLC with LM. These patients underwent CSF cfDNA analysis using a 118-gene targeted panel for NGS, with comprehensive clinical data collected. Among 25 enrolled patients, 22 (88.0 %) had EGFR mutations, while three (12.0 %) had EML4-ALK fusion, KIF5B-RET fusion, and ERBB2 A775_G776insSVMA. CSF cfDNA sequencing of 27 samples (from 25 patients) all confirmed their original driver mutations. Of total cohort, 18 patients (72.0 %) underwent intrathecal pemetrexed (ITP), with a median survival time of 7.4 months (95.0 % confidence interval, 3.3–11.6) from the initiation of ITP to death. Among them, ten individuals (55.6 %) survived beyond 6 months. Notably, MET copy number gain (CNG) correlated significantly with survival time exceeding 6 months after ITP (p = 0.007). The coexistence of EGFR T790M and EGFR-independent resistance alterations was associated with shorter survival times after ITP, with a median survival time of 1.9 months compared to 9.9 months for those without EGFR T790M (p = 0.010). Our results highlight CSF cfDNA NGS's potential in LM resistance understanding and ITP efficacy prediction. MET CNG positively impacts survival for ITP recipients, whereas the coexistence of EGFR T790M and EGFR-independent resistance mechanisms leads to poor outcomes.