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

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.