Genomic profiling and prognostic factors of leptomeningeal metastasis in EGFR-mutant NSCLC after resistant to third-generation EGFR-tyrosine kinase inhibitors

Background: Leptomeningeal metastasis (LM) is a devastating complication of advanced non-small cell lung cancer (NSCLC). Currently, there is no valid data and effective treatment for LM after resistance to third-generation EGFR-TKIs. This study aimed to analyze the genomic profiling and prognostic factors of EGFR-mutant NSCLC-LM after resistance to third-generation EGFR-TKIs. Methods: This study included 116 patients with EGFR-mutated NSCLC-LM at the Affiliated Brain Hospital of Nanjing Medical University from January 2021 to January 2024. Circulating tumor DNA from cerebrospinal fluid (CSF) and matched plasma samples were analyzed using next-generation sequencing (NGS). Genomic profiling, clinical features, and prognosis were collected and analyzed. Results: ctDNA abundance in CSF was higher than in paired plasma samples (0.76 vs 0.21, P < 0.001). Compared to plasma, mutations were more easily detected in CSF, including EGFR mutations (73 % vs. 29 %, P < 0.001), TP53 mutations (61 % vs. 35 %, P < 0.001), CDK4_amp (57 % vs 0, P < 0.001), CDKN2A_del (27 % vs. 0, P < 0.001), EGFR_amp (22 % vs. 0, P < 0.001), and CDK12 mutations (12 % vs. 2 %, P = 0.006). Pathway analysis indicates that genes enriched in CSF are altered in multiple oncogenic signaling pathways, including cell cycle (80 % vs 23 %, P < 0.001), KRAS/RAF (27 % vs 8 %, P < 0.001), and WNT (18 % vs 4 %, P = 0.002) pathways. Furthermore, CSF exhibits significantly greater copy number variations (CNVs; P = 0.022) and missense mutations (P = 0.015) compared to plasma. The median intracranial progression-free survival and overall survival after LM diagnosis were 6.60 and 14.42 months, respectively. Multivariate analysis demonstrated that baseline Eastern Cooperative Oncology Group performance status (ECOG PS) 1-2, >= 40 mg pemetrexed per time for IVC, and the combination of furmonertinib and bevacizumab were independent favorable predictors of survival. Finally, we reported a case of LM in which ctDNA dynamic changes in CSF were well consistent with his clinical condition. Conclusions: Compared to plasma, CSF ctDNA is more sensitive and specific in detecting somatic mutations and metastasis-related pathways. Good performance status, furmonertinib combined with bevacizumab, and high-dose pemetrexed for IVC can improve the prognosis of NSCLC-LM patients after resistance to third-generation EGFR-TKIs.