Xie Yuwen, Yang Liangfeng, Fang Hehui, Yu Chuanyong, Wang Xiaoyue, Liu Na, Xu Ting, Xia Hongping, Fang Shencun
Department of Respiratory Medicine, Nanjing Chest Hospital, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China.
Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China.
Lung Cancer. 2025 Jul;205:108593. doi: 10.1016/j.lungcan.2025.108593. Epub 2025 May 26.
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.
背景：软脑膜转移（LM）是晚期非小细胞肺癌（NSCLC）的一种毁灭性并发症。目前，对于第三代EGFR-TKIs耐药后的LM，尚无有效的数据和治疗方法。本研究旨在分析第三代EGFR-TKIs耐药后EGFR突变型NSCLC-LM的基因组图谱和预后因素。 方法：本研究纳入了2021年1月至2024年1月在南京医科大学附属脑科医院就诊的116例EGFR突变型NSCLC-LM患者。使用二代测序（NGS）分析脑脊液（CSF）和配对血浆样本中的循环肿瘤DNA。收集并分析基因组图谱、临床特征和预后情况。 结果：CSF中的ctDNA丰度高于配对血浆样本（0.76对0.21，P<0.001）。与血浆相比，CSF中更容易检测到突变，包括EGFR突变（73%对29%，P<0.001）、TP53突变（61%对35%，P＜0.001）、CDK4扩增（57%对0，P＜0.001）、CDKN2A缺失（27%对0，P＜0.001）、EGFR扩增（22%对0，P＜0.001）和CDK12突变（12%对2%，P = 0.006）。通路分析表明，CSF中富集的基因在多个致癌信号通路中发生改变，包括细胞周期（80%对23%，P<0.001）、KRAS/RAF（27%对8%，P<0.001）和WNT（18%对4%，P = 0.002）通路。此外，与血浆相比，CSF表现出明显更多的拷贝数变异（CNV；P = 0.022）和错义突变（P = 0.015）。LM诊断后的中位颅内无进展生存期和总生存期分别为6.60个月和14.42个月。多因素分析表明，基线东部肿瘤协作组体能状态（ECOG PS）为1-2、静脉化疗每次培美曲塞≥40mg，以及伏美替尼与贝伐单抗联合使用是生存的独立有利预测因素。最后，我们报告了1例LM病例，其中CSF中ctDNA的动态变化与他的临床情况高度一致。 结论：与血浆相比，CSF ctDNA在检测体细胞突变和转移相关通路方面更敏感、更特异。良好的体能状态、伏美替尼联合贝伐单抗以及静脉化疗使用高剂量培美曲塞可改善第三代EGFR-TKIs耐药后NSCLC-LM患者的预后。
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