Introduction: Leptomeningeal metastases (LMs) indicated a poor prognosis in NSCLC. LMs were more frequent in driver gene–mutated patients, and cerebrospinal fluid (CSF) cell‐free DNA has shown unique genetic profiles of LM in EGFR‐mutated LM. However, studies in patients with ALK receptor tyrosine kinase gene (ALK)‐rearranged NSCLC with LMs are scarce. Methods: Patients with lung cancer with ALK rearrangement were screened from September 2011 to February 2018 at our institute. CSF and paired plasma were tested by next‐generation sequencing. Results: LMs were diagnosed in 30 (10.3%) of 291 patients with ALK‐rearranged lung cancer. A total of 11 paired CSF and plasma samples tested by next‐generation sequencing were analyzed. Driver genes were detected in 81.8% of the CSF samples (9 of 11) and 45.5% of the plasma samples (5 of 11) (p = 0.183). The maximum allelic fractions were all higher in CSF than in plasma (p = 0.009). ALK and tumor protein p53 gene (TP53) were the two most frequently mutated genes in CSF. Gatekeeper gene ALK G1202R and C1156F mutations were identified in CSF after resistance to alectinib. Multiple copy number variants were mainly found in CSF, including in EGFR, cyclin D1 gene (CCND1), fibroblast growth factor 3 gene (FGF3), and fibroblast growth factor 4 gene (FGF4). Also found were v‐myc avian myelocytomatosis viral oncogene homolog gene (MYC) copy number gains and TP53 and cyclin dependent kinase inhibitor 2A gene (CDKN2A) copy number deletions. Brigatinib seemed to be effective in controlling LM. One case showed that CSF could be used to monitor disease development of LM and longitudinally monitor tumor response. Conclusion: Liquid biopsy of CSF is more sensitive than liquid biopsy of plasma to detect targetable alterations, characterizing resistance mechanisms on progression and monitoring tumor response in patients with ALK‐rearranged NSCLC with LM. Thus, CSF might be promising as a medium of liquid biopsy in LM.

中文翻译：

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简要报告：脑脊液游离 DNA 作为液体活检用于 ALK 重排 NSCLC 中的软脑膜转移的临床效用

简介：软脑膜转移（LMs）表明非小细胞肺癌预后不良。LMs 在驱动基因突变的患者中更常见，脑脊液 (CSF) 无细胞 DNA 显示出 EGFR 突变的 LM 中 LM 的独特遗传谱。然而，关于 ALK 受体酪氨酸激酶基因 (ALK) 重排的 NSCLC 患者的研究很少。方法：2011年9月至2018年2月在我院筛查ALK重排肺癌患者。CSF 和配对血浆通过二代测序进行检测。结果：291 名 ALK 重排肺癌患者中有 30 名 (10.3%) 被诊断出 LM。总共分析了 11 个配对的 CSF 和血浆样本，这些样本通过下一代测序进行了测试。在 81.8% 的 CSF 样本（11 个中的 9 个）和 45.5% 的血浆样本（11 个中的 5 个）中检测到驱动基因（p = 0.183）。CSF 中的最大等位基因分数均高于血浆（p = 0.009）。ALK 和肿瘤蛋白 p53 基因 (TP53) 是脑脊液中两个最常见的突变基因。在对艾乐替尼耐药后，在 CSF 中发现了 Gatekeeper 基因 ALK G1202R 和 C1156F 突变。多拷贝数变异主要在CSF中发现，包括EGFR、细胞周期蛋白D1基因（CCND1）、成纤维细胞生长因子3基因（FGF3）和成纤维细胞生长因子4基因（FGF4）。还发现 v-myc 禽骨髓细胞瘤病毒癌基因同源基因 (MYC) 拷贝数增加和 TP53 和细胞周期蛋白依赖性激酶抑制剂 2A 基因 (CDKN2A) 拷贝数缺失。Brigatinib 似乎对控制 LM 有效。一个案例表明，CSF 可用于监测 LM 的疾病发展和纵向监测肿瘤反应。结论：CSF 液体活检比血浆液体活检更灵敏，可检测靶向改变，表征 ALK 重排 NSCLC 伴 LM 患者的进展耐药机制和监测肿瘤反应。因此，CSF 可能有希望作为 LM 中的液体活检介质。