脑脊液肿瘤来源的 DNA (CSF-tDNA) 分析是监测中枢神经系统肿瘤过程的一种有前途的方法。我们对 24 名肺癌患者的 81 份脑脊液、血液和组织样本应用了肺癌特异性测序面板 (CAPP-Seq)，这些患者因疑似软脑膜疾病 (LMD) 接受了腰椎穿刺 (LP)。该队列的一个子集 (N = 12) 参与了奥希替尼治疗难治性 LMD 的前瞻性试验，其中在治疗前和治疗期间进行了连续的 LP。 CSF-tDNA 变异等位基因分数 (VAF) 显着高于血浆循环肿瘤 DNA (ctDNA) VAF（中位 CSF-tDNA，32.7%；中位血浆 ctDNA，1.8%；P<0.0001）。 CSF和血浆中肿瘤DNA的浓度呈正相关（Spearman's ρ，0.45；P = 0.03）。对于 LMD 诊断，细胞学的敏感性为 81.8%，CSF-tDNA 的敏感性为 91.7%。 CSF-tDNA 对总生存期也有很强的预测作用（HR = 7.1；P = 0.02）。在靶向治疗进展的患者中，耐药突变（例如 EGFR T790M 和 MET 扩增）在外周血中很常见，但在时间匹配的脑脊液中很少见，这表明基于解剖区室的耐药机制存在差异。在奥希替尼队列中，CNS 进展的患者在随访 LP 时 CSF-tDNA VAF 增加。奥希替尼治疗后 CSF-tDNA VAF 对于 CNS 进展有很强的预后作用（HR = 6.2，P = 0.009）。在疑似 LMD 的肺癌患者中检测 CSF-tDNA 是可行的，并且可能具有临床实用性。 CSF-tDNA 提高了 LMD 诊断的敏感性，改善了预后，并推动了考虑耐药机制空间异质性的治疗策略。© 2024。作者。

Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman's ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.© 2024. The Author(s).