Department of Respiratory Disease, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
Department of Outpatients, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
Thorac Cancer. 2022 Sep;13(18):2574-2583. doi: 10.1111/1759-7714.14592. Epub 2022 Jul 27.
The prognosis of non-small-cell lung cancer (NSCLC) with leptomeningeal metastasis (LM) is poor. Detection of cell-free DNA (cfDNA) by next generation sequencing (NGS) in cerebrospinal fluid (CSF) may facilitate diagnosis of LM and identification of drug resistance mechanisms, yet its clinical use needs to be further verified.
We performed a retrospective cohort study to assess the genetic profiles of paired CSF and plasma samples in lung cancer patients with LM. Of 17 patients screened, a total of 14 patients with LM and paired NGS tests were enrolled.
All patients harbor driver gene mutations, including 12 epidermal growth factor receptor (EGFR) activating mutations, 1 anaplastic lymphoma kinase (ALK) rearrangement, and 1 ROS-1 fusion. Genetic mutations were detected in CSF cfDNA from 92.9% patients (13/14), which was significantly higher than that from the plasma (9/14, 64.2%). The mutations were highly divergent between CSF and plasma cfDNA, with a concordance rate of 24.38% and 10 mutations shared by the two media. CSF cfDNA could also benefit the analysis of resistance mechanisms to targeted therapies. In five patients who experienced progression on 1st or 2nd generation EGFR-tyrosine kinase inhibitors (TKIs), RB1 mutation, and amplification of MET and EGFR were detected in CSF cfDNA only. In eight patients with LM progression on osimertinib resistance, EGFR amplification was detected in CSF cfDNA from four patients, whereas no CNVs were detected in the matched plasma samples.
In conclusion, CSF could be superior to plasma in providing a more comprehensive genetic landscape of LM to find out drug resistance mechanisms and guide subsequent treatments.
非小细胞肺癌（NSCLC）伴脑膜转移（LM）的预后较差。通过下一代测序（NGS）检测脑脊液（CSF）中的无细胞 DNA（cfDNA）有助于诊断 LM 和识别耐药机制，但需要进一步验证其临床应用。
我们进行了一项回顾性队列研究，以评估肺癌伴 LM 患者 CSF 和血浆样本的基因谱。在筛选的 17 名患者中，共纳入了 14 名 LM 患者和配对的 NGS 检测患者。
所有患者均携带驱动基因突变，包括 12 例表皮生长因子受体（EGFR）激活突变、1 例间变性淋巴瘤激酶（ALK）重排和 1 例 ROS-1 融合。92.9%（13/14）的患者 CSF cfDNA 中可检测到基因突变，明显高于血浆（9/14，64.2%）。CSF cfDNA 与血浆 cfDNA 中的基因突变高度不同，一致性率为 24.38%，两种介质中有 10 个突变共享。CSF cfDNA 也有利于分析针对靶向治疗的耐药机制。在 5 名首次或第二代 EGFR 酪氨酸激酶抑制剂（TKI）治疗进展的患者中，仅在 CSF cfDNA 中检测到 RB1 突变和 MET 和 EGFR 扩增。在 8 名奥希替尼耐药 LM 进展的患者中，4 名患者 CSF cfDNA 中检测到 EGFR 扩增，而配对血浆样本中未检测到 CNV。
总之，CSF 可能优于血浆，为发现耐药机制和指导后续治疗提供更全面的 LM 遗传图谱。
