PDF(Pubmed)
Abstract：
Molecular-based targeted therapies have significantly benefited certain patients with cancer; however, those with leptomeningeal disease (LMD) persistently exhibit a poor prognosis and are often excluded from clinical trials. Tumor-derived cell-free (cf)DNA, found in the cerebrospinal fluid (CSF) of patients with LMD, can assist in diagnosis and tracking of disease progression. However, the utilization of CSF to direct targeted cancer therapy has yet to be extensively explored. The present study reported the case of a patient with lung adenocarcinoma and LMD who was monitored by performing a series of liquid biopsies of CSF and blood. Targeted sequencing was performed on cfDNA from the CSF and plasma, and the variant allele frequencies (VAFs) of BRAF and NRAS mutations were assessed and analyzed in conjunction with the clinical presentation of the patient. The patient then underwent serial chemotherapy, radiation therapy, immunotherapy and targeted treatment based on the results of the liquid biopsies. Upon the LMD diagnosis, a BRAF p.V600E mutation was detected in plasma cfDNA. Consequently, the patient was treated with vemurafenib and responded favorably to this consolidation treatment for 13 months. After a relapse in July 2018, both BRAF p.V600E and NRAS p.Q61K mutations were detected in CSF supernatant and sediment cell samples, suggesting drug resistance. Therefore, the treatment strategy for the patient changed to cobimetnib plus vemurafenib. Notably, the changes of VAF in the CSF supernatant samples were associated with the clinical status of the patient. The patient survived for 33 months post-LMD diagnosis. The present case report highlights the potential use of liquid biopsy in personalized therapy, as it was instrumental in informing the combinational treatment plan of the patient, which ultimately proved beneficial.
摘要：
基于分子的靶向治疗对某些癌症患者有显著的益处；然而，患有软脑膜疾病(LMD)的患者持续表现出不良预后,通常被排除在临床试验之外.肿瘤来源的无细胞（cf）DNA，在LMD患者的脑脊液（CSF）中发现，可以协助诊断和跟踪疾病进展。然而,使用CSF指导靶向癌症治疗尚待广泛探索.本研究报告了一名患有肺腺癌和LMD的患者，该患者通过对CSF和血液进行一系列液体活检来进行监测。对来自CSF和血浆的cfDNA进行靶向测序，并结合患者的临床表现对BRAF和NRAS突变的变异等位基因频率(VAFs)进行评估和分析.然后病人接受了连续化疗,放射治疗,基于液体活检结果的免疫治疗和靶向治疗。在LMD诊断后，在血浆cfDNA中检测到BRAFp.V600E突变。因此,患者接受vemurafenib治疗,持续13个月对巩固治疗反应良好.在2018年7月复发后，在CSF上清液和沉淀细胞样品中检测到BRAFp.V600E和NRASp.Q61K突变，提示耐药性。因此,患者的治疗策略改为cobimetnib+vemurafenib。值得注意的是,CSF上清液中VAF的变化与患者的临床状况相关。患者在LMD诊断后存活33个月。本病例报告强调了液体活检在个性化治疗中的潜在用途，因为它有助于告知患者的联合治疗计划，最终证明是有益的。
