Osimertinib Quantitative and Gene Variation Analyses in Cerebrospinal Fluid and Plasma of a Non-small Cell Lung Cancer Patient with Lepto-meningeal Metastases
Osimertinib Quantitative and Gene Variation Analyses in Cerebrospinal Fluid and Plasma of a Non-small Cell Lung Cancer Patient with Lepto-meningeal Metastases
复制标题
非小细胞肺癌软脑膜转移患者脑脊液和血浆中奥希替尼的定量和基因变异分析。
DOI：
10.2174/1568009618666181017114111
复制
发表时间：
2019-01-01
影响因子：
3
通讯作者：
Shi, Yuankai
中科院分区：
文献类型：
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作者：
Song, Yuanyuan;Liu, Peng;Shi, Yuankai
背景
脑膜转移（LM）在携带表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者中更为常见。奥希替尼是第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），对LM显示出良好的疗效。
目的
本研究的目的是分析奥希替尼的浓度和人血浆和脑脊液（CSF）中循环肿瘤DNA（ctDNA）的基因变异。此外，我们还探讨了CSF中的ctDNA是否可用作预测和监测治疗反应的生物标志物。
方法
从LM获得性EGFR-TKI耐药的NSCLC患者中采集动态配对CSF和血液样本。开发并验证了一种基于超高效液相色谱-串联质谱（UPLC-MS/MS）的方法，用于检测CSF和血浆样本中的奥希替尼。ctDNA的基因变异通过下一代测序用一组1021个基因进行测试。
结果
奥希替尼在CSF中的浓度显著低于血浆中的浓度（渗透率为1.47%）。在来自血浆和CSF样品的ctDNA中探索突变，包括mTOR、EGFR、ERK 1、ABCC11和TP53。脑脊液标本的突变检出率高于血浆标本（50%比25%）。结果表明，脑脊液ctDNA的等位基因频率（VAF）和分子肿瘤负荷指数（mTBI）与治疗效果呈负相关。
结论
脑脊液ctDNA可作为监测LM疗效的生物标志物，并可作为MRI的有效补充。
BACKGROUND
Leptomeningeal metastases (LM) are much more frequent in patients of non-small lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) shows promising efficacy for LM.
OBJECTIVE
The aim of this study was to analyze the concentration of osimertinib and gene variation of circulating tumor DNA (ctDNA) in human plasma and cerebrospinal fluid (CSF). Furthermore, we explored whether ctDNA in CSF might be used as a biomarker to predict and monitor therapeutic responses.
METHODS
The dynamic paired CSF and blood samples were collected from the NSCLC patient with LM acquired EGFR-TKI resistance. A method based on ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and validated for detecting osimertinib in CSF and plasma samples. Gene variations of ctDNA were tested by next-generation sequencing with a panel of 1021 genes.
RESULTS
The concentrations of osimertinib in CSF were significantly lower than that in plasma (penetration rate was 1.47 %). Mutations included mTOR, EGFR, CHECK1, ABCC11, and TP53 were explored in ctDNA from plasma and CSF samples. The detected mutation rate of CSF samples was higher than that of plasma samples (50% vs. 25%). Our data further revealed that the variations allele frequency (VAF) and molecular tumor burden index (mTBI) of ctDNA derived from CSF exhibited the negative correlation with efficacy of treatment.
CONCLUSIONS
ctDNA from CSF might be a useful biomarker for monitoring the efficacy of treatment and an effective complement to nuclear magnetic resonance (MRI) for LM.