脑脊髓液基因分型与 EGFR 突变 NSCLC 脑膜转移奥希替尼反应和耐药的关系。
Genotyping of Cerebrospinal Fluid Associated With Osimertinib Response and Resistance for Leptomeningeal Metastases in EGFR-Mutated NSCLC.
机构信息
Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
出版信息
J Thorac Oncol. 2021 Feb;16(2):250-258. doi: 10.1016/j.jtho.2020.10.008. Epub 2020 Oct 26.
INTRODUCTION
Patients with NSCLC with leptomeningeal metastases (LM) presented dismal prognosis. Cerebrospinal fluid (CSF) is suggested as a medium of liquid biopsy of LM. However, the clinical implications of CSF genotyping on treatment outcomes remained elusive.
METHODS
Patients with EGFR-mutated advanced NSCLC with LM were included: cohort 1, patients with LM who were treated with osimertinib with CSF and plasma genotyping performed before the first dosing of osimertinib (baseline, n = 45); cohort 2, CSF genotyping on progression on osimertinib and development of LM (the progression event on osimertinib is the diagnosis of LM, n = 35). Circulating tumor DNA in CSF underwent next-generation sequencing.
RESULTS
Sensitivity of CSF genotyping for EGFR-sensitizing mutations was 93.3% (42 of 45) and 97.1% (34 of 35) in cohorts 1 and 2, respectively. In cohort 1, patients with EGFR exon 19 deletion had higher median intracranial progression free survival (iPFS) than those with EGFR exon 21 L858R mutation (11.9 versus 2.8 mo; p = 0.02). Median iPFS was significantly longer in patients with T790M-positive CSF genotyping (15.6 mo) than T790M-negative CSF (7.0 mo, p = 0.04). Concurrent CDK4 (2.8 versus 11.6 mo, p = 0.002) and CDKN2A (2.5 versus 9.6 mo, p = 0.04) mutation with EGFR-sensitizing mutations indicated lower median iPFS. Patients with T790M-negative CSF, EGFR exon 21 L858R mutation, concurrent FGF3 alteration, and over first-line osimertinib had shortened iPFS. In cohort 2, possible EGFR-related and EGFR-independent resistance mechanisms were found including C797S mutation, MET dysregulation, and TP53 plus RB1 co-occurrence. Patients with loss of T790M in CSF had a shorter median iPFS (7.4 mo) compared with those with reserved T790M (13.6 mo, p = 0.01).
CONCLUSIONS
Genotyping of CSF indicated heterogeneous response to osimertinib and revealed the genetic characteristic of LM on osimertinib failure in patients with EGFR-mutated NSCLC diagnosed with LM.
简介
患有脑膜转移（LM）的非小细胞肺癌（NSCLC）患者预后较差。脑脊液（CSF）被认为是 LM 液体活检的媒介。然而，CSF 基因分型对治疗结果的临床意义仍不清楚。
方法
纳入 EGFR 突变的晚期 NSCLC 合并 LM 患者：队列 1，在奥希替尼首次给药前进行 CSF 和血浆基因分型的 LM 患者（基线，n=45）；队列 2，奥希替尼进展和 LM 发展时的 CSF 基因分型（奥希替尼进展事件为 LM 诊断，n=35）。CSF 中的循环肿瘤 DNA 进行下一代测序。
结果
在队列 1 和 2 中，CSF 基因分型检测 EGFR 敏感突变的敏感性分别为 93.3%（42/45）和 97.1%（34/35）。在队列 1 中，EGFR 外显子 19 缺失的患者颅内无进展生存期（iPFS）明显长于 EGFR 外显子 21 L858R 突变的患者（11.9 个月比 2.8 个月；p=0.02）。CSF 基因分型 T790M 阳性的患者中位 iPFS 明显长于 T790M 阴性的患者（15.6 个月比 7.0 个月，p=0.04）。CSF 中同时存在 CDK4（2.8 个月比 11.6 个月，p=0.002）和 CDKN2A（2.5 个月比 9.6 个月，p=0.04）突变与 EGFR 敏感突变患者的 iPFS 较短。CSF 中 T790M 阴性、EGFR 外显子 21 L858R 突变、同时存在 FGF3 改变和一线奥希替尼耐药的患者 iPFS 缩短。在队列 2 中，发现了可能的 EGFR 相关和 EGFR 不相关的耐药机制，包括 C797S 突变、MET 失调和 TP53 与 RB1 共同发生。CSF 中 T790M 丢失的患者中位 iPFS 较短（7.4 个月），与保留 T790M 的患者（13.6 个月，p=0.01）相比。
结论
CSF 基因分型表明奥希替尼的反应存在异质性，并揭示了在 LM 诊断的 EGFR 突变 NSCLC 患者中，LM 对奥希替尼失败的遗传特征。
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