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【WCLC2016】范云教授通过NGS发现EGFR+NSCLC软脑膜转移的作用机制

2016年12月08日

来源：肿瘤资讯

【背景】

软脑膜转移（leptomeningeal metastasis，LM) 是非小细胞肺癌（NSCLC）的少见并发症。EGFR突变的非小细胞肺癌（NSCLC）患者中约有10%在初始诊断或治疗期间将发展出软脑膜转移（LM）。 LM是与不良预后相关的NSCLC的严重并发症，有LM的NSCLC患者的中位总生存期仅为4.5-11个月，约有60％的死亡是由LM或LM加上系统性病变。然而，我们对于于肺癌软脑膜转移转移过程的基础机制仍然很少了解。

【方法】

我们对来自11例EGFRm + NSCLC患者的原发性肿瘤组织，脑脊液（CSF）和匹配的正常对照进行NGS测序。其中，2例患者在首次诊断时有LM，8例患者在第一代EGFR-TKI治疗期间发展为LM，而1例患者的临床信息缺失。

【结果】

EGFR活性突变的状态在所有患者的原发性肿瘤和CSF中相同，除了EGFR突变不可检测，在主要位点可能是由于低序列覆盖。总共有8例EGFR L858R，1例19Del，2例L858R＆19Del双重突变。一位患者在原发部位也有新的EGFR T790M。没有CSF样品显示EGFR T790M突变，这表明它不是在TKI治疗期间发展LM的8个患者的抗性机制。 PIK3CA E545K和H1047L，和PTEN R130Q

在6位患者的原发部位和/或CSF中。虽然样本量较小，但这个比率远远高于一般的EGFR L858R或19Del阳性肺腺癌患者人群（从4个数据集中为〜2％），这说明PI3K途径的变化可能与LM风险相关。有趣的是，在11个患者中的9个中，CSF样品中仅0.9％-7.8％的变体与初级位点中的变体重叠，这表明在LM发展期间肿瘤有异质性和进化。此外，当我们发现> 5名患者的复发性CSF独特的体细胞基因组改变。

【结论】

根据上述结果：

第一、证实脑脊液与原发肿瘤标本在EGFR突变上存在高度的一致性；有意思的是，在所有患者的脑积液标本中均未检测到T790M突变。

第二、PI3K通路的基因异常可能是NSCLC出现脑膜转移的危险因素之一。

第三、脑脊液基因表达与原发肿瘤之间存在非常明显的差异性，反映了肿瘤的基因变异及克隆进化。第四、细胞周期调节和DNA损伤修复通路在LM的形成中可能起到一定的作用。

本研究揭示了LM的基因组变异的特点，为这种未满足的治疗需求寻找潜在的治疗方法作了铺垫。

OA08.01: Exploration of the Underlying Mechanisms of Leptomeningeal Metastasis inNSCLC Patients through NGS of Cerebrospinal Fluid

Background:

About 10% of non-small cell lung cancer (NSCLC) patients withEGFR mutations will develop leptomeningeal metastasis (LM) either at initialdiagnosis or during treatment. LM is a devastating complication of NSCLCassociated with poor prognosis. The median overall survival is 4.5-11 months,with ~60% death due to LM or LM together with systemic lesions. However,the underlying mechanisms of the metastasis process are still poorlyunderstood.

Methods:

we performed next-generation panel sequencing ofprimary tumor tissue, cerebrospinal fluid (CSF) and matched normal controlsfrom 11 EGFRm+ NSCLC patients with LM. Among them, 2 patients had LM atinitial diagnosis, and 8 patients developed LM during 1st generation EGFR-TKItreatment, while such clinical information was missing for 1 patient. Results:The status of EGFR active mutations was the same in the primary tumor andCSF of all the patients, except one whose EGFR mutation was undetectable
in the primary site probably due to low sequence coverage. In total, therewere 8 patients with EGFR L858R, 1 with 19Del, and 2 with L858R & 19Del dualmutation. One patient also had de novo EGFR T790M in the primary site. Noneof the CSF samples showed EGFR T790M mutation, suggesting that it wasnot the resistance mechanism for the 8 patients who developed LM duringTKI treatment. PIK3CA E545K and H1047L, and PTEN R130Q were identified

in primary site and/or CSF of 6 patients. Although with small sample size, thisratio is much higher than what was reported in general EGFR L858R or 19Delpositive lung adenocarcinoma patient population (~2% from 4 datasets),implicating that alternations in PI3K pathway may associate with LM risk.Interestingly, in 9 of the 11 patients, only 0.9%-7.8% of variants in CSF samplesoverlapped with those in primary site, suggesting tumor heterogeneity,divergence and clonal evolution during LM development. Moreover, when wecataloged the recurrent CSF-unique somatic genomic alterations existing in>5 patients, we identified genes involved in DNA repair pathway, cell cycleregulation and epigenetic reprogramming (NPM1, RAD50, MRE11A, POLE,CHEK1, XPC, KMT2B, KMT2C, KMT2D, and ATRX). Conclusion: In summary, ourstudy has shed light on the genomic variations of LM and paved the way forpotential therapeutic approaches to this unmet medical need.