识别伴有中枢神经系统转移的EGFR突变型肺癌的基因组图谱。

Identifying the genomic landscape of EGFR-mutant lung cancers with central nervous system metastases.

作者信息

Wilcox J A, Jeng M Y, Tischfield S, Sui J S Y, Nemirovsky D, Heller G, Choudhury N J, Ross J S, Rudin C M, Riely G J, Kris M G, Donoghue M, Boire A A, Yu H A

机构信息

Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, USA.

Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, USA.

出版信息

Ann Oncol. 2025 Jun 16. doi: 10.1016/j.annonc.2025.06.001.

DOI:10.1016/j.annonc.2025.06.001

PMID:40532851

Abstract

BACKGROUND

Despite the intracranial efficacy of osimertinib, central nervous system (CNS) metastases remain a major cause of morbidity and mortality in EGFR-mutant non-small-cell lung cancer (NSCLC). The genomic drivers of CNS dissemination are poorly understood.

PATIENTS AND METHODS

We analyzed the clinicogenomic features of patients with EGFR-mutant NSCLC receiving first-line osimertinib with extracranial next generation sequencing (NGS) (n = 262) and individuals with intracranial NGS (n = 81). Paired extra- and intracranial NGS was available for 14 patients. Time-to-event analyses were conducted from time of metastatic diagnosis, except for time-to-treatment discontinuation (TTD), which began at treatment initiation.

RESULTS

Among 262 patients receiving first-line osimertinib, 53% developed CNS metastases (36% de novo, 16% acquired on treatment). The cumulative incidence of brain (BrM) and leptomeningeal metastases (LM) was 39% and 2% at 1 year, 49% and 6% at 3 years, and 54% and 12% at 5 years, respectively. CNS metastases correlated with a higher frequency of CARD11 amplifications (14% versus 3%, P = 0.031) and a lower frequency of MDM2 amplifications (1% versus 13%, P = 0.008) in extracranial NGS specimens, with otherwise similar genomic profiles. Patients who developed CNS metastases on treatment had worse overall survival (OS) [hazard ratio (HR) = 3.67, 95% confidence interval (CI) 2.41 to 5.59], followed by those with de novo (HR = 1.61, 95% CI 1.15 to 2.26), compared with those who never developed CNS metastases (P < 0.001). In multivariable Cox regression, atypical EGFR mutations were associated with shorter OS. Cell cycle pathway alterations were more frequent in BrM than LM samples (93% versus 47%, P = 0.003, q = 0.03). No other significant genomic differences were found between BrM and LM, or between paired CNS and systemic samples.

CONCLUSIONS

Patients with atypical EGFR mutations or acquired CNS metastases on osimertinib have worse outcomes. Comparative NGS profiling of intra- and extracranial tumors suggest that CNS dissemination is driven by mechanisms beyond single-gene alterations.

摘要

背景

尽管奥希替尼对颅内病灶有效，但中枢神经系统（CNS）转移仍是表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者发病和死亡的主要原因。CNS转移的基因组驱动因素尚不清楚。

患者与方法

我们分析了接受一线奥希替尼治疗且进行颅外下一代测序（NGS）的EGFR突变NSCLC患者（n = 262）以及进行颅内NGS的患者（n = 81）的临床基因组特征。14例患者可获得配对的颅外和颅内NGS数据。除治疗中断时间（TTD）从治疗开始时计算外，其余事件发生时间分析均从转移诊断时开始。

结果

在262例接受一线奥希替尼治疗的患者中，53%发生了CNS转移（36%为新发，16%为治疗期间获得性转移）。脑转移（BrM）和软脑膜转移（LM）的累积发生率在1年时分别为39%和2%，3年时分别为49%和6%，5年时分别为54%和12%。在颅外NGS样本中，CNS转移与CARD11扩增频率较高（14%对3%，P = 0.031）和MDM2扩增频率较低（1%对13%，P = 0.008）相关，其他方面的基因组特征相似。在治疗期间发生CNS转移的患者总生存期（OS）较差[风险比（HR）= 3.67，95%置信区间（CI）2.41至5.59]，其次是新发转移患者（HR = 1.61，95%CI 1.15至2.26），而从未发生CNS转移的患者则较好（P < 0.001）。在多变量Cox回归分析中，非典型EGFR突变与较短的OS相关。与LM样本相比，细胞周期通路改变在BrM样本中更常见（93%对47%，P = 0.003，q = 0.03）。在BrM与LM之间，或配对的CNS与全身样本之间未发现其他显著的基因组差异。