Institute of Pathology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Clin Lung Cancer. 2018 Jul;19(4):e441-e463. doi: 10.1016/j.cllc.2018.03.010. Epub 2018 Mar 17.
The receptor tyrosine kinase MET is implicated in malignant transformation, tumor progression, metastasis, and acquired treatment resistance. We conducted an analysis of the effect of MET expression and MET genomic aberrations on the outcome of patients with advanced or metastatic pulmonary adenocarcinomas prospectively enrolled in an institutional precision oncology program.
Standardized immunohistochemistry (IHC) analyses of MET and markers of pathway activation were available in 384 patients, and next-generation sequencing-based MET hotspot mutation analyses were available from 892 patients. Clinical data were retrieved with a median follow-up from initial diagnosis of 37 months.
High MET expression, defined as MET IHC 3+ or MET H-Score in the upper quartile, was observed in 102 of 384 patients (26.6%). MET exon 14 mutations were only detected in 7 of 892 patients (0.78%). High MET expression correlated with activation markers of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways only in cases without Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), v-Raf murine sarcoma viral oncogene homolog B (BRAF), anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) aberrations. There was no association of MET expression with outcome during chemotherapy. High MET expression negatively affected the outcome during EGFR-targeting therapy but was associated with more favorable results with programmed death 1/programmed death ligand 1 (PD-L1)-directed therapy, independent of smoking history, PD-L1 expression or KRAS mutation. Two patients with MET exon 14 mutation and high PD-L1 expression failed to respond to pembrolizumab.
MET expression affects the outcomes of targeted therapies in non-small-cell lung cancer, thus supporting the development of biomarker-informed combination strategies. The interaction of MET expression and MET mutation with immune checkpoint inhibitor therapy is novel and merits further investigation.
受体酪氨酸激酶 MET 参与恶性转化、肿瘤进展、转移和获得性治疗耐药。我们对前瞻性纳入机构精准肿瘤学计划的晚期或转移性肺腺癌患者进行了 MET 表达和 MET 基因组异常对患者结局影响的分析。
384 例患者可进行标准化免疫组化（IHC）分析 MET 和通路激活标志物，892 例患者可进行基于下一代测序的 MET 热点突变分析。从初始诊断开始，中位随访 37 个月后检索临床数据。
384 例患者中有 102 例（26.6%）观察到高 MET 表达，定义为 MET IHC 3+或 MET H-Score 在上四分位数。892 例患者中仅检测到 7 例（0.78%）MET 外显子 14 突变。高 MET 表达仅与无 Kirsten 大鼠肉瘤病毒致癌基因同源物（KRAS）、表皮生长因子受体（EGFR）、v-Raf 鼠肉瘤病毒致癌基因同源物 B（BRAF）、间变性淋巴瘤激酶（ALK）和原癌基因酪氨酸蛋白激酶 ROS（ROS1）异常的 MAPK 和 PI3K/AKT 通路的激活标志物相关。在化疗期间，MET 表达与结局无关联。高 MET 表达对 EGFR 靶向治疗的结局有负面影响，但与程序性死亡 1/程序性死亡配体 1（PD-L1）靶向治疗的更有利结果相关，与吸烟史、PD-L1 表达或 KRAS 突变无关。两名 MET 外显子 14 突变且高 PD-L1 表达的患者对 pembrolizumab 无反应。
MET 表达影响非小细胞肺癌靶向治疗的结局，因此支持开发基于生物标志物的联合策略。MET 表达与免疫检查点抑制剂治疗的相互作用是新颖的，值得进一步研究。
