Background: Gastric cancer (GC) is a major global cancer burden and the second most common cause of global cancer-related deaths. The addition of anti-ERBB2 (HER2) targeted therapy to chemotherapy improves survival for ERBB2-amplified advanced GC patients; however, the majority of GC patients do not harbor this alteration and thus cannot benefit from targeted therapy under current practice paradigms.
Materials and methods: Prospective comprehensive genomic profiling of 116 predominantly locally advanced or metastatic (90.0%) gastric cancer cases was performed to identify genomic alterations (GAs) associated with a potential response to targeted therapies approved by the U.S. Food and Drug Administration or targeted therapy-based clinical trials.
Results: Overall, 78% of GC cases harbored one clinically relevant GA or more, with the most frequent alterations being found in TP53 (50%), ARID1A (24%), KRAS (16%), CDH1 (15%), CDKN2A (14%), CCND1 (9.5%), ERBB2 (8.5%), PIK3CA (8.6%), MLL2 (6.9%), FGFR2 (6.0%), and MET (6.0%). Receptor tyrosine kinase genomic alterations were detected in 20.6% of cases, primarily ERBB2, FGFR2, and MET amplification, with ERBB2 alterations evenly split between amplifications and base substitutions. Rare BRAF mutations (2.6%) were also observed. One MET-amplified GC patient responded for 5 months to crizotinib, a multitargeted ALK/ROS1/MET inhibitor.
Conclusion: Comprehensive genomic profiling of GC identifies clinically relevant GAs that suggest benefit from targeted therapy including MET-amplified GC and ERBB2 base substitutions.
摘要
背景. 胃癌（GC）在全球范围都是严重的癌症负担，同时也是全球癌症相关死亡的第二大原因。化疗联合抗ERBB2（HER2）靶向治疗改善了ERBB2扩增的进展期胃癌患者的生存；但是多数胃癌患者的肿瘤中并没有这一基因变异，因此不能从这一治疗范例的靶向治疗中获益。
材料与方法. 对116例患者进行前瞻性综合性基因组分析，以鉴别与靶向治疗（美国食品和药物管理局批准的靶向治疗，或以靶向治疗为基础的临床试验）部分缓解相关的基因变异（GA），患者主要为局部进展期或转移性胃癌（90.0%）。
结果. 总体而言，78%的胃癌病例含有≥ 1个临床相关性GA。最常见的基因变异见于TP53（50%）、ARID1A（24%）、KRAS（16%）、CDH1（15%）、CDKN2A（14%）、CCND1（9.5%）、ERBB2（8.5%）、PIK3CA（8.6%）、MLL2（6.9%）、FGFR2（6.0%）和MET（6.0%）。20.6%的病例可检测到受体酪氨酸激酶基因变异，主要为ERBB2、FGFR2和MET扩增，而ERBB2变异中扩增和碱基置换各占一半。还观察到少量BRAF突变（2.6%）。一例MET扩增胃癌患者经克唑替尼（ALK/ROS1/MET多靶点抑制剂）治疗5个月有应答。
结论. 对胃癌进行综合性基因组分析可鉴别出临床相关性GA，提示可从针对包括MET扩增胃癌和ERBB2碱基置换在内的靶向治疗中获益。The Oncologist 2015;20:499–507
Keywords: Gastric cancer; MET; Mutation; Profiling; Sequencing; Targeted therapy.
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