Barry Garrett S, Cheang Maggie C, Chang Hector Li, Kennecke Hagen F
Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
The Institute of Cancer Research, Sutton, London, Surrey SM2 5NG, United Kingdom.
Oncotarget. 2016 Apr 5;7(14):18953-64. doi: 10.18632/oncotarget.8006.
A prospective study was conducted to identify biomarkers associated with resistance to panitumumab monotherapy in patients with metastatic colorectal cancer (mCRC). Patients with previously treated, codon 12/13 KRAS wt, mCRC were prospectively administered panitumumab 6 mg/kg IV q2weeks. Of 34 panitumumab-treated patients, 11 (32%) had progressive disease at 8 weeks and were classified as non-responders. A Nanostring nCounter-based assay identified a 5-gene expression signature (ERBB2, MLPH, IRX3, MYRF, and KLK6) associated with panitumumab resistance (P = 0.001). Immunohistochemistry and in situ hybridization determined that the HER2 (ERBB2) protein was overexpressed in 4/11 non-responding and 0/21 responding cases (P = 0.035). Two non-responding tumors had ERBB2 gene amplification only, and one demonstrated both ERBB2 amplification and mutation. A non-codon 12/13 KRAS mutation occurred in one panitumumab-resistant patient and was mutually exclusive with ERBB2/HER2 abnormalities. This study identifies a 5-gene signature associated with non-response to single agent panitumumab, including a subgroup of non-responders with evidence of aberrant ERBB2/HER2 signaling. KRAS wt tumors resistant to EGFRi may be identified by gene signature analysis, and the HER2 pathway plays an important role in resistance to therapy.
开展了一项前瞻性研究，以确定与转移性结直肠癌（mCRC）患者对帕尼单抗单药治疗耐药相关的生物标志物。对先前接受过治疗、密码子12/13 KRAS野生型的mCRC患者前瞻性给予帕尼单抗6 mg/kg静脉注射，每2周一次。在34例接受帕尼单抗治疗的患者中，11例（32%）在8周时出现疾病进展，被归类为无反应者。基于纳米串nCounter的检测确定了一个与帕尼单抗耐药相关的5基因表达特征（ERBB2、MLPH、IRX3、MYRF和KLK6）（P = 0.001）。免疫组织化学和原位杂交确定，HER2（ERBB2）蛋白在4/11例无反应病例中过度表达，而在21例有反应病例中无过度表达（P = 0.035）。2例无反应肿瘤仅出现ERBB2基因扩增，1例同时出现ERBB2扩增和突变。1例帕尼单抗耐药患者发生了非密码子12/13 KRAS突变，且与ERBB2/HER2异常相互排斥。本研究确定了一个与对单药帕尼单抗无反应相关的5基因特征，包括一组有异常ERBB2/HER2信号证据的无反应者。对表皮生长因子受体抑制剂（EGFRi）耐药的KRAS野生型肿瘤可通过基因特征分析来识别，且HER2通路在治疗耐药中起重要作用。
