ERBB2扩增是许多癌症中的致癌遗传改变之一，并且最近在转移性结直肠癌（mCRC）中也被纳入治疗可操作的生物标志物之一。相比之下，ERBB2点突变的作用仍需评估，这些突变在最多3％的结直肠癌患者中可检测到。在这项系统性回顾中，我们收集了有关ERBB2点突变在mCRC患者中作为预测性生物标志物的抗EGFR和抗HER2靶向药物，以及作为经任何抗HER2方案治疗的ERBB2扩增mCRC的获得性耐药机制的临床和临床前数据。在临床前和临床研究中，大多数ERBB2点突变与抗EGFR药物的耐药性相关，特别是发生在HER2蛋白激酶结构域中的L755S和R784G。在mCRC患者中，没有ERBB2突变与HER2靶向药物的肿瘤反应相关，尽管在临床前模型中观察到了活性信号。目前有八项正在进行的临床试验以测试不同的抗HER2治疗在ERBB2突变的mCRC中的应用。一些报告记录了在进展到抗HER2药物的ERBB2扩增mCRC的循环肿瘤DNA（ctDNA）中出现ERBB2突变的出现，因此暗示了其在获得性耐药中的作用。 版权所有 © 2022 Elsevier Ltd. 未经许可，不得转载。

ERBB2 amplification is a driver oncogenic alteration in many cancers and it has recently been incorporated among therapeutically actionable biomarkers also in metastatic colorectal cancer (mCRC). In contrast, the role of ERBB2 point mutations, which are detectable in up to 3% of CRC patients, remains to be assessed. In this systematic review, we collected preclinical and clinical data addressing the role of ERBB2 point mutations in mCRC patients as a predictive biomarker for anti-EGFR and anti-HER2 targeted agents, and as mechanism of acquired resistance to ERBB2 amplified mCRC treated with any anti-HER2 regimen. In both preclinical and clinical studies, most ERBB2 point mutations were associated with resistance to anti-EGFR agents, particularly L755S and R784G, which occur in the HER2 protein kinase domain. No ERBB2 mutation was associated with tumor response to HER2-targeted agents in mCRC patients, although signals of activity were observed in preclinical models. Eight ongoing clinical trials are underway to test different anti-HER2 treatments in ERBB2 mutant mCRC. Several reports documented the emergence of ERBB2 mutations in the circulating tumor DNA (ctDNA) of ERBB2 amplified mCRC progressing to anti-HER2 agents, thus hinting a role in acquired resistance.Copyright © 2022. Published by Elsevier Ltd.