Gastric cancer is one of the most common malignancy worldwide. In unresectable or metastatic disease, the prognosis is poor and in generally less than a year. HER2 expression remains an important biomarker to lead the addition of trastuzumab to first-line systemic chemotherapy in unresectable or metastatic gastroesophageal adenocarcinoma. To date, a major issue is represented by resistance to trastuzumab developed during treatment, considering the not improved outcomes in this molecular subtype of gastroesophageal adenocarcinoma to other HER2 target strategies. In this review, we summarize the available data on the mechanisms underlying primary and secondary resistance to HER2-targeted therapy and current challenges in the treatment of HER2-positive advanced gastric cancer refractory to trastuzumab. Furthermore, we describe the prognostic value of new non-invasive screening methods, under development novel agents (e.g., HER2 antibody-drug conjugates and bispecific antibodies) and strategies with antitumor activity in early studies.

胃癌是全球最常见的恶性肿瘤之一。在不可切除或转移的疾病中，预后很差，一般不到一年。HER2 表达仍然是导致将曲妥珠单抗添加到不可切除或转移性胃食管腺癌的一线全身化疗的重要生物标志物。迄今为止，一个主要问题是治疗期间对曲妥珠单抗产生耐药性，考虑到这种分子亚型胃食管腺癌的结果与其他 HER2 靶标策略相比没有改善。在这篇综述中，我们总结了关于 HER2 靶向治疗原发性和继发性耐药机制的现有数据，以及目前治疗曲妥珠单抗难治性 HER2 阳性晚期胃癌的挑战。此外，