Kahraman Seda, Yalcin Suayib
Yıldırım Beyazıt University Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey.
Hacettepe University Institute of Cancer, Department of Medical Oncology, Ankara, Turkey.
Onco Targets Ther. 2021 Jul 13;14:4149-4162. doi: 10.2147/OTT.S315252. eCollection 2021.
Gastric cancer (GC) is the fifth most common cancer worldwide. Despite recent improvements in treatment quality and options, advanced gastric cancer remains one of the hardest to cure cancers, with a median overall survival (OS) of 10-12 months and a 5-year OS of approximately 5-20%. There is an unmet need for further efforts to palliate disease-related symptoms, improve quality of life, increase tumor response rate, and prolong progression free and overall survival while balancing the toxicities of therapy. The most common type of GC is adenocarcinoma, which demonstrates morphological, biological, and clinical heterogeneity. A plethora of genomic alterations and the activation of numerous molecular pathways including human epidermal growth receptor 2 (HER2), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor-2 (FGFR2), mesenchymal epidermal transforming factor receptor (MET), and the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) are responsible for the complex heterogeneity of GC. Efforts to validate the therapeutic effects of inhibiting some of these aberrantly expressed pathways have failed to lead to a clinically meaningful outcome apart from the overexpression/amplification of the HER2 gene, inhibition of which has had a significant impact on clinical practice. The only available biomarkers to guide the effective treatment of patients with advanced GC are HER2 overexpression, MSI/PD-L1 status, and FGFR alterations. Various anti-HER2 agents have been evaluated after the success of the ToGA trial, but none led to a significant enough clinical improvement to be considered a viable alternative for HER2-targeted therapy in advanced GC until the global Keynote-811 trial, which added pembrolizumab to trastuzumab in combination with chemotherapy. This combination demonstrated a survival advantage for the first time in the 11 years since ToGA. Trastuzumab deruxtecan (T-DXd) was also found to be effective in patients who had already received >2 previous lines of treatment. Despite these promising avenues, the optimal management of HER-2 positive GC still requires further development.
胃癌（GC）是全球第五大常见癌症。尽管近期治疗质量和选择有所改善，但晚期胃癌仍是最难治愈的癌症之一，中位总生存期（OS）为10 - 12个月，5年OS约为5% - 20%。在平衡治疗毒性的同时，缓解疾病相关症状、提高生活质量、提高肿瘤反应率以及延长无进展生存期和总生存期方面仍有未满足的需求。最常见的GC类型是腺癌，其表现出形态学、生物学和临床异质性。大量的基因组改变以及包括人表皮生长因子受体2（HER2）、表皮生长因子受体（EGFR）、成纤维细胞生长因子受体-2（FGFR2）、间充质表皮转化因子受体（MET）和磷脂酰肌醇3激酶（PI3K）/雷帕霉素哺乳动物靶蛋白（mTOR）在内的众多分子途径的激活导致了GC的复杂异质性。除了HER2基因的过表达/扩增外，验证抑制这些异常表达途径的治疗效果的努力未能带来具有临床意义的结果，HER2基因的抑制对临床实践产生了重大影响。指导晚期GC患者有效治疗的唯一可用生物标志物是HER2过表达、微卫星不稳定性（MSI）/程序性死亡配体1（PD-L1）状态和FGFR改变。在ToGA试验成功后，各种抗HER2药物都进行了评估，但在全球KEYNOTE-811试验之前，没有一种药物能带来足够显著的临床改善，从而被认为是晚期GC中HER2靶向治疗的可行替代方案，KEYNOTE-811试验在曲妥珠单抗联合化疗中加入了帕博利珠单抗。这种联合用药自ToGA试验以来的11年中首次显示出生存优势。曲妥珠单抗德瓦鲁单抗（T-DXd）也被发现对已经接受过超过2线先前治疗的患者有效。尽管有这些有前景的途径，但HER-2阳性GC的最佳管理仍需要进一步发展。
