Lote Hazel, Valeri Nicola, Chau Ian
Centre for Molecular Pathology, Institute of Cancer Research, Sutton SM2 5NG, United Kingdom.
Department of Medicine, Royal Marsden Hospital, Sutton SM2 5PT, United Kingdom.
World J Gastrointest Oncol. 2018 Jul 15;10(7):159-171. doi: 10.4251/wjgo.v10.i7.159.
Human epidermal growth factor receptor 2 (HER2)-inhibition is an important therapeutic strategy in HER2-amplified gastro-oesophageal cancer (GOC). A significant proportion of GOC patients display HER2 amplification, yet HER2 inhibition in these patients has not displayed the success seen in HER2 amplified breast cancer. Much of the current evidence surrounding HER2 has been obtained from studies in breast cancer, and we are only recently beginning to improve our understanding of HER2-amplified GOC. Whilst there are numerous licensed HER2 inhibitors in breast cancer, trastuzumab remains the only licensed HER2 inhibitor for HER2-amplified GOC. Clinical trials investigating lapatinib, trastuzumab emtansine, pertuzumab and MM-111 in GOC have demonstrated disappointing results and have not yet changed the treatment paradigm. Trastuzumab deruxtecan may hold promise and is currently being investigated in phase II trials. HER2 amplified GOC differs from breast cancer due to inherent differences in the HER2 amino-truncation and mutation rate, loss of HER2 expression, alterations in HER2 signalling pathways and differences in insulin-like growth factor-1 receptor and MET expression. Epigenetic alterations involving different microRNA profiles in GOC as compared to breast cancer and intrinsic differences in the immune environment are likely to play a role. The key to effective treatment of HER2 amplified GOC lies in understanding these mechanisms and tailoring HER2 inhibition for GOC patients in order to improve clinical outcomes.
人表皮生长因子受体2（HER2）抑制是HER2扩增的胃食管癌（GOC）的重要治疗策略。相当一部分GOC患者存在HER2扩增，但这些患者的HER2抑制并未取得在HER2扩增乳腺癌中所见的成功。目前关于HER2的许多证据来自乳腺癌研究，而我们直到最近才开始加深对HER2扩增GOC的理解。虽然乳腺癌中有多种已获许可的HER2抑制剂，但曲妥珠单抗仍然是HER2扩增GOC唯一获许可的HER2抑制剂。在GOC中研究拉帕替尼、曲妥珠单抗恩美曲妥珠单抗、帕妥珠单抗和MM-111的临床试验结果令人失望，尚未改变治疗模式。曲妥珠单抗德曲妥珠单抗可能有前景，目前正在进行II期试验研究。HER2扩增GOC与乳腺癌不同，原因在于HER2氨基截断和突变率、HER2表达缺失、HER2信号通路改变以及胰岛素样生长因子-1受体和MET表达存在固有差异。与乳腺癌相比，GOC中涉及不同微小RNA谱的表观遗传改变以及免疫环境的内在差异可能起作用。有效治疗HER2扩增GOC的关键在于理解这些机制，并为GOC患者量身定制HER2抑制方案，以改善临床结局。
