Table_1_ERBB2D16 Expression in HER2 Positive Gastric Cancer Is Associated With Resistance to Trastuzumab.docx

The human epidermal growth factor receptor-2 (ERBB2; formerly HER2)isoform ERBB2ΔEx16 (ERBB2d16) was oncogenic by mediating epithelial-mesenchymal transition (EMT), immune evasion, and resistance cell death to the anti-HER2 (trastuzumab) therapy. However, its physiological implications in gastric cancer were unclear. In this study, we examined a total of 110 patients with either locally advanced or metastatic HER2+ gastric cancer for the expression of ERBB2d16 and EMT markers, and the infiltration of CD3+ T cells in tumor tissues, and evaluated their relevance with the responses to the standard chemotherapy plus trastuzumab according to the RECIST criteria. We found that the ERBB2d16 isoform was present at a relatively high level in about half of the tumor samples examined (53/110) and an elevated ERBB2d16/ERBB2 ratio was positively associated with the expression of high E-cadherin and low vimentin indicating EMT, and with poor CD3+ T cell infiltration and strong intratumoral expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) as well as reduced diversity of T cell receptor clones. Moreover, the progression-free survival and overall survival of patients treated with trastuzumab were substantially shorter in those with a high ERBB2d16/ERBB2 ratio. In agreement, analysis by Cox proportional hazards models confirmed that high ERBB2d16 expression was a risk factor associated with an adverse prognosis. Thus, our data fit well with an oncogenic role of ERBB2d16 in gastric cancer by promoting EMT and immunosuppression. We also found that ERBB2d16 expression resists gastric cell death in patients treated with trustuzumab, and the ERBB2d16/ERBB2 ratio may serve as a novel prognostic maker for patients with gastric cancer that receive trastuzumab therapy.

人表皮生长因子受体2（ERBB2；旧称HER2）的剪接异构体ERBB2ΔEx16（ERBB2d16）可通过介导上皮间质转化（epithelial-mesenchymal transition, EMT）、免疫逃逸以及对抗曲妥珠单抗（抗HER2靶向治疗）的细胞死亡耐药性发挥致癌作用。然而其在胃癌中的生理病理意义尚不明确。本研究共纳入110例局部晚期或转移性HER2阳性胃癌患者，检测了肿瘤组织中ERBB2d16与上皮间质转化标志物的表达水平，以及CD3+ T细胞的浸润情况，并依据实体瘤疗效评价标准（Response Evaluation Criteria in Solid Tumors, RECIST）评估其与标准化疗联合曲妥珠单抗治疗应答的相关性。研究发现，约半数检测样本（53/110）中ERBB2d16异构体呈相对高表达；ERBB2d16/ERBB2比值升高与高E-钙粘蛋白、低波形蛋白的表达（提示上皮间质转化状态）、CD3+ T细胞浸润减少、肿瘤组织内程序性死亡蛋白1（programmed death 1, PD-1）与程序性死亡配体1（programmed death ligand 1, PD-L1）高表达，以及T细胞受体克隆多样性降低呈正相关。此外，接受曲妥珠单抗治疗的患者中，ERBB2d16/ERBB2比值较高者的无进展生存期与总生存期显著更短。Cox比例风险模型分析进一步证实，高ERBB2d16表达是不良预后的独立危险因素。综上，本研究数据支持ERBB2d16通过促进上皮间质转化与免疫抑制在胃癌中发挥致癌作用。本研究还发现，ERBB2d16的表达可使胃癌细胞对曲妥珠单抗诱导的细胞死亡产生耐药，且ERBB2d16/ERBB2比值有望作为接受曲妥珠单抗治疗的胃癌患者的新型预后标志物。