食管胃癌双重 Erb B 抑制 (DEBIOC) 试验报告了新辅助奥沙利铂和卡培他滨 (Xelox) ± AZD8931 在食管腺癌 (OAC) 中的安全性可接受，但疗效有限。我们使用独特的软件驱动解决方案评估了新辅助 Xelox ± AZD8931（一种对表皮生长因子受体 (EGFR)、人表皮生长因子受体 (HER)2 和 HER3 具有等效活性的新型小分子抑制剂）对生物途径的影响使用 Almac claraT 总 mRNA 报告分析，对 25 个治疗前福尔马林固定石蜡包埋的 OAC 活检样本和 18 个匹配的切除样本进行转录组分析，这些样本分别用 Xelox AZD8931 (n = 16) 和单独 Xelox (n = 9) 处理92 个基因特征、100 个独特的单基因药物靶点和 10 个癌症标志的 7337 个单基因。基因集富集分析（GSEA）用于研究控制病理反应的途径。使用 QuPath 软件对肿瘤浸润淋巴细胞 (TIL) 进行数字化评估。分层聚类确定了根据先天免疫信号激活进行分类的三个分子亚组。免疫高亚组与新辅助治疗后 HER2 阳性、病理反应增加以及免疫信号和 TIL 显着减少相关。免疫低簇主要是 HER2/EGFR 阴性，EGFR 阳性与免疫混合亚组相关。新辅助疗法诱导了常见的耐药机制，例如血管生成和上皮间质转化信号传导，以及 DNA 修复特征的减少。添加 AZD8931 与 EGFR、HER2 和 AKT 通路表达的减少相关，并且还促进免疫抑制微环境。 GSEA 显示，对治疗有病理反应的患者免疫信号增强，而对新辅助治疗无反应的患者通过 E2F 转录因子的作用，核苷酸修复和细胞生长得到丰富。OAC 可分为三个免疫相关亚组针对新辅助治疗的调节，显着抑制 HER2 阳性/免疫高肿瘤中的免疫微环境。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

The Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC) trial reported an acceptable safety profile for neoadjuvant oxaliplatin and capecitabine (Xelox) ± AZD8931 in oesophageal adenocarcinoma (OAC) but limited efficacy. We evaluated the impact of neoadjuvant Xelox ± AZD8931, a novel small-molecule inhibitor with equipotent activity against epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2 and HER3, on biological pathways using a unique software-driven solution.Transcriptomic profiles from 25 pre-treatment formalin-fixed paraffin-embedded OAC biopsies and 18 matched resection specimens, treated with Xelox + AZD8931 (n = 16) and Xelox alone (n = 9), were analysed using the Almac claraT total mRNA report analysing 92 gene signatures, 100 unique single-gene drug targets and 7337 single genes across 10 hallmarks of cancer. Gene-set enrichment analysis (GSEA) was utilised to investigate pathways governing pathological response. Tumour-infiltrating lymphocytes (TILs) were assessed digitally using the QuPath software.Hierarchical clustering identified three molecular subgroups classified by activation of innate immune signalling. The immune-high subgroup was associated with HER2 positivity, increased pathological response and a marked reduction in immune signalling and TILs following neoadjuvant therapy. The immune-low cluster was predominantly HER2/EGFR-negative, and EGFR positivity was associated with the immune-mixed subgroup. Treatment with neoadjuvant therapy induced common resistance mechanisms, such as angiogenesis and epithelial-mesenchymal transition signalling, and a reduction in DNA repair signatures. Addition of AZD8931 was associated with reduction of expression of EGFR, HER2 and AKT pathways and also promoted an immunosuppressive microenvironment. GSEA showed that patients with a pathological response to treatment had increased immune signalling, whereas non-responders to neoadjuvant therapy were enriched for nucleotide repair and cellular growth through the action of E2F transcription factors.OAC may be subdivided into three immune-related subgroups which undergo modulation in response to neoadjuvant therapy with marked suppression of the immune microenvironment in HER2-positive/immune-high tumours.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.