Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee; Tayside Cancer Centre, Ninewells Hospital and Medical School, NHS Tayside, Dundee.
Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee.
ESMO Open. 2024 May;9(5):103450. doi: 10.1016/j.esmoop.2024.103450. Epub 2024 May 13.
An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA.
Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430).
In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME.
Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours.
需要更好地了解哪些胃食管腺癌（GOA）患者对化疗和免疫检查点抑制剂（ICI）均有反应。我们研究了 44 基因 DNA 损伤免疫反应（DDIR）标志物在晚期 GOA 患者中的预测作用及其潜在生物学机制。
对接受铂类化疗（三个剂量水平）的 252 例 GOA 患者的预处理组织进行了转录谱分析，这些患者均来自随机 III 期 GO2 试验。在具有转录谱、免疫细胞免疫组织化学和表皮生长因子受体（EGFR）荧光原位杂交（FISH）的两个独立 GOA 队列中进行了验证（n=430）。
在 GO2 试验中，DDIR 阳性肿瘤的影像学反应更大（51.7%对 28.5%，P=0.022），且总生存呈剂量依赖性改善（P=0.028）。DDIR 阳性与预处理炎症肿瘤微环境（TME）相关，并且与 ICI 反应相关的生物标志物（如 CD274（程序性死亡配体 1，PD-L1）和微卫星不稳定性 RNA 特征）的表达增加相关。共识途径分析确定 EGFR 是 DDIR 标志物的潜在关键决定因素。EGFR 扩增与 DDIR 阴性和免疫冷 TME 相关。
我们的研究结果表明 GOA TME 在化疗反应中的重要性，以及其与 DNA 损伤修复的关系和 EGFR 作为免疫冷 TME 的可靶向驱动因素。化疗敏感的炎症 GOA 可能会受益于与标准化疗联合使用的 ICI。在 EGFR 扩增的患者中，联合使用 EGFR 抑制剂和 ICI 值得进一步研究。
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