Angerilli Valentina, Callegarin Matilde, Govoni Ilaria, De Lisi Giuseppe, Paudice Michele, Fugazzola Paola, Vanoli Alessandro, Parente Paola, Bergamo Francesca, Luchini Claudio, Dei Tos Angelo Paolo, Grillo Federica, Lonardi Sara, Mastracci Luca, Spolverato Gaya, Fassan Matteo
Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, via Gabelli 61, 35121, Padua, Italy.
ULSS2 Marca Trevigiana, Treviso, Italy.
Gastric Cancer. 2025 Apr 9. doi: 10.1007/s10120-025-01609-7.
Temporal and spatial molecular heterogeneity contributes to resistance to targeted and immune therapies in gastric and esophagogastric junction carcinoma (G/EGJ). This study evaluates differences in biomarker expression between primary G/EGJ and paired peritoneal metastases (PM).
We analyzed 74 cases of primary G/EGJ and paired PM using immunohistochemistry for HER2, PD-L1, Claudin18 (CLDN18), DNA mismatch repair (MMR) proteins, p53, E-cadherin, and in situ hybridization for EBER. Biomarker concordance between primary and metastatic tumors was assessed.
Primary G/EGJ were predominantly poorly cohesive (45.9%) or mixed-type (37.8%). Regarding predictive biomarkers, low rates of HER2 overexpression (5.4%), MMR deficiency (4.1%), and EBER positivity (1.4%) were observed, while PD-L1 CPS ≥ 1 occurred in 79.7% of cases and CLDN18 positivity was observed in 31.1% of cases. Concordance was perfect for MMR and EBER, while PD-L1 showed the highest discordance (32.4%). HER2 had a low discordance rate (2.7%). CLDN18 exhibited good concordance (86.5%) and showed consistent positivity in PD-L1- and HER2-negative primary tumors (28.6%).
G/EGJ with PM show distinct molecular features and spatial heterogeneity, with MMR, EBER, and HER2 demonstrating strong concordance, while PD-L1 showed greater variability. As for novel biomarkers, CLDN18.2 shows substantial concordance between primary G/EGJ and PM and could be a promising target in HER2/PD-L1-negative G/EGJ with PM.
时空分子异质性导致胃和食管胃交界癌（G/EGJ）对靶向治疗和免疫治疗产生耐药性。本研究评估原发性G/EGJ与配对腹膜转移瘤（PM）之间生物标志物表达的差异。
我们对74例原发性G/EGJ及其配对的PM进行分析，采用免疫组化检测HER2、PD-L1、Claudin18（CLDN18）、DNA错配修复（MMR）蛋白、p53、E-钙黏蛋白，并采用原位杂交检测EBER。评估原发性肿瘤与转移瘤之间生物标志物的一致性。
原发性G/EGJ主要为低黏附性（45.9%）或混合型（37.8%）。关于预测性生物标志物，HER2过表达率低（5.4%）、MMR缺陷率低（4.1%）、EBER阳性率低（1.4%），而79.7%的病例PD-L1 CPS≥1，31.1%的病例CLDN18阳性。MMR和EBER的一致性完美，而PD-L1的不一致性最高（32.4%）。HER2的不一致率低（2.7%）。CLDN18表现出良好的一致性（86.5%），在PD-L1和HER2阴性的原发性肿瘤中呈一致阳性（28.6%）。
伴有PM的G/EGJ表现出独特的分子特征和空间异质性，MMR、EBER和HER2表现出高度一致性，而PD-L1表现出更大的变异性。至于新型生物标志物，CLDN18.2在原发性G/EGJ与PM之间表现出高度一致性，可能是伴有PM的HER2/PD-L1阴性G/EGJ中有前景的靶点。
