Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
ETOP Statistical Office, Frontier Science Foundation-Hellas, Athens, Greece.
Mod Pathol. 2022 Dec;35(12):1888-1899. doi: 10.1038/s41379-022-01145-0. Epub 2022 Sep 17.
Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p < 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies.
胸膜间皮瘤（PM）是一种侵袭性恶性肿瘤，预后不良。虽然组织学和病理分期是重要的预后因素，但需要更好的预后生物标志物。核糖体蛋白 S6 是参与蛋白质合成和细胞增殖的磷脂酰肌醇 3-激酶（PI3K）途径的下游靶标。在以前的研究中，PM 患者中低磷酸化 S6（pS6）免疫反应性与更长的无进展生存期（PFS）和总生存期（OS）显著相关。我们旨在通过欧洲胸肿瘤学平台（ETOP）Mesoscape 项目的一部分，将 pS6 表达与大型多中心 PM 队列的临床数据相关联。构建了胸膜间皮瘤组织微阵列（TMA），并通过半定量聚集 H 评分评估 pS6 的表达。表达结果与患者特征以及 OS/PFS 相关。来自 9 个中心的 364 名诊断为 1999 年至 2017 年之间的患者的 pS6 IHC 结果可用。包括肿瘤的主要组织学为上皮样（70.3％），其次为双相性（24.2％）和肉瘤样（5.5％）。TMA 既包括未经治疗的肿瘤组织，也包括诱导化疗后采集的肿瘤组织。高 pS6 表达（H 评分>1.41 的 181 例患者）与不完全切除明显相关。在整个队列中，pS6-低和 pS6-高患者的 OS/PFS 无显著差异。在亚组分析中，高 pS6 表达的非上皮样（双相和肉瘤样）患者的 OS（p<0.001，10.7 与 16.9 个月）和 PFS（p<0.001，6.2 与 10.8 个月）明显缩短。在亚组分析中，在非上皮样 PM 患者中，高 pS6 表达与 OS 和 PFS 明显缩短相关。这些探索性发现表明非上皮样 PM 中存在临床相关的 PI3K 途径激活，这可能为未来的靶向治疗策略奠定基础。
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