Department of Pathology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands.
Department of Oral and Maxillofacial Surgery, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands.
Head Neck Pathol. 2023 Sep;17(3):697-707. doi: 10.1007/s12105-023-01576-4. Epub 2023 Jul 24.
Survival rates of head and neck squamous cell carcinoma (HNSCC) have only marginally improved in the last decades. Hence there is a need for predictive biomarkers for long-time survival that can help to guide treatment decisions and might lead to the development of new therapies. The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway is the most frequently altered pathway in HNSCC, genes are often mutated, amplificated and overexpressed causing aberrant signaling affecting cell growth and differentiation. Numerous genetic alterations of upstream and downstream factors have currently been clarified. However, their predictive value has yet to be established. Therefore we assess the predictive value of p-mTOR, p-ERK and PTEN expression.
Tissue microarrays (TMA's) of HPV-negative patients with oropharyngeal (n = 48), hypopharyngeal (n = 16) or laryngeal (n = 13) SCC, treated with primary chemoradiation (cisplatin/carboplatin/cetuximab and radiotherapy), were histologically stained for p-mTOR, PTEN and p-ERK. Expression was correlated to overall survival (OS), disease free survival (DFS) and locoregional control (LRC). Also p-mTOR was histologically stained in a separate cohort of HNSCC organoids (n = 8) and correlated to mTOR-inhibitor everolimus response.
High p-mTOR expression correlated significantly with worse OS in multivariate analysis in the whole patient cohort [Hazar Ratio (HR) 1.06, 95%CI 1.01-1.11, p = 0.03] and in the cisplatin/carboplatin group with both worse OS (HR 1.09, 95%CI 1.02-1.16, p = 0.02) and DFS (HR 1.06, 95%CI 1.00-1.12, p = 0,04). p-ERK expression correlated significantly with DFS in univariate analysis in the whole patient cohort (HR 1.03, 95%CI 1.00-1.05, p = 0.04) and cisplatin/carboplatin group (HR 1.03, 95%CI 1.00-1.07, p = 0.04). PTEN-expression did not correlate with OS/DFS/LRC. Better organoid response to everolimus correlated significantly to higher p-mTOR expression (Rs = - 0.731, p = 0.04).
High p-mTOR expression predicts and high p-ERK expression tends to predict worse treatment outcome in HPV negative HNSCC patients treated with chemoradiation, providing additional evidence that these markers are candidate prognostic biomarkers for survival in this patient population. Also this study shows that the use of HNSCC organoids for biomarker research has potential. The role of PTEN expression as prognostic biomarker remains unclear, as consistent evidence on its prognostic and predictive value is lacking.
过去几十年，头颈部鳞状细胞癌（HNSCC）的生存率仅略有提高。因此，需要预测长期生存的生物标志物，以帮助指导治疗决策，并可能导致新疗法的发展。磷脂酰肌醇 3-激酶（PI3K）/AKT/mTOR 信号通路是 HNSCC 中最常改变的通路，基因经常发生突变、扩增和过表达，导致异常信号影响细胞生长和分化。目前已经阐明了许多上游和下游因子的遗传改变。然而，它们的预测价值尚未建立。因此，我们评估了 p-mTOR、p-ERK 和 PTEN 表达的预测价值。
对接受顺铂/卡铂/西妥昔单抗和放疗的 HPV 阴性口咽（n=48）、下咽（n=16）或喉（n=13）SCC 患者的组织微阵列（TMA）进行组织学染色，以检测 p-mTOR、PTEN 和 p-ERK。表达与总生存（OS）、无病生存（DFS）和局部区域控制（LRC）相关。此外，在另一组 HNSCC 类器官（n=8）中对 p-mTOR 进行了组织学染色，并与 mTOR 抑制剂依维莫司的反应相关联。
多变量分析显示，高 p-mTOR 表达与整个患者队列的 OS 显著相关[风险比（HR）1.06，95%CI 1.01-1.11，p=0.03]，在顺铂/卡铂组，OS 和 DFS 均较差[HR 1.09，95%CI 1.02-1.16，p=0.02]和 DFS（HR 1.06，95%CI 1.00-1.12，p=0.04）。p-ERK 表达在整个患者队列的单变量分析中与 DFS 显著相关（HR 1.03，95%CI 1.00-1.05，p=0.04）和顺铂/卡铂组（HR 1.03，95%CI 1.00-1.07，p=0.04）。PTEN 表达与 OS/DFS/LRC 无相关性。对依维莫司的更好的类器官反应与更高的 p-mTOR 表达显著相关（Rs=-0.731，p=0.04）。
高 p-mTOR 表达可预测 HPV 阴性 HNSCC 患者接受放化疗后的治疗结果较差，高 p-ERK 表达则倾向于预测治疗结果较差，为这些标志物作为该患者群体生存的候选预后生物标志物提供了额外证据。此外，本研究还表明，使用 HNSCC 类器官进行生物标志物研究具有潜力。PTEN 表达作为预后生物标志物的作用尚不清楚，因为缺乏其预后和预测价值的一致性证据。
