Khanna Suchin, Palackdharry Sarah, Roof Logan, Wicker Christina A, Mark Jonathan, Zhu Zheng, Jandorav Roman, Molinolo Alfredo, Takiar Vinita, Wise-Draper Trisha M
Division of Hematology/Oncology, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street WWW 201 Attn: Suchin Khanna, New Haven, CT 06510 USA.
Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH USA.
Cancers Head Neck. 2020 Sep 9;5:11. doi: 10.1186/s41199-020-00058-2. eCollection 2020.
Human papillomavirus (HPV) associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than HNSCC due to other risk factors. However, there is significant heterogeneity within HPV-associated HNSCC and 25% of these patients still do poorly despite receiving aggressive therapy. We currently have no good molecular tools to differentiate and exclude this "high-risk" sub-population and focus on "low-risk" patients for clinical trials. This has been a potential barrier to identifying successful de-escalation treatment strategies in HPV-associated HNSCC. We conducted an analysis of molecular markers with a well-known role in the pathogenesis of HPV-associated HNSCC and hypothesized that these markers could help independently predict recurrence and prognosis in these patients and therefore help identify at the molecular level "low-risk" patients suitable for de-escalation trials.
We analyzed 24 tumor specimens of patients with p16+ HNSCC who underwent definitive resection as primary treatment. Tissue microarray (TMA) was generated from the 24 pathology blocks and immunohistochemistry (IHC) was performed using highly specific antibodies for our chosen biomarkers (PI3K-PTEN, AKT pathway, mTOR, 4EBP1, S6, and pAMPK, ERCC-1). Transcriptome data was also obtained for 7 p16+ HNSCC patients from The Cancer Genome Atlas (TCGA). Data from the TMA and TCGA were analyzed for association of relapse-free survival (RFS) and overall survival (OS) with protein and gene expression of the chosen biomarkers.
Increased pAMPK protein activity by IHC and AMPK gene expression by TCGA gene expression data was correlated with improved RFS with a trend towards statistical significance.
This data suggests that increased pAMPK activity and expression may portend a better prognosis in HPV-associated HNSCC undergoing primary definitive resection. However, these findings require validation in larger studies.
人乳头瘤病毒（HPV）相关的头颈部鳞状细胞癌（HNSCC）比由其他风险因素导致的HNSCC预后更好。然而，HPV相关的HNSCC存在显著的异质性，尽管接受了积极治疗，仍有25%的此类患者预后较差。目前我们没有良好的分子工具来区分和排除这一“高危”亚群，而是将重点放在“低危”患者上进行临床试验。这已成为在HPV相关的HNSCC中确定成功的降阶梯治疗策略的潜在障碍。我们对在HPV相关的HNSCC发病机制中具有重要作用的分子标志物进行了分析，并假设这些标志物可独立预测这些患者的复发和预后，从而有助于在分子水平上识别适合降阶梯试验的“低危”患者。
我们分析了24例接受根治性切除作为主要治疗的p16 + HNSCC患者的肿瘤标本。从24个病理切片制作组织微阵列（TMA），并使用针对我们所选生物标志物（PI3K - PTEN、AKT通路、mTOR、4EBP1、S6和pAMPK、ERCC - 1）的高特异性抗体进行免疫组织化学（IHC）检测。还从癌症基因组图谱（TCGA）获得了7例p16 + HNSCC患者的转录组数据。分析TMA和TCGA的数据，以确定无复发生存期（RFS）和总生存期（OS）与所选生物标志物的蛋白质和基因表达之间的关联。
通过IHC检测到的pAMPK蛋白活性增加以及通过TCGA基因表达数据检测到的AMPK基因表达增加与改善的RFS相关，具有统计学意义的趋势。
这些数据表明，pAMPK活性和表达增加可能预示着接受原发性根治性切除的HPV相关HNSCC患者预后较好。然而，这些发现需要在更大规模的研究中进行验证。
