Project 2: Optimizing patient selection and deintensified therapy for human papillomavirus positive (HPV+) oropharyngeal cancer (OPC)

项目概要-项目2 人乳头瘤病毒阳性（HPV+）口咽癌（OPC）是一个国家和全球性的健康问题。 由于HPV+ OPC具有非常好的生存结局，因此目前治疗的长期毒性， 联合化疗和放疗（CRT）是毁灭性的。经口腔机器人手术（TORS），一种 Ferris博士和其他人开创的技术已经被研究用于降低HPV+ OPC治疗的毒性， 在ECOG 3311中达到高潮，这是一项TORS的前瞻性试验，随后进行风险适应性辅助治疗， 肿瘤和淋巴结病理学尽管本试验（ASCO 2020，摘要#6500）的生存率很高，但 超过30%的患者被发现患有高危颈部疾病（HRND），其特征在于大体结节性病变， 延伸（ENE，> 1 mm）或≥5个阳性淋巴结，要求使用辅助、高剂量CRT， 强化治疗，其中去强化是目标。然而，由于约70%的患者是候选人， 对于去强化，TORS作为一种策略的兴趣仍然很高，特别是如果HRND患者可以 手术前确认。为此，在核心A和核心B的协助下，我们确定了40个 从HCC（作为最高累积部位）入组的ECOG 3311患者， 转录组学和放射组学分析了他们的肿瘤。这些初步数据使我们能够生成一个四- 约80%的HRND患者存在基因突变特征，头颈部也有类似的发现。 癌症基因组图谱中的队列。此外，我们观察到肿瘤中存在严重的免疫抑制， 来自HRND患者。在本项目中，我们将分析扩展到另外200例HPV+ OPC患者， 已在器官特异性数据库（核心A中的OSD）中确定了组织已可用（核心B） 然后在ECOG 3311的200多个其他肿瘤中验证我们的签名。此外，我们计划 概括了我们的签名中的突变，以及我们的共同研究员Burtness博士发现的其他突变， 在临床前模型中，似乎与HPV+ OPC中的免疫浸润相关，以识别潜在的驱动因素 免疫渗透最后，为了解决HRND的管理问题，我们将进行临床试验HCC 18-034 (PI：Ferris）设计用于该SPORE项目，检查TORS、低剂量RT和抗PD的组合。 在HRND患者中，与放化疗相比， 基于审查者反馈以及ECOG 3311，新添加对照组。肿瘤突变的影响， 免疫浸润和外周血IFN信号对本试验结果也将进行检查。 该项目的成功将产生：1）一个有效的和立即适用的预测签名， HRND; 2）HRND中观察到的免疫浸润抑制的解释; 3）生活质量/毒性 比较和生物学相关性来自一项新的HRND去强化试验。

PROJECT SUMMARY – PROJECT 2 Human papillomavirus positive (HPV+) oropharynx cancer (OPC) is a national and global health issue. Because HPV+ OPC has very good survival outcomes, the long-term toxicity of current treatment, typically combined chemotherapy and radiation (CRT) is devastating. Trans-oral robotic surgery (TORS), a surgical technique pioneered by Dr. Ferris and others, has been studied to reduce toxicity of HPV+ OPC treatment, culminating in ECOG 3311, a prospective trial of TORS followed by risk-adapted adjuvant therapy depending on tumor and nodal pathology. Despite excellent survival in this trial (ASCO 2020, Abstract #6500), slightly over 30% of patients were found to have high risk neck disease (HRND), characterized by gross extranodal extension (ENE, >1mm) or ≥5 positive lymph nodes, which mandated the use of adjuvant, high dose CRT, an intensification of treatment where de-intensification is the goal. However, as ~70% of patients were candidates for de-intensification, interest remains high in TORS as a strategy, particularly if patients with HRND can be identified prior to surgery. To this end, and with the assistance of Core A and Core B we have identified 40 patients from ECOG 3311 enrolled from HCC (as the highest accruing site) and comprehensively genomically, transcriptomically and radiomically profiled their tumors. This preliminary data allowed us to generate a four- gene mutational signature present in ~80% of patients with HRND, with similar findings in the Head and Neck cohort from the Cancer Genome Atlas. Additionally, we observed a profound immune repression in tumors from patients with HRND. In this Project we expand our analysis to an additional 200 HPV+ OPC patients we have identified in the organ specific database (OSD in Core A) for which tissue is already available (Core B) and then validate our signature in over 200 additional tumors from ECOG 3311. Additionally, we plan to recapitulate the mutations from our signature, as well as others identified by our co-I Dr. Burtness, which appear to be associated with immune infiltrate in HPV+ OPC, in pre-clinical models to identify potential drivers of immune infiltrate. Finally, to address the management of HRND, we will conduct a clinical trial HCC 18-034 (PI: Ferris) designed for this SPORE project examining the combination of TORS, lower dose RT and anti-PD- 1 therapy in patients with HRND to improve toxicity and quality of life compared to chemoradiation in both a newly added control arm based on reviewer feedback as well as ECOG 3311. The effect of tumor mutation, immune infiltrate, and peripheral blood IFN signature on outcome in this trial will also be examined. Success of this project will produce: 1) a validated and immediately applicable predictive signature for HRND; 2) an explanation for the repressed immune infiltrate seen with HRND; 3) quality of life/toxicity comparisons and biologic correlatives from a novel deintensification trial in HRND.