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

项目摘要--项目2 人类乳头瘤病毒阳性(HPV+)口咽癌(OPC)是一个全国性和全球性的健康问题。 由于HPV+OPC具有非常好的生存结果，目前治疗的长期毒性通常 联合化疗和放疗(CRT)是毁灭性的。经口腔机器人手术(TORS)，一种外科手术 由Ferris博士和其他人开创的技术已经被研究用来减少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，随后是根据风险适应的辅助治疗 关于肿瘤和结节病理学。尽管在这项试验中存活良好(ASCO 2020，摘要#6500)，但略有 超过30%的患者被发现患有以结外大体为特征的高危颈部疾病(HRND) 扩展(ENE，&gt；1 mm)或≥5阳性淋巴结，这要求使用佐剂，高剂量CRT，和 以去强化为目标的强化治疗。然而，约70%的患者是应聘者 对于去强化，作为一种策略，人们对Tors仍然很感兴趣，特别是如果HRND患者可以 在手术前被确认。为此，在核心A和核心B的协助下，我们确定了40 ECOG 3311的患者从肝细胞癌(作为最高聚集部位)登记，并综合基因组学， 转录和放射学描绘了他们的肿瘤。这一初步数据使我们产生了四个- 约80%的HRND患者存在基因突变特征，在头部和颈部也有类似的发现 来自癌症基因组图谱的队列。此外，我们在肿瘤中观察到了一种深刻的免疫抑制。 来自HRND患者。在这个项目中，我们将我们的分析扩展到另外200名HPV+OPC患者 已在器官特定数据库(核心A中的OSD)中确定已有组织可供使用(核心B) 然后在ECOG 3311的另外200多个肿瘤中验证我们的签名。此外，我们计划 概括我们签名的突变，以及我们的合作伙伴Burness博士确定的其他突变，这 在临床前模型中，似乎与HPV+OPC中的免疫渗透有关，以确定潜在的驱动因素 免疫渗入。最后，为了解决HRND的管理，我们将进行一项临床试验，HCC18-034 (PI：Ferris)是为这个孢子项目设计的，研究了Tors、低剂量RT和抗PD- 1与放化疗相比，HRND患者的毒性和生活质量均有改善 根据评审员的反馈和ECOG 3311新增控制臂。肿瘤突变的影响， 在这项试验中，还将检查免疫渗透和外周血干扰素签名对结果的影响。 该项目的成功将产生：1)有效且立即适用的预测性签名 HRND；2)对HRND所见免疫浸润性抑制的解释；3)生活质量/毒性 HRND中一项新的去强化试验的比较和生物学相关性。

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.