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

项目 2：优化人乳头瘤病毒阳性 (HPV) 口咽癌 (OPC) 的患者选择和去强化治疗

• 批准号: 10704509
• 负责人: Heath Devin Skinner
• 金额: $ 35.09万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704509
• 关键词: Address; Adjuvant; Adjuvant Therapy; American Society of Clinical Oncology; Biological; Cancer Center; Cancer Model; Cancer Patient; Chemotherapy and/or radiation; Cisplatin; Clinical; Clinical Trials; Combination Drug Therapy; Coupled; Data; Databases; Disease; Eastern Cooperative Oncology Group; Enrollment; Excision; Extranodal; Feedback; Flow Cytometry; Gene Expression; Gene Mutation; Genes; Genomics; Goals; HPV oropharyngeal cancer; Head and Neck Cancer; Head and neck structure; High Dose Chemotherapy; Human Papilloma Virus-Related Malignant Neoplasm; Image; Immune; Immunotherapy; Interferons; Knock-out; Letters; Low Dose Radiation; Malignant Neoplasms; Mediating; Methods; Modality; Mutation; Mutation Analysis; Neck; Neck Disorder; Nivolumab; Nodal; Operative Surgical Procedures; Oral; Organ; Outcome; PD-1 blockade; Pathology; Pathway interactions; Patient Selection; Patients; Positive Lymph Node; Postoperative Period; Pre-Clinical Model; Primary Neoplasm; Prognosis; Protocols documentation; Quality of life; Radiation Dose Unit; Radiation therapy; Randomized; Reporting; Repression; Resected; Risk; Robotics; Sampling; Scanning; Signal Transduction; Site; TNF receptor-associated factor 3; Techniques; The Cancer Genome Atlas; Therapeutic; Tissues; Toxic effect; Treatment-related toxicity; United States; Work; X-Ray Computed Tomography; anti-PD-1; anti-PD1 therapy; arm; cancer therapy; chemoradiation; clinic ready; clinically significant; cohort; design; exome sequencing; genetic signature; global health; high risk; human papilloma virus oropharyngeal squamous cell carcinoma; immune cell infiltrate; improved; in vivo; interest; lymph nodes; malignant oropharynx neoplasm; novel; participant enrollment; peripheral blood; precision oncology; predictive signature; prospective; radiomics; randomized, clinical trials; success; survival outcome; synergism; transcriptome sequencing; transcriptomics; tumor; tumor growth

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.

项目摘要 – 项目 2 人乳头瘤病毒阳性 (HPV+) 口咽癌 (OPC) 是一个国家和全球健康问题。 由于 HPV+ OPC 具有非常好的生存结果，因此当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）是一种外科手术 Ferris 博士等人首创的技术已被研究用于降低 HPV+ OPC 治疗的毒性， ECOG 3311 是一项 TORS 前瞻性试验，随后根据情况进行风险适应辅助治疗 关于肿瘤和淋巴结病理学。尽管在本次试验中生存率极好（ASCO 2020，摘要#6500），但 超过 30% 的患者被发现患有高危颈部疾病 (HRND)，其特征是肉眼可见的结外病变 扩展（ENE，>1mm）或≥5个阳性淋巴结，这要求使用辅助、高剂量CRT、 以去强化为目标的强化治疗。然而，由于约 70% 的患者是候选者 对于去强化治疗，TORS 作为一种策略仍然很受关注，特别是如果 HRND 患者可以 术前确定。为此，在核心 A 和核心 B 的帮助下，我们确定了 40 来自 ECOG 3311 的患者从 HCC（作为最高累积位点）入组，并进行了全面的基因组分析， 从转录组学和放射学角度分析了他们的肿瘤。这些初步数据使我们能够生成四个 约 80% 的 HRND 患者存在基因突变特征，头颈部也有类似的发现 来自癌症基因组图谱的队列。此外，我们观察到肿瘤中存在深刻的免疫抑制 来自 HRND 患者。在这个项目中，我们将分析范围扩大到另外 200 名 HPV+ OPC 患者 已在器官特异性数据库（核心 A 中的 OSD）中确定了哪些组织已经可用（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 重述我们签名中的突变，以及我们的同事 Burtness 博士发现的其他突变，其中 在临床前模型中，似乎与 HPV+ OPC 中的免疫浸润有关，以识别潜在的驱动因素 的免疫浸润。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）专为 SPORE 项目设计，检查 TORS、低剂量 RT 和抗 PD 的组合 与放化疗相比，HRND 患者的 1 种疗法可改善毒性和生活质量 根据审稿人反馈以及 ECOG 3311 新添加的控制臂。肿瘤突变的影响， 还将检查免疫浸润和外周血干扰素特征对本试验结果的影响。 该项目的成功将产生：1）经过验证且立即适用的预测签名 HRND； 2) 对 HRND 中观察到的抑制免疫浸润的解释； 3) 生活质量/毒性 HRND 中一项新型去强化试验的比较和生物学相关性。