Observational study to validate circulating HPVDNA and prognostic genomic biomarkers for diagnosis and treatment of HPV-associated OPSCC

验证循环 HPVDNA 和预后基因组生物标志物用于诊断和治疗 HPV 相关 OPSCC 的观察性研究

• 批准号: 10197101
• 负责人: Natalia Issaeva
• 金额: $ 76.15万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10197101
• 关键词: Adoption; Aftercare; Biological Assay; Biological Markers; Cancer Center; Cancer Control; Cancer Detection; Case-Control Studies; Characteristics; Cisplatin; Clinic; Clinical; Clinical Treatment; Clinical Trials; Community Clinical Oncology Program; Defect; Detection; Diagnosis; Disease; Early Diagnosis; Early Intervention; Enrollment; Epidemic; Face; Gene Mutation; General Population; Genes; Genome; Head and neck structure; High Prevalence; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Incidence; Individual; Knowledge; Lead; Longevity; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measures; Methods; Monitor; Morbidity - disease rate; Mutation; Newly Diagnosed; Nodal; Non-Malignant; Observational Study; Oncogenic; Operative Surgical Procedures; Oropharyngeal Squamous Cell Carcinoma; Outcome; Patient Care; Patients; Physicians; Plasma; Predictive Value; Prognostic Marker; Progression-Free Survivals; Radiation; Radiation Dose Unit; Recurrence; Recurrent disease; Research Design; Risk; Risk Factors; Salvage Therapy; Sampling; Screening for cancer; Screening procedure; Sensitivity and Specificity; Smoking History; Specificity; TNF receptor-associated factor 3; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Trials; Time; Tumor Tissue; United States; University of Texas M D Anderson Cancer Center; Validation; Virus Integration; aged; aggressive therapy; base; cancer recurrence; cervical and uterine cancer; chemotherapy; clinical Diagnosis; clinical care; cohort; detection assay; digital; epidemiological model; follow-up; genomic biomarker; high risk; improved; men; novel; novel marker; novel therapeutics; oral HPV; oral HPV infection; oral infection; outcome prediction; personalized care; personalized medicine; personalized screening; personalized therapeutic; predicting response; prevent; prognostic; prognostic assays; prospective; screening; sexually active; side effect; surveillance strategy; tool; treatment response; tumor; validation studies; viral DNA

The incidence of HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC) has rapidly increased over the last two decades surpassing uterine cervical cancer as the most frequently diagnosed HPV-associated cancer in the United States by 2012. This “epidemic” is expected to continue through 2060. Patients are typically diagnosed with metastatic nodal disease treated with high dose radiation with concurrent cisplatin. This treatment was not designed for HPV+ OPSCC but was based on results of trials of therapeutic escalation for HPV-negative cancers. This aggressive treatment results in lifelong morbidity, and side effects of therapy may also shorten lifespan. For the approximately 25% of these patients who will recur, late identification of recurrence limits salvage options for a portion. Early detection of initial disease and recurrences would allow less morbid therapy that may also increase survival. The head and neck oncology community has recently focused on personalization of therapy for HPV+ OPSCC, in particular on therapeutic de-intensification. The major stumbling block that is preventing widespread adoption of these therapeutic strategies is inability to identify patients at low risk of recurrence who are appropriate for less intensive therapy. Our group identified and piloted prognostic biomarkers and an assay for detection of treatment response and for early detection of initial or recurrent HPV+ OPSCC. The prognostic biomarker is based on deletion or mutations of TRAF3 or CYLD in tumors. Analysis of the TCGA cohort revealed that survival of HPV+ OPSCC patients with TRAF or CYLD defects was significantly better than those whose tumors lacked defects. Remarkably, HPV+ OPSCC tumors lacking TRAF3 or CYLD defects had survival that was indistinguishable from HPV-negative patients, suggesting that the improved survival in HPV+ OPSCC is largely attributable to the subset with these mutations. We also have piloted detection of circulating HPVDNA using ultrasensitive digital PCR as a measure of treatment response, predictor of recurrence, and for early detection of recurrent disease. These assays that we piloted for prognostication, as well as treatment response and early detection of initial or recurrent HPV+ OPSCC require validation before they will be clinically useful. Here we propose to partner with MD Anderson Cancer Center to leverage an ongoing trial and use detection of circulating HPVDNA to distinguish patients with oral HPV infection from those with early HPV+ OPSCC. We will also conduct a prospective observational clinical trial to validate TRAF3 and CYLD mutations as prognostic biomarkers and validate detection of circulating plasma HPVDNA for early detection of recurrent HPV+ OPSCC. Validation of prognostic biomarkers will aid appropriate selection of HPV+ OPSCC patients for de-intensified therapy while also identifying those who need aggressive or novel therapies to improve survival. Validation of a tool for prediction of response and early detection of recurrence will also change practice by identifying patients who are at increased risk of recurrence for heightened surveillance or early intervention.

HPV 相关口咽鳞状细胞癌 (HPV+ OPSCC) 的发病率 近二十年来增长迅速，超过宫颈癌成为最常见的癌症 到 2012 年，美国频繁诊断出 HPV 相关癌症。这种“流行病”是 预计将持续到 2060 年。患者通常被诊断患有转移性淋巴结疾病 接受高剂量放射治疗并同时使用顺铂。这种治疗不适用于。 HPV+ OPSCC，但基于 HPV 阴性的治疗升级试验结果 这种积极的治疗会导致终生发病，并且治疗可能会产生副作用。 大约 25% 的患者会在晚期复发。 复发的识别限制了部分初始疾病的早期发现。 复发可以减少病态治疗，也可能提高生存率。 颈部肿瘤学界最近关注 HPV+ OPSCC 的个性化治疗， 特别是在治疗去强化方面，这是阻碍的主要障碍。 这些治疗策略的广泛采用无法识别低风险患者 复发者适合强度较低的治疗。 我们的小组确定并试点了预后生物标志物和检测治疗的测定法 反应以及早期检测初始或复发 HPV+ OPSCC 的预后生物标志物。 基于肿瘤中 TRAF3 或 CYLD 的缺失或突变的 TCGA 队列分析。 研究表明，具有 TRAF 或 CYLD 缺陷的 HPV+ OPSCC 患者的生存率显着提高 值得注意的是，HPV+ OPSCC 肿瘤缺乏缺陷。 TRAF3 或 CYLD 缺陷患者的生存率与 HPV 阴性患者没有区别， 表明 HPV+ OPSCC 的生存率提高很大程度上归因于具有以下特征的子集： 我们还使用超灵敏数字技术对循环 HPVDNA 进行了试点检测。 PCR 作为治疗反应的衡量标准、复发的预测因子以及早期检测 疾病反复发作。 我们试验的这些检测用于预测、治疗反应和早期治疗 初次或复发性 HPV+ OPSCC 的检测需要经过验证才能用于临床。 在这里，我们建议与 MD 安德森癌症中心合作，利用正在进行的试验和 使用循环 HPVDNA 检测来区分口腔 HPV 感染患者和口腔 HPV 感染患者 我们还将进行一项前瞻性观察性临床试验来验证早期 HPV+ OPSCC。 TRAF3 和 CYLD 突变作为预后生物标志物并验证循环检测 血浆 HPVDNA 用于早期检测复发性 HPV+ OPSCC 的预后验证。 生物标志物将有助于适当选择 HPV+ OPSCC 患者进行去强化治疗，同时 还包括那些需要积极或寻找新疗法来提高生存率的患者。 预测反应和早期检测复发的工具也将改变实践 因哮喘监测或早期发现复发风险较高的患者 干涉。