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: 10458612
• 负责人: Natalia Issaeva
• 金额: $ 74.13万
• 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/10458612
• 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 care; clinical diagnosis; 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; prognostication; 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 在过去的二十年里，宫颈癌的发病率迅速上升，超过了宫颈癌，成为世界上最严重的宫颈癌。 到2012年，在美国经常诊断出HPV相关癌症。这场“疫情”是 预计将持续到2060年患者通常被诊断为转移性淋巴结疾病 用高剂量放疗同时用顺铂治疗。这种治疗不是为 HPV+ OPSCC，但基于HPV阴性患者治疗递增试验的结果 癌的这种积极的治疗导致终身发病率，治疗的副作用可能 也会缩短寿命。对于大约25%的这些患者谁会复发，晚 复发的识别限制了部分的挽救选择。早期发现初始疾病 并且复发将允许较少的病态治疗，这也可能增加存活率。头部和 颈部肿瘤学界最近关注HPV+ OPSCC的个性化治疗， 特别是在治疗性去强化方面。阻碍我们发展的主要障碍 这些治疗策略的广泛采用不能识别低风险的患者， 复发者适合接受强度较低的治疗。 我们的研究小组确定并试验了预后生物标志物和检测治疗的方法。 早期检测初始或复发的HPV+ OPSCC。预后生物标志物 基于肿瘤中TRAF3或CYLD的缺失或突变。TCGA队列分析 发现TRAF或CYLD缺陷的HPV+ OPSCC患者的生存率显著高于 比那些肿瘤没有缺陷的人更好。值得注意的是，HPV+ OPSCC肿瘤缺乏 TRAF3或CYLD缺陷患者的生存率与HPV阴性患者的生存率无法区分， 提示HPV+ OPSCC的生存率改善主要归因于以下亚组： 这些突变。我们还使用超灵敏的数字成像技术对循环HPVDNA进行了试点检测， PCR作为治疗反应的测量、复发的预测因子以及用于早期检测 复发性疾病 这些试验，我们试点的示范，以及治疗反应和早期 初始或复发性HPV+ OPSCC的检测在临床上有用之前需要验证。 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， 使用循环HPVDNA检测来区分口腔HPV感染的患者和 早期HPV+ OPSCC我们还将进行一项前瞻性观察性临床试验， TRAF3和CYLD突变作为预后生物标志物并验证循环 血浆HPVDNA用于复发性HPV+ OPSCC的早期检测。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， 同时也确定那些需要积极或新的治疗方法来提高生存率的患者。的验证 一种预测缓解和早期发现复发的工具也将改变实践， 识别复发风险增加的患者，以加强监测或早期 干预