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: 10615775
• 负责人: Natalia Issaeva
• 金额: $ 73.56万
• 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/10615775
• 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; DNA; 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; Institution; 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 Malignant Neoplasm; Recurrent disease; Research Design; Risk; Risk Factors; Salvage Therapy; Sampling; Screening for cancer; Screening procedure; Sensitivity and Specificity; Smoking History; Specific qualifier value; Specificity; TNF receptor-associated factor 3; Testing; The Cancer Genome Atlas; Therapeutic; Time; Tumor Tissue; United States; University of Texas M D Anderson Cancer Center; Validation; aged; aggressive therapy; cancer recurrence; cervical and uterine cancer; chemotherapy; clinical care; clinical diagnosis; cohort; detection assay; digital; epidemiological model; follow-up; genomic biomarker; high risk; human papilloma virus oropharyngeal squamous cell carcinoma; 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; predictive tools; prevent; prognostic; prognostication; prospective; screening; sexually active; side effect; surveillance strategy; treatment response; tumor; validation studies

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.

人乳头瘤病毒相关性口咽鳞状细胞癌(HPV+OPSCC)的发病率 在过去的二十年里迅速增长，超过子宫颈癌成为 到2012年，在美国经常被诊断为HPV相关癌症。这种“流行病”就是 预计将持续到2060年。患者通常被诊断为转移性结节疾病。 大剂量照射联合顺铂治疗。这种治疗不是为 HPV+OPSCC，但基于对HPV阴性的治疗升级试验的结果 癌症。这种积极的治疗会导致终生发病率，而且治疗的副作用可能 也会缩短寿命。对于大约25%的将会复发的晚期患者 对复发的识别限制了一部分的抢救选择。早期发现初始疾病 复发可以减少病态治疗，也可以提高存活率。头和头 颈部肿瘤界最近将重点放在HPV+OPSCC的个性化治疗上， 特别是在治疗去强化方面。阻碍发展的主要绊脚石 这些治疗策略的广泛采用是无法识别出低风险的患者 复发者适合进行强度较小的治疗。 我们小组确定并试点了预后生物标记物和检测治疗情况的检测方法 对初发或复发的HPV+OPSCC进行早期检测。预测预后的生物标记物 是基于肿瘤中TRAF3或CyLD的缺失或突变。TCGA队列分析 有TRAF或CyLD缺陷的HPV+OPSCC患者的存活率显著提高 比那些肿瘤没有缺陷的人要好。值得注意的是，HPV+OPSCC肿瘤缺乏 TRAF3或CyLD缺陷患者的存活率与HPV阴性患者无法区分， 提示HPV+OPSCC患者存活率的提高在很大程度上可归因于 这些突变。我们还使用超灵敏数字设备对循环中的HPVDNA进行了初步检测 聚合酶链式反应可作为治疗反应、复发的预测指标和早期检测 复发性疾病。 我们试验的这些检测方法用于预测，以及治疗反应和早期 首次或复发HPV+OPSCC的检测需要验证，然后才能在临床上使用。 在这里，我们建议与MD Anderson癌症中心合作，利用正在进行的试验和 用循环HPVDNA检测鉴别口腔HPV感染患者 早期HPV+OPSCC。我们还将进行一项前瞻性观察性临床试验，以验证 TRAF3和CyLD突变作为预测预后的生物标志物和验证循环检测 血浆HPVDNA对HPV+OPSCC复发的早期检测对预后的确认 生物标志物将有助于适当选择HPV+OPSCC患者进行去强化治疗 并确定那些需要积极或新的治疗方法来提高存活率的人。验证 预测反应和及早发现复发的工具也将通过以下方式改变做法 识别复发风险较高的患者，加强监测或及早 干预。

项目成果

NF-κB over-activation portends improved outcomes in HPV-associated head and neck cancer.

• DOI: 10.18632/oncotarget.28232
• 发表时间: 2022
• 期刊: ONCOTARGET
• 作者: Schrank, Travis P;Prince, Andrew C;Sathe, Tejas;Wang, Xiaowei;Liu, Xinyi;Alzhanov, Damir T;Burtness, Barbara;Baldwin, Albert S;Yarbrough, Wendell G;Issaeva, Natalia
• 通讯作者: Issaeva, Natalia

Noncanonical HPV carcinogenesis drives radiosensitization of head and neck tumors.

• DOI: 10.1073/pnas.2216532120
• 发表时间: 2023-08-08
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Schrank, Travis P.;Kothari, Aditi;Weir, William H.;Stepp, Wesley H.;Rehmani, Hina;Liu, Xinyi;Wang, Xiaowei;Sewell, Andrew;Li, Xue;Tasoulas, Jason;Kim, Sulgi;Yarbrough, Gray;Xie, Yue;Flamand, Yael;Marur, Shanthi;Hayward, Michele C.;Wu, Di;Burtness, Barbara;Anderson, Karen S.;Baldwin, Albert S.;Yarbrough, Wendell G.;Issaeva, Natalia
• 通讯作者: Issaeva, Natalia