Optimization of urinary DNA deep sequencing tests to enhance clinical staging of bladder cancer patients

优化尿液 DNA 深度测序测试以提高膀胱癌患者的临床分期

基本信息

批准号：
10454366
负责人：
Philip Abbosh
金额：
$ 41.42万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10454366
关键词：
Address Adopted Affect Algorithms Benchmarking Biological Markers Biopsy CDK4 gene Cancer Patient Cells Cisplatin Clinic Clinical Clinical Trials Collection Cryopreservation DNA DNA Sequence Alteration Development Doxorubicin Fox Chase Cancer Center Funding Genes Goals Hospitals Hour Immunotherapy In complete remission Institution Intention Knowledge Libraries Life Malignant neoplasm of urinary bladder Medical Oncologist Methodology Methods Methotrexate Muscle Mutate Mutation Nature Neoadjuvant Therapy Neoplasm Metastasis Nivolumab Nucleic Acids Operative Surgical Procedures Organ Outcome Pathologic Patients Point Mutation Predictive Value Preparation Procedures Process Protocols documentation Public Health Publishing Radiation Radiation Oncologist Radical Cystectomy Recurrence Research Residual Cancers Residual Tumors Residual state Sampling Shipping Ships Specimen Staging Temperature Testing Time Triage Tumor Tissue Urinary Diversion Urine Urologist Urostomy Validation Vinblastine base cancer clinical trial cancer therapy chemoradiation chemotherapy clinically relevant cohort deep sequencing experimental study inhibitor interest mortality muscle invasive bladder cancer next generation sequencing performance tests preservation prospective response skills success tool tumor urinary

项目摘要

PROJECT SUMMARY/ABSTRACT Muscle-invasive bladder cancer (MIBC) is optimally treated with neoadjuvant chemotherapy followed by radical cystectomy (RC), whereby ~35% of patients will have a pathologic complete response (pCR). Given the morbid, complicated, and expensive nature of RC and the well-established pCR rate, there is a groundswell of interest in RC avoidance for patients achieving pCR. However, identifying pCR clinically (as opposed to pathologically) is an inaccurate process. In published studies, patients who avoid RC after being deemed clinical complete responders have a 25-60% likelihood of recurrence, metastasis, or bladder cancer mortality. Better tools to assess residual disease status are needed. To address this need, we developed a urine biopsy test which we call UTeRD (Urine Test for Residual Disease). In UTeRD, DNA is isolated from urine and subjected to next generation sequencing to detect point mutations in a targeted panel of genes. Using UTeRD, most mutations in tumor tissue are detectable as mutations in urine. Further, presence or absence of residual MU after completion of chemotherapy strongly associates with residual disease or pCR at the time of RC, respectively. Therefore, UTeRD could be used after neoadjuvant therapy to better identify patients for RC avoidance. Although UTeRD performs well in distinguishing patients with pCR from residual disease, the negative predictive value (NPV) of UTeRD is only 76%, some urine samples were nondiagnostic, and a urinary DNA preservation protocol needs to be developed in order for the test to be widely adopted. Pre-analytical factors and methodology improvements which we believe will increase the NPV and decrease nondiagnostic rates will be studied in Aim 1. In Aim 2, we will determine if urine preservatives can be used to facilitate shipping to a centralized lab without loss of fidelity of the test. Lastly, in Aim 3, we will determine if the absence of mutations from a urine biopsy is associated with pCR regardless of the pre-surgical therapy. To answer this question, samples obtained on 5 prospective MIBC clinical trials from multiple institutions will be studied using the optimized protocols identified through this research. The research team is comprised of a urologist, medical oncologists, a radiation oncologist, a statistician, a computational biologist who are experts in their fields. The skills and contributions of the team are complimentary and will culminate in the development of a unique and robust biomarker that addresses a significant clinical need using a one-of-a-kind sample cohort. UTeRD may enhance the ability of a bladder cancer clinician to answer highly relevant clinical question, namely, “Does this patient have residual disease after pre- surgical therapy, and therefore, will he/she benefit from RC?”

项目概要/摘要肌层浸润性膀胱癌 (MIBC) 的最佳治疗方法是新辅助化疗，然后进行根治性膀胱切除术 (RC)，因此约 35% 的患者将获得病理完全缓解 (pCR)。由于 RC 的病态、复杂和昂贵的性质以及既定的 PCR 率，出现了一股热潮对实现 pCR 的患者避免 RC 的兴趣然而，在临床上识别 pCR（而不是）。在已发表的研究中，在被视为临床后避免 RC 的患者是一个不准确的过程。完全缓解者有 25-60% 的复发、转移或膀胱癌死亡率的可能性。需要评估残留疾病状态的工具。为了满足这一需求，我们开发了一种尿液活检测试，我们称之为 UTeRD（尿液残留测试）在 UTeRD 中，从尿液中分离 DNA 并进行下一代测序以检测点。使用 UTeRD，可以检测到肿瘤组织中的大多数突变。此外，化疗完成后是否存在残留 MU 也与尿液中的突变密切相关。分别与 RC 时的残留病灶或 pCR 相关，因此，可以在 RC 之后使用 UTeRD。新辅助治疗可更好地识别避免 RC 的患者。尽管 UTeRD 在区分 pCR 患者和残留疾病方面表现良好，但阴性结果 UTeRD 的预测值 (NPV) 仅 76%，部分尿样无法诊断，尿 DNA 需要制定保存协议以便广泛采用预分析因素。我们相信方法的改进将提高 NPV 并降低非诊断率在目标 1 中进行研究。在目标 2 中，我们将确定是否可以使用尿液防腐剂来促进运送到最后，在目标 3 中，我们将确定是否不存在突变。无论术前治疗如何，尿液活检的结果与 pCR 相关。来自多个机构的 5 项前瞻性 MIBC 临床试验中获得的样本将使用通过本研究确定的优化方案。研究团队由泌尿科医生、肿瘤内科医生、放射肿瘤科医生、统计学家、计算生物学家是各自领域的专家，团队的技能和贡献是。互补，并将最终开发出一种独特且强大的生物标志物，解决使用独一无二的 UTeRD 样本队列的重大临床需求可能会增强膀胱癌的治疗能力。临床医生回答高度相关的临床问题，即“该患者在预治疗后是否有残留疾病” 手术治疗，因此，他/她会从 RC 中受益吗？”