RP-1: Defining Predictors of Sensitivity to Cisplatin-Based Chemotherapy in Urothelial Cancer

RP-1：尿路上皮癌顺铂化疗敏感性的定义预测因子

• 批准号: 10226969
• 负责人: David B Solit
• 金额: $ 36.84万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-24 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226969
• 关键词: Basic Science; Bioinformatics; Biological Assay; Biological Markers; Biological Specimen Banks; Biometry; Biopsy; Bladder; Bladder Neoplasm; Blood; Cancer Patient; Chemoresistance; Cisplatin; Clinical; Clinical Sciences; Clinical Trials; Clonal Evolution; Collaborations; Combination Drug Therapy; Combined Modality Therapy; Cystectomy; Cystoscopy; DNA Damage; DNA analysis; Data; Diagnostic; Diagnostic radiologic examination; Disease; Dose; Drug resistance; ERCC2 gene; Early identification; Eligibility Determination; Enrollment; Exhibits; Future; Gene Mutation; Genes; Genomics; Guidelines; Heritability; Heterogeneity; Immunotherapy; In Vitro; In complete remission; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Medical; Methods; Modeling; Molecular; Molecular Profiling; Multi-Institutional Clinical Trial; Mutation; Neoadjuvant Therapy; Nucleotide Excision Repair; Oncology; Organ; Organoids; Pathologic; Patients; Publishing; Radical Cystectomy; Recurrence; Residual Neoplasm; Sampling; Site; Somatic Mutation; Specific qualifier value; Staging; Systemic Therapy; Testing; Time; Toxicity due to chemotherapy; Transitional Cell Carcinoma; Transurethral Resection; Urine; Urothelium; Variant; base; cancer imaging; cell free DNA; chemotherapy; co-clinical trial; cohort; curative treatments; exome sequencing; gemcitabine; muscle invasive bladder cancer; mutational status; next generation sequencing; novel; patient population; patient response; predicting response; predictive marker; predictive signature; preservation; primary endpoint; prospective; response; response biomarker; standard of care; tumor; tumor heterogeneity; variant of unknown significance

Project Summary/Abstract Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is a standard of care for the curative-intent treatment of muscle-invasive bladder cancer (MIBC). This project is based on the scientific premise that prospective molecular profiling can identify patients with MIBC (cT2-4aN0M0) for whom transurethral resection of the bladder tumor (TURBT) and systemic chemotherapy is curative without the need for RC. It builds upon prior retrospective data demonstrating that 1) deleterious alterations in DNA damage response (DDR) genes, most frequently in the nucleotide excision repair gene ERCC2, are predictive of response to cisplatin-based combination chemotherapy in MIBC and 2) small cohorts of patients who achieve clinical complete responses to NAC and refuse or are medically unfit for RC survive long-term with their bladders intact. The hypothesis that select patients with MIBC can be successfully managed with TURBT and chemotherapy alone, without the need for RC, will be tested in Aim 1 in the context of a prospective, multicenter clinical trial performed by the Alliance for Clinical Trials in Oncology (A031701). In this study, pre- treatment diagnostic TURBT samples will undergo next-generation sequencing analysis of 468 cancer- associated genes. All patients will receive dose-dense gemcitabine and cisplatin for 6 cycles followed by clinical re-staging and will be managed with either bladder preservation or RC based upon 1) post- chemotherapy response as assessed by repeat cystoscopy, TURBT, and imaging, and 2) somatic mutation status of DDR-related genes in the patient's pre-treatment tumor. Patients with deleterious somatic alterations in at least 1 of 9 DDR-associated genes who achieve a clinical complete response or down-staging to noninvasive disease (<cT1) following NAC will be candidates for bladder preservation. Patients with DDR gene mutations who have ≥cT1 disease after chemotherapy will undergo RC, as will all DDR gene wild-type patients, regardless of response. Recognizing that ~60% of NAC responders lack somatic DDR gene alterations, whole exome sequencing will be performed in Aim 2, using the tumor material collected pre- treatment from all patients enrolled on A031701, to identify additional biomarkers of chemo-sensitivity, including mutation signatures of DDR deficiency. In Aim 3, we will assess whether analysis of cell-free DNA from blood and urine is a sensitive, noninvasive method to identify patients with minimal residual disease and to explore tumor heterogeneity and its relationship to drug resistance and disease recurrence. The proposed studies rely extensively on support from the Biospecimen Repository and the Biostatistics & Bioinformatics Core to achieve the project's translational objectives. If successful, the studies proposed could significantly expand the use of organ-sparing therapy for the curative-intent treatment of patients with MIBC. The prospective molecular characterization platform used in this project could also accelerate testing of novel immunotherapy or targeted approaches in patients unlikely to respond to cisplatin-based NAC.

项目概要/摘要 以顺铂为基础的新辅助化疗 (NAC) 随后进行根治性膀胱切除术 (RC) 是一种标准治疗 用于肌肉浸润性膀胱癌（MIBC）的治愈性治疗。 前瞻性分子谱分析可以识别 MIBC (cT2-4aN0M0) 患者的科学前提 经尿道膀胱肿瘤切除术 (TURBT) 和全身化疗即可治愈，无需 对于 RC，它建立在先前的回顾性数据之上，证明 1) DNA 损伤的有害改变。 反应（DDR）基因，最常见的是核苷酸切除修复基因 ERCC2，可以预测 MIBC 中对基于顺铂的联合化疗的反应以及 2) 一小群患者实现了 对 NAC 具有临床完全反应并拒绝或在医学上不适合 RC 的患者可长期生存 膀胱完好无损的假设：某些 MIBC 患者可以通过 TURBT 成功治疗。 单独化疗，无需 RC，将在目标 1 中进行前瞻性测试， 由肿瘤学临床试验联盟 (A031701) 进行的多中心临床试验。 治疗诊断 TURBT 样本将对 468 种癌症进行下一代测序分析 所有患者将接受 6 个周期的剂量密集吉西他滨和顺铂治疗，然后接受治疗。 临床重新分期，将根据以下情况通过膀胱保留或 RC 进行管理：1) 术后 通过重复膀胱镜检查、TURBT 和影像学评估化疗反应，以及 2) 体细胞突变 患者治疗前肿瘤中 DDR 相关基因的状态 患有有害体细胞改变的患者。 9 个 DDR 相关基因中的至少 1 个基因达到临床完全缓解或降期 NAC 后的非侵袭性疾病（<cT1）将是保留膀胱的患者。 化疗后患有≥cT1疾病的突变将经历RC，所有DDR基因野生型也将经历RC 认识到约 60% 的 NAC 应答者缺乏体细胞 DDR 基因。 改变，将在目标 2 中使用预先收集的肿瘤材料进行全外显子组测序 对所有参加 A031701 的患者进行治疗，以确定化疗敏感性的其他生物标志物， 包括 DDR 缺陷的突变特征 在目标 3 中，我们将评估是否分析游离 DNA。 从血液和尿液中检测是一种灵敏、无创的方法，可识别患有微小残留病的患者 探讨肿瘤异质性及其与耐药性和疾病复发的关系。 研究主要依靠生物样本库和生物统计与生物信息学的支持 实现该项目转化目标的核心如果成功，所提出的研究将具有重大意义。 扩大器官保留疗法在 MIBC 患者治疗中的应用。 该项目中使用的前瞻性分子表征平台还可以加速新型药物的测试 对不太可能对基于顺铂的 NAC 产生反应的患者进行免疫治疗或靶向治疗。