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

项目摘要/摘要 以顺铂为基础的新辅助化疗(NAC)和根治性膀胱切除术(RC)是一种标准的治疗方法 用于治疗肌肉浸润性膀胱癌(MIBC)。这个项目是基于 前瞻性分子图谱可以为谁识别MIBC(ct2-4aN0M0)患者的科学前提 经尿道膀胱肿瘤电切术(TURBT)和全身化疗是不需要治愈的 对于RC。它建立在先前回顾数据的基础上，表明1)DNA损伤中的有害变化 反应(DDR)基因，最常见的在核苷酸切除修复基因ERCC2中，是预测 MIBC患者对以顺铂为基础的联合化疗的反应和2)获得 临床对NAC的完全应答和拒绝或医学上不适合接受RC长期存活 膀胱完好无损。假设选择患有MIBC的患者可以通过TURBT和 单独的化疗，不需要RC，将在目标1的前瞻性背景下进行测试， 肿瘤学临床试验联盟进行的多中心临床试验(A031701)。在这项研究中，Pre- 治疗诊断TURBT样本将对468例癌症进行下一代测序分析- 相关基因。所有患者将接受剂量密集的吉西他滨和顺铂治疗6个周期，然后 临床重新分期，将根据1)术后情况采用保留膀胱术或RC术 通过重复膀胱镜、TURBT和成像评估化疗反应，以及2)体细胞突变 DDR相关基因在患者治疗前肿瘤中的表达患有有害的躯体改变的患者 在9个与DDR相关的基因中，至少有1个实现了临床完全应答或降级 NAC后的非侵袭性疾病(&lt；CT1)将是保留膀胱的候选。携带DDR基因的患者 化疗后患有DDRCT1病的突变患者将接受RC，所有≥基因野生型患者都将接受RC 患者，无论反应如何。认识到约60%的NAC应答者缺乏体细胞DDR基因 改变，整个外显子组测序将在目标2中进行，使用预先收集的肿瘤材料 来自A031701登记的所有患者的治疗，以确定更多的化疗敏感性生物标志物， 包括DDR缺乏症的突变特征。在目标3中，我们将评估对无细胞DNA的分析 是一种敏感的、非侵入性的方法来识别患者的微小残留疾病和 探讨肿瘤的异质性及其与耐药和疾病复发的关系。建议数 研究广泛依赖于生物谱系资料库和生物统计与生物信息学的支持 核心，以实现项目的翻译目标。如果成功，拟议中的研究可能会显著 扩大保留器官治疗在MIBC患者治疗意向中的应用。这个 本项目中使用的预期分子表征平台也可以加速对新的 对基于顺铂的NAC不太可能有反应的患者进行免疫治疗或靶向治疗。

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.