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

项目总结/摘要 以顺铂为基础的新辅助化疗（NAC）后行根治性化疗（RC）是标准治疗 用于肌肉浸润性膀胱癌（MIBC）的治愈性治疗。该项目基于 前瞻性分子分析可以识别MIBC（cT 2 - 4aN 0 M0）患者的科学前提， 经尿道膀胱肿瘤切除术（TURBT）和全身化疗是治愈性的， 对于RC。它建立在先前的回顾性数据的基础上，这些数据表明：1）DNA损伤中的有害改变 在核苷酸切除修复基因ERCC 2中最常见的DDR反应基因，是预测 MIBC中对基于顺铂的联合化疗的反应和2）达到以下目标的小队列患者 临床上对NAC完全反应，拒绝或在医学上不适合RC， 膀胱完好无损假设选择的MIBC患者可以成功地用TURBT治疗， 不需要RC的单独化疗将在目标1中在前瞻性， 肿瘤临床试验联盟开展的多中心临床试验（A031701）。在这项研究中，预- 治疗诊断TURBT样本将进行下一代测序分析的468癌症- 相关基因所有患者将接受6个周期的剂量密集型吉西他滨和顺铂治疗， 临床再分期，并将根据1）术后 通过重复膀胱镜检查、TURBT和成像评估化疗反应，和2）体细胞突变 患者治疗前肿瘤中DDR相关基因的状态。有害躯体改变患者 在9个DDR相关基因中的至少1个中， NAC后的非侵袭性疾病（<cT 1）将是膀胱保留的候选者。DDR基因患者 化疗后有≥ cT 1疾病的突变将经历RC，所有DDR基因野生型也将经历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，将在Aim 2中进行全外显子组测序，使用之前收集的肿瘤材料。 所有入组A031701的患者的治疗，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，我们将评估分析游离DNA是否 是一种敏感的、非侵入性的方法，用于识别微小残留病患者， 探讨肿瘤异质性及其与耐药和复发的关系。拟议 研究广泛依赖于生物标本库和生物统计学与生物信息学的支持 核心是实现项目的翻译目标。如果成功，拟议的研究将大大 扩大器官保留疗法在MIBC患者的治愈性治疗中的应用。的 该项目中使用的前瞻性分子表征平台也可以加速新的 免疫疗法或靶向方法在不太可能响应基于顺铂的NAC的患者中的应用。

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.