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 (
This project is based on the scientific premise that molecular profiling before treatment can identify patients with muscle-invasive bladder cancer for whom transurethral resection of the bladder tumor and systemic chemotherapy will be curative, without the need for radical cystectomy. Targeted and whole exome sequencing in patients enrolled on a prospective clinical trial will be used to better define the population of patients for whom such an approach would be most appropriate. The project will also investigate the use of cell-free DNA from blood and urine as a platform for early identification of minimal residual disease and to explore tumor heterogeneity as a mechanism of drug resistance.