Genomic profiling of advanced bladder cancer to guide the use of targeted therapeutics

For patients with metastatic bladder cancer, the 5-year survival rate is only 5%, and until recently, there had been no major advances in the treatment of metastatic disease for more than 3 decades. Historically, the field of bladder cancer has been grossly underfunded and underresearched, and this in part accounts for the lack of progress in the field. Although only 5% of patients present with metastatic disease, approximately 50% of patients with localized, muscle-invasive bladder cancer will progress to metastatic disease. There are no Food and Drug Administration–approved treatment options for patients with metastatic bladder cancer who progress after first-line, cisplatin-based combination chemotherapy. Recent progress with targeted therapies for many malignancies has led to a renewed interest in the development of treatments for patients with metastatic bladder cancer. The Cancer Genome Atlas genomic analysis of 131 high-grade, muscle-invasive bladder carcinomas revealed that approximately 70% of bladder tumors have potentially actionable genomic alterations. The article by Ross et al accompanying this editorial reports on the use of the FoundationOne sequencing platform to detect the presence of the coding exons of 236 cancer-related genes and 47 introns from 19 genes frequently rearranged in cancer in 295 high-grade and clinically advanced-stage urothelial carcinomas of the bladder. Ross et al, using real-world experience, illustrate the potential promise of next-generation sequencing to genomically characterize bladder tumors for time-sensitive clinical decision making and thus potentially provide an opportunity for the use of targeted therapies and clinical trials of novel targeted agents according to the molecular profile of a patient’s tumor. Ross et al demonstrate a high frequency of clinically relevant genomic alterations among urothelial carcinomas of the bladder, with 93% of tumor specimens exhibiting at least 1 actionable alteration with a mean of 2.6 potentially actionable alterations per tumor. The most common potentially clinically relevant genomic alterations found include the genes CDKN2A (34%), FGFR3 (21%), PIK3CA (20%), and ERBB2 (17%); these findings are similar to The Cancer Genome Atlas experience with somewhat different frequencies. The study also demonstrates that ERBB2 alterations are enriched in micropapillary tumors, a clinically aggressive variant. The authors provide several anecdotes of clinical responses to targeted therapies, including the agents pazopanib and everolimus, based on the results of individual genomic profiling in patients with metastatic bladder cancer. In a prior phase 2 study involving patients with progressive metastatic urothelial cancer, the mammalian target of rapamycin pathway inhibitor everolimus had no significant impact on overall progression-free survival; however, a single patient demonstrated a durable complete response and was subsequently discovered to have 2 genetic alterations associated with mammalian target of rapamycin dependence. Such exceptionalresponder analyses provide one mechanism for better understanding the potential role of targeted therapies in genomically selected patients. The excitement of next-generation sequencing for accelerating the development of targeted therapeutics and improving patient outcomes must be tempered by a realistic expectation of the overall clinical benefit that these efforts may ultimately achieve. Despite the many potentially clinically actionable genetic alterations in urothelial cancer, the genomic complexity of bladder tumors may lead to difficulty in achieving major responses and durable outcomes with agents targeting a specific genetic event or pathway. It is very likely that combinations of targeted therapies will be necessary to achieve major responses and potentially abrogate resistance mechanisms that may arise when a single targeted agent is being used. For example, in metastatic melanoma, the combination of RAF kinase inhibitors with mitogen activated