Push for Molecular Profiling Could Transform Advanced Bladder Cancer Care

New National Comprehensive Cancer Network (NCCN) guidelines regarding genomic profiling will likely yield important opportunities to improve the care of patients with advanced bladder cancer, according to experts. Increasing use of targeted agents and accelerated enrollment in clinical trials based on that profiling could help push a difficult field forward.

The management of advanced bladder cancer remains somewhat primitive in comparison with other more common malignancies, such as breast and lung cancer. First-line therapy generally involves a decision to use cisplatin-based regimens or not, and there are no currently approved options in the second-line setting.

“The landscape of bladder cancer therapy, however, is evolving,” wrote authors led by Sumanta Kumar Pal, MD, of the City of Hope Comprehensive Cancer Center in Duarte, California, in a special article published in the Journal of Clinical Oncology. There is increasing evidence that programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors could have significant activity, and recent studies on gene expression profiles have found gene signatures that have significant prognostic utility. These findings support the recent NCCN guidelines, which recommend molecular profiling of patients with advanced bladder cancer.

Importantly, the genetic studies done to date have shown that the malignancy has a remarkably diverse molecular profile. In one study, 69% of patients had actionable therapeutic targets; most of these were in the mTOR signaling pathway (42% of patients), while 17% of patients had inactivating PIK3CA mutations, 9% had a mutation or deletion of TSC1 or TSC2, and 17% had pathway alterations in FGFR3.

Determining which drugs to use against which targets, of course, is the next challenge in the field. In one recent study, patients with TSC1 mutations derived substantial benefit from everolimus; one patient with both a TSC1 and an NF2 mutation saw the best results, with a near complete response lasting 23 months. FGFR3 antagonists have also shown promise, with 50% objective response rates in phase I studies.

The authors wrote that the NCCN recommendations for comprehensive molecular profiling will likely expand the use of diagnostic tests. “As a consequence, patients with salient alterations, for example, TSC1 alteration, may be guided toward more rational therapies,” they wrote, adding that “purists” would suggest that randomized trials are required before such therapies are used over traditional cytotoxic agents. Such trials have been completed in other malignancies such as lung cancer, but are likely much more difficult in a disease that is far less prevalent.

However, the abundant use of profiling will undoubtedly aid in the recruitment to those clinical trials. The authors noted that trials testing agents that inhibit signaling through FGFR3, CDKN2A, CREBBP, and EP300 are currently ongoing in bladder cancer patients. “The noted recommendations from the NCCN panel will hopefully reconcile the apparent paradox that exists today-a push toward personalized medicine, but a lack of support for the platforms that facilitate their use,” the authors concluded.