Advanced Bladder Cancer Has High Rate of Clinically Relevant Genomic Alterations

Comprehensive genomic profiling of patients with advanced urothelial carcinoma has revealed a very high frequency of clinically relevant genomic alterations (CRGAs).

“For patients with locoregionally advanced and metastatic [urothelial carcinoma of the urinary bladder], targeted therapies have not been approved and patients have limited therapeutic options because chemoresistance to the standard anticancer therapies develops,” wrote study authors led by Sumanta K. Pal, MD, of the City of Hope Comprehensive Cancer Center in Duarte, California. As a result, interest in developing targeted therapies for this population has grown in recent years.

The new study involved comprehensive genomic profiling of 295 consecutive cases of recurrent or metastatic urothelial cancer. CRGAs were defined as alterations that are linked to drugs currently on the market or currently under clinical evaluation. The results were published online ahead of print in Cancer.

All but one of the 295 patients (99.7%) had at least one genomic alteration of any kind, with a mean of 6.4 alterations per urothelial carcinoma. A total of 275 patients (93%) had at least one CRGA; these involved 75 different genes, and patients had a mean of 2.6 CRGAs per case.

The most common CRGAs were in the cyclin-dependent kinase inhibitor 2A gene (CDKN2A), occurring in 34% of patients. Other common CRGAs included fibroblast growth factor receptor 3 (FGFR3, 21%), PIK3CA (20%), and ERBB2 (17%). With regard to the latter, the authors noted that ERBB2 substitutions were highly enriched in patients with micropapillary urothelial carcinoma, which is a particularly aggressive form of the malignancy.

The authors concluded that the wide diversity of these theoretically actionable alterations could open the door to new targeted therapies involving multiple biologic mechanisms and pathways. In an email, Pal said that “perhaps a high mutational rate lends itself to sensitivity to new immune-based treatments.”

In an accompanying editorial, Angela K. Green, MD, and Matthew I. Milowsky, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, wrote that the genomic complexity of bladder cancer may make it difficult to improve outcomes with agents that target specific pathways. “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,” they wrote. That complexity also complicates the design of clinical trials.

Still, they noted that the findings suggest further research into the genomics and related potential therapeutic avenues in this malignancy are certainly warranted.