Expert: Bladder Cancer Study Validates Personalized Medicine Concept

Gopal N. Gupta, MD

In the study by Wagle et al, “Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib,” the authors report a remarkable observation of a patient with metastatic urothelial carcinoma that endured a complete remission of 14 months in a phase I trial of everolimus and pazopanib. This was validated by whole genome sequencing and identification of two activating mutations of the mTOR gene.

What makes this study so interesting is the validation of the concept of personalized medicine; by working backwards, the investigators have identified a genetic susceptibility to targeted therapy in a tumor. mTOR activation alone is not novel in urothelial carcinoma; however, demonstrating causality of an activating mutation of mTOR and therapy targeted towards mTOR activation is exciting.

The real work ahead is determining how to identify patients who will respond to a particular targeted therapy—should all patients undergo whole genome sequencing? If so, which mutations will be the “driver” mutation? In addition, are there agents that are effective against these targets?

We are just at the tip of the iceberg and it is an exciting time in personalized medicine. This is particularly true in bladder cancer, where there have been no U.S. Food and Drug Administration–approved targeted therapy agents. Perhaps in the future, there will be more phase 1/2 trials of mTOR kinase inhibitors, especially for patients that experience treatment failure with first-line chemotherapy.