Emerging biomarkers and targeted therapies in urothelial carcinoma

The use of immunotherapy has revolutionized the management of patients with locally advanced, unresectable, and metastatic urothelial carcinoma (UC); however, platinum-based chemotherapy remains a therapeutic cornerstone both in localized muscle-invasive and advanced UC. There is still no predictive molecular biomarker with clinical utility to help guide treatment and select patients most likely to derive benefit from a particular therapeutic modality or regimen. However, recent research has further characterized the inherent biology and immunology landscapes of UC leading to the development of potential biomarkers and therapeutic targets that could be used upon further validation. Emerging interrogation of The Cancer Genome Atlas (TCGA) and other molecular profiling datasets has led to the identification of distinct molecular subtypes with diverse clinical behaviors with potential sensitivity to various therapies. It has also led to the discovery of multiple frequently altered genes and proteins that could lead to perturbation of intracellular signaling pathways and of the dynamic interactions between tumor cells, their "microenvironment", and the host "macro-environment". The advent of molecular profiling and deeper next-generation sequencing has the potential to change biomarker and "real time" drug sensitivity assessment, introducing and testing the premise of "precision oncology" and personalized medicine. Within this review, we summarize emerging biomarkers that may predict response to cisplatin-based chemotherapy, immunotherapy, emerging targeted therapies, and promising combination strategies. We also highlight a few examples of 'precision medicine' trials aiming to improve outcomes in UC. Since our review is not exhaustive we strongly recommend the readers to follow the continuously changing literature in the very interesting and dynamic field of UC.