Harnessing genomic profiling for improved urothelial cancer outcomes

INTRODUCTION: Genomic profiling has revolutionized the management of Urothelial carcinomas (UC), particularly in muscle-invasive bladder cancer (MIBC) and metastatic UC, by identifying molecular subtypes and actionable mutations that guide personalized therapies and prognostication. AREAS COVERED: The integration of genomic profiling in UC, potential prognostic and predictive biomarkers of prognosis, and the current landscape of systemic therapies in UC, including FGFR inhibitors (FGFRi), antibody-drug conjugates (ADC), immune checkpoint inhibitors (ICI), and chemotherapy are discussed herein as a narrative and descriptive review. EXPERT OPINION: Genomic profiling has advanced our understanding of UC diagnosis and treatment, but its routine clinical use remains limited to confirming biomarkers such as FGFR alterations and HER2 amplification for approved targeted therapies such as erdafitinib, a FGFRi, and trastuzumab deruxtecan, a HER2-directed ADC. Testing for other biomarkers such as PD-L1, tumor mutational burden (TMB), and Nectin-4 can be useful, but not required for the use of ICI and enfortumab vedotin. Circulating tumor DNA (ctDNA) is an emerging tool for monitoring disease and guiding therapy, with trials underway to confirm its clinical utility.