Precision medicine for urothelial bladder cancer: update on tumour genomics and immunotherapy

Key Points Mutations in the DNA repair pathway genes ERCC2 , FANCC , ATM , and RB1 correlate with complete pathological response to neoadjuvant chemotherapy and should be further evaluated for their utility in clinical decision making Gene mutations, copy number variations, and rearrangements in receptor tyrosine kinase (RTK)– MAPK and PI3K–MTOR pathways are found in ∼70% of bladder tumours; recent studies show that these alterations, in addition to having prognostic significance, can be predictive of response Several ongoing, large pan-cancer trials match patients to a targeted agent (or agents) on the basis of molecular and genetic tumour features, testing for increased efficacy of this personalized medicine approach Immune checkpoint inhibitors that target programmed cell death protein 1 (PD1) and its ligand PDL1 show promise in clinical trials and are approved for bladder cancer treatment; further research is required to personalize the use of these agents Personalized peptide vaccines that are created on the basis of patient leukocyte antigen immune subtypes are currently being tested in clinical trials Felsenstein and Theodorescu discuss advances in therapy response prediction in patients with bladder cancer based on tumour genomics. They summarize current clinical approaches and future requirements in personalized precision medicine including targeted as well as immunotherapeutic strategies. Effective management of advanced urothelial bladder cancer is challenging. New discoveries that improve our understanding of molecular bladder cancer subtypes have revealed numerous potentially targetable genomic alterations and demonstrated the efficacy of treatments that harness the immune system. These findings have begun to change paradigms of bladder cancer therapy. For example, DNA repair pathway mutations in genes such as ERCC2 , FANCC , ATM , RB1 , and others can predict responses to neoadjuvant platinum-based chemotherapies and to targeted therapies on the basis of mutation status. Furthermore, an increasing number of pan-cancer clinical trials (commonly referred to as basket or umbrella trials) are enrolling patients on the basis of molecular and genetic predictors of response. These studies promise to provide improved insight into the true utility of personalized medicine in the treatment of bladder cancer and many other cancer types. Finally, therapies that modulate immune responses have shown great benefit in many cancer types. Several immune checkp