Mutational analysis using next-generation DNA sequencing in platinum-resistant muscle-invasive bladder cancer.

Abstract

e16006 Background: Platinum-resistant muscle-invasive bladder cancer (prMIBC) is the main cause of bladder cancer mortality. Recent advances in next-generation DNA sequencing (NGS) has allowed characterization of the molecular landscape of MIBC. Yet, the correlation between the molecular alteration and the poor outcome of prMIBC is still lacking. This study aims to explore the potential genetic alterations in this group of patients. Methods: A retrospective study of prMIBC patients that had NGS molecular profiling at a single center from November 2014 to October 2018 was conducted. The prMIBC was defined as patients who had a significant residual disease or disease progression following cisplatin-based chemotherapy in a neoadjuvant or metastatic disease setting. NGS was performed on formalin-fixed paraffin-embedded tissue samples through commercial companies. Results: A total of 17 prMIBC with the median age of 65 [51-74] years old were included in this study. At the end of the study, 8 patients were alive and 9 deceased. A total of 58 mutations were identified. 7 of the 58 genes were mutated in ≥20% of cases: TP53 (65%), TERT promoter -124C > T (59%), ARID1A (35%), CDKN2A/B (30%), RB1 (24%), PIK3CA (24%), and FLCN (20%). Less frequent mutations (12% each) include MDM2, AKT2, KDM6A, SMARCA4, FGF3, FGF4, BRCA2, STAG2, and CCNE1 genes. Analysis of the mutations revealed key pathways including TP53/cell cycle pathway altered in 82%, PI-3K/mTOR pathway in 71%, Telomere regulation in 59%, SWI/SNF complex in 35% and histone modification in 24% of cases. Conclusions: Among patients with prMIBC, mutations in the p53/cell cycle pathway are the most common findings. Genetic alteration involving the PI-3K/mTOR pathway is frequently associated with prMIBC, which could provide an important lead for a predictive model and targeted intervention. Interestingly, the TERT promoter -124C > T mutation is a very common molecular alteration in prMIBC that has not been reported before. Telomere regulation may play a role in contributing to platinum-resistance in bladder cancer. Further elucidation of the molecular landscape in prMIBC on a larger scale would help to establish a molecular model to predict platinum-response in MIBC.