ATM/RB1 mutations to predict shorter overall survival (OS) in bladder cancer.

Abstract

393 Background: DNA repair defect plays an important role in tumorigenesis, progression and treatment outcomes of urothelial cancer. Somatic mutations of ATM/RB1 genes are frequently found in urothelial cancer and have been associated with a better response to cisplatin-based neoadjuvant chemotherapy. However, their prognostic value overall in urothelial cancer have not been determined. Methods: Exome sequencing data of 130 urothelial bladder cancer patients (pts) from The Cancer Genome Atlas (TCGA) dataset were analyzed as a discovery cohort to determine the prognostic value of ATM and RB1 mutations. Results from discovery dataset were further validated by an independent cohort of 79 advanced urothelial cancer pts who received comprehensive genomic sequencing for urothelial cancer with FoundationOne. OS was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Results: In the discovery dataset, somatic mutations of ATM/RB1 genes were present in 24% of pts and were associated with significantly shorter OS [all stages: adjusted HR = 2.67, 95% CI, 1.45–4.92, P = 0.002; stage II-III only: adjHR = 2.76, 95% CI, 1.23–6.20, P = 0.014]. There was high mutation load in pts carrying ATM/RB1 mutations (median mutation count: 196 versus 160, P = 0.09). In the validation (stage IV) dataset, ATM/RB1 mutations were present in 31.7% of pts and tended to associate with shorter OS (adjHR = 1.97, 95% CI, 0.89–4.40, P = 0.094) and higher mutation load (median mutation load: 8.1 versus 7.2 per Mb, P = 0.136), although statistical significance was not reached. Conclusions: These results suggest that ATM/RB1 mutations may be considered as a poor prognostic biomarker in unselected urothelial cancer pts and may correlate with higher mutational load. Further studies are required to determine patient characteristics that can further stratify prognosis based on ATM/RB1 mutation status, and evaluate the potential predictive role of ATM/RB1 mutation status in response to immunotherapy.