Prognostic Value of DNA Damage Response Genomic Alterations in Relapsed/Advanced Urothelial Cancer

BACKGROUND: DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remains unclear. METHODS: We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from TCGA bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. RESULTS: DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91) and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared to other predefined DDR genes was substantially different (ATM: adjHR = 2.03, 95% CI 1.03-4, p = .04; other DDR: adjusted HR = 0.49, 95% CI 0.31-0.8, p = .003). CONCLUSIONS: Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed/advanced UC. ATM may have a complex role in UC progression. IMPLICATIONS FOR PRACTICE: Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer (UC), and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, we found ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. Our study suggests a complex role of ATM in tumor progression and calls for further studies to to determine the underlying mechanisms and biomarker clinical utility.