PD18-10 IDENTIFYING THE FREQUENCY OF ACTIONABLE GENOMIC ALTERATIONS IN LOCALIZED AND METASTATIC UPPER TRACT UROTHELIAL CARCINOMA

Abstract

INTRODUCTION AND OBJECTIVE: Upper tract urothelial carcinoma (UTUC) tumors have distinct genomic profiles differentiating them from bladder cancer. In this study we characterized the prevalence of actionable genomic alterations and evidence supporting susceptibility to targeted therapies. We also evaluated prevalence of DNA-damage response (DDR) alterations, associated with response to platinum-based chemotherapy and PD-1/PD-L1 blockade. METHODS: UTUC tumors that underwent next-generation sequencing were identified from our prospectively-maintained institutional database. Patients were grouped by clinical disease state (localized vs. metastatic) at time of sequencing. Actionable cancer gene alterations were identified using the OncoKB platform and classified based on level of evidence. RESULTS: In total 206 tumors were sequenced, with at least one actionable alteration found in 187 (91%) of the cohort [135 (93%) of patients with localized disease and 54 (89%) of metastatic patients]. 40% of the localized cohort and 23% of the metastatic cohort harbored specific FGFR3 mutations and fusions, recognized to predict response to erdafitinib included in the labeling of accelerated FDA-approval for treatment of urothelial cancer (Level 1 evidence). Microsatellite Instability-High, an approved biomarker predictive of response to pembrolizumab (Level 1), was found in 13% and 6% of the localized and metastatic cohort, respectively. There were 59 patients (32%) with alterations supported by level 2B evidence in approved therapeutics; most prevalent were alterations in BRCA2 (8%) and TSC1 (8%). Alterations supported by Level 3A/B evidence, indicating susceptibility to targeted drugs with compelling clinical evidence, were identified in 75% of the cohort (138 patients). Compelling biological evidence (Level 4) supports drugs targeting alterations found in 67% of the cohort (124 patients). At least one DDR alteration was found in 39% of the overall UTUC cohort, including 38% of clinically localized and 40% of metastatic patients. CONCLUSIONS: The majority of UTUC tumors evaluated in our cohort harbor actionable genomic alterations in both the localized and metastatic setting with potential to influence clinical management and direct future research studies in UTUC.Source of Funding: This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology and the National Cancer Institute Cancer Center Core Grant No. P30-CA008748