929 NEXT-GENERATION DEEP SEQUENCING IDENTIFIES RECURRENT AND TARGETABLE GENETIC ALTERATIONS IN HIGH GRADE BLADDER UROTHELIAL CARCINOMA

Abstract

INTRODUCTION AND OBJECTIVES: High grade urothelial carcinoma (UC) is an aggressive malignancy with limited therapeutic options in the advanced, metastatic, or recurrent disease setting. Targeted genetic analysis of high grade tumors was performed to determine the prevalence of known cancer genes and to identify potential targets for therapy. METHODS: Frozen high grade bladder tumors and matched germline blood DNA were obtained from 60 patients undergoing transurethral resection (TUR) or cystectomy. Specimens were analyzed using a targeted, deep-sequencing assay designed to identify point mutations, indels, and copy number alterations in 275 cancer-associated genes. RESULTS: The cohort was predominantly male (N 49, 81%) with a median age of 71 (IQR 61, 76). Frozen tumor was obtained from radical cystectomy(RC) in 53 patients (88%), TUR in 6 (10%), and partial cystectomy in 1 (2%). 11 patients (18%) had a history of intravesical therapy. Tumor pathologic stage was Ta in 5 (8%), T1 in 5 (8 %), T2 in 11 (18%), T3 in 30 (50%), and T4 in 9 (15%). Of the 53 patients undergoing RC and lymph node dissection, 17 received neoadjuvant chemotherapy (32%) and 24 (45%) had lymph node metastases. Mean target coverage for all sequenced exons was 512X. The most common genomic event was somatic mutation of TP53, identified in 33 patients (55%). RB mutations were identified in 11 (18%). Alterations in the PI3K/AKT/mTOR signaling pathway were also common; 12 patients had mutations in PIK3CA (20%), and non-overlapping mutations were identified in other genes within the pathway including AKT1, PTEN, and MTOR. Frequent mutations in chromatin remodeling genes were also identified. KDM6A mutations were identified in 21 tumors (35%), MLL2 in 18 (30%), and ARID1A in 17 (28%). Overall, 60% of all analyzed tumors harbored potentially targetable genomic alterations, including those with alterations in ERBB2, BRAF, and FGFR3 (Figure). CONCLUSIONS: Genetic alterations are frequent in high grade bladder UC. Over half of the tumors analyzed harbor alterations in genes that have been targeted for therapeutic benefit in other solid tumors, thus providing a compelling case for clinical trials using novel agents. Analysis for correlations with clinical outcomes is ongoing to assess for the prognostic significance of these genetic events. Source of Funding: Sidney Kimmel Center for Prostate and Urologic Cancers, Michael and Zena Wiener Research and Therapeutics Program in Bladder Cancer