Next generation sequencing of non-muscle invasive bladder cancer to reveal potential biomarkers and rational therapeutic targets

• Published in: Journal of clinical oncology Vol. 35; no. 6_suppl; p. 302
• Main Authors: Pietzak, Eugene J., Cha, Eugene K., Bagrodia, Aditya, Drill, Esther N., Iyer, Gopa, Isharwal, Sumit, Li, Qiang, Baez, Priscilla, Berger, Michael F., Zehir, Ahmet, Ostrovnaya, Irina, Schultz, Nikolaus, Bajorin, Dean F., Rosenberg, Jonathan E., Dalbagni, Guido, Al-Ahmadie, Hikmat, Solit, David B., Bochner, Bernard H.
• Format: Journal Article
• Language: English
• Published: 20.02.2017
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2017.35.6_suppl.302

Abstract only 302 Background: We examined a cohort of index pre-treatment NMIBC tumors using Next Generation Sequencing to identify genetic alterations with potential clinical implications. Methods: 105 patients on a prospective IRB-approved protocol had their pre-treatment index NMIBC tumor and matched germline DNA sequenced with a 341 cancer-associated gene panel in a CLIA-certified clinical laboratory. A genitourinary pathologist reviewed representative H&E slides to confirm grade, stage, and urothelial histology. Restaging TUR was performed in all HGT1 tumors. Results: To characterize the genomic landscape of NMIBC, we analyzed 105 tumors across the disease spectrum including LGTa (n = 23), HGTis (n = 12), HGTa (n = 32) and HGT1 (n = 38). The most frequently altered genes in NMIBC were the TERT promoter (74%), FGFR3 (50%), KDM6A (47%), ARID1A (28%), PIK3CA (27%), KMT2D (24%), STAG2 (21%), and CDKN2A (17%). 81% of tumors had inactivating alterations in a chromatin-modifying gene. Alterations in the RTK/RAS/PIK3 pathway occurred in 83% of tumors, including 58% of high-grade NMIBC having alterations in either ERBB2 or FGFR3. Of the 105 patients, 62 were treated uniformly with a 6-week induction course of BCG without maintenance. We investigated all genes altered on the 341-gene panel in at least 5 patients for their association with recurrence after BCG therapy in this 62 patient cohort. On cox-regression analysis, only truncating mutations in the chromatin-modifying gene ARID1A were associated with recurrence after BCG (HR = 3.14 [95%CI = 1.51, 6.51] p = 0.002). This remained significant when adjusting for multiple comparisons (p = 0.04) and when including ARID1A missense mutations of unknown significance (p = 0.002). Conclusions: Next Generation Sequencing of index pre-treatment NMIBC tumors identified an association between ARID1A mutations and recurrence after BCG therapy. Further investigation is needed to determine whether ARID1A mutations are a potential predictive/prognostic biomarker or therapeutic target. Moreover, most NMIBC tumors had at least one potentially “actionable” alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy.