Abstract: PD48-11
Sources of Funding: Supported by the Sidney Kimmel Center for Prostate and Urologic Cancers at Memorial Sloan Kettering Cancer Center, Pin Down Bladder Cancer, and the Michael A. and Zena Wiener Research and Therapeutics Program in Bladder Cancer.

Introduction

To identify genetic alterations with potential clinical implications through next generation sequencing of index pretreatment non-muscle invasive bladder cancer (NMIBC) tumors.

Methods

We analyzed index pretreatment NMIBC tumors and matched germline DNA of 105 patients with a 341 cancer-associated gene panel in a CLIA-certified clinical laboratory. Representative hematoxylin and eosin slides were reviewed by a genitourinary pathologist 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 mutated genes in NMIBC tumors were TERT promoter (74%), FGFR3 (50%), KDM6A (47%), ARID1A (28%), PIK3CA (27%), KMT2D (24%), STAG2 (21%), and CDKN2A (17%). Of 105 tumors, 81% harbored at least one inactivating alteration in a chromatin-modifying gene. Alterations in the RTK/RAS/PIK3 pathway were present in 83% of tumors, including 58% of high-grade NMIBC tumors with either ERBB2 or FGFR3 alterations in a mutually exclusive pattern. Of 105 patients, 62 were treated uniformly with a 6-week induction course of BCG without maintenance. Genes altered with ≥5% frequency on the 341-gene panel were investigated for an association with recurrence after Bacillus Calmette-Guerin (BCG) therapy. 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) (Table 1). This remained significant when adjusting for multiple comparisons (p=0.04) and when including ARID1A missense mutations of unknown significance (HR=3.08 [95%CI=1.49-6.35] p=0.002).

Conclusions

Next Generation Sequencing of index pretreatment NMIBC tumors showed an association between ARID1A mutations and recurrence after BCG therapy. Whether ARID1A mutations in NMIBC can serve as potential predictive or prognostic biomarkers or as therapeutic targets warrants further investigation. Moreover, the majority of NMIBC tumors had at least one potentially &[Prime]actionable&[Prime] alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy.

Funding

Supported by the Sidney Kimmel Center for Prostate and Urologic Cancers at Memorial Sloan Kettering Cancer Center, Pin Down Bladder Cancer, and the Michael A. and Zena Wiener Research and Therapeutics Program in Bladder Cancer.