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Patients with high grade papillary Ta (HGTa) non-muscle invasive bladder cancer (NMIBC) comprise a heterogeneous group with variable risk of long-term progression. Risk classification, and consequently treatment choices, for some NMIBC remains controversial and classification schemas vary, including between AUA and EAU guidelines. For patients with NMIBC, the presence of carcinoma in situ (CIS) is an adverse prognostic factor associated with increased risk of progression. We hypothesized that there would be distinct genomic features differentiating high-grade papillary Ta bladder cancer with and without concomitant CIS. Patients with NMIBC who had patient-matched tumor and normal blood samples sequenced as part of the prospective Memorial Sloan-Kettering Integrated Mutation Profiling of Actionable Cancer (MSK-IMPACT) initiative were identified for inclusion. MSK-IMPACT is a targeted next generation sequencing assay designed to identify somatic mutations, copy number alterations and structural variants in up to 505 cancer-associated genes. AUA low-risk tumors (solitary LG Ta ≤ 3cm, PUNLMP) were excluded. The cohort was stratified into two mutually exclusive groups: (1) HG Ta, with or without CIS, and (2) AUA intermediate- (multifocal/recurrent LGTa or LGT1) and high-risk (HGT1 or CIS alone) tumors. Clinicopathologic and genomic differences in selected actionable genes commonly altered in urothelial cancer were compared between the groups. The Benjamini-Hochberg procedure was used to estimate false discovery rate (q). 383 patients were included: HGTa without CIS (n=128), HGTa with CIS (n=32), AUA intermediate-risk (n=28) and high-risk (n=195). The average age at diagnosis was 65 years (SD 11.1), and 285 (74%) patients were male. HGTa tumors without CIS were enriched for FGFR3 alterations (65% vs. 12%, p<0.001, q<0.001), whereas TP53 alterations (13% vs. 44%, p<0.001, q=0.068) were less common compared to those with CIS (Figure 1). Among other oncogenic genes, alterations in KDM6A, KMT2D, CDKN2A, and EP300 were more common in tumors without CIS, whereas alterations in ARID1A and RB1 were more common in those with CIS. The profile of alterations in HGTa without CIS more closely aligned with that of AUA intermediate risk tumors compared to those classified as high-risk (Figure 2). There were no significant differences in alteration frequency of any tested genes among HGTa without CIS tumors when stratified by tumor size < or > 3cm. In a cohort of patients with HGTa NMIBC, the presence or absence of concomitant CIS was associated with a distinct pattern of alterations in selected targetable oncogenes, including FGFR3.;Investigations into whether the integration of genomic mutational profiles with standard clinicopathologic features will improve risk stratification for patients with NMIBC are ongoing. [ABSTRACT FROM AUTHOR]