Abstract 787P
Background
Although both URAC and NURAC are adenocarcinomas, their sites of origin and etiology are unique. We queried whether their genomic alteration (GA) signatures would also reflect their differences.
Methods
From a series of 4,863 FFPE tissues from clinically advanced bladder tumors, 85 cases of URAC and 143 cases of NURAC underwent hybrid-capture based CGP to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci.
Results
There were significantly more women with NURAC and more men with URAC (p=0.028). Median ages and age ranges were similar. On CGP, the GA/tumor were similar as were GA in major currently untargetable genes including TP53 and KRAS. GA in SMAD4 and MYC were more common in URAC and GA in TERT, ARID1A and APC were more frequent in NURAC than URAC. Male patients had more frequent GA in SMAD4 and APC and females had more GA in KRAS. The major currently targetable GA in both tumor types included PIK3CA (10% in NURAC and 5% in URAC) and ERBB2 (8% in NURAC and 6% in URAC). Biomarkers indicating potential benefit from immunotherapy (IO) were infrequent in both tumor types which generally were MSI stable, featured a low TMB and did not frequently stain for PD-L1 expression even at a low cut-off of ≥ 1%. Table: 787P
| NURAC | URAC | |
| Number of Cases | 143 | 85 |
| Males/Females | 57/86 | 47/38 |
| Median age (range) in years | 58 (24-83) | 57 (23-82) |
| GA/tumor | 5.4 | 5.1 |
| Selected Top Untargetable GA TP53 KRAS SMAD4 MYC TERT ARID1A APC | 79% 30% 14% 13% 12% 10% 8% | 85% 32% 21% 18% 1% 6% 0% |
| Top Targetable GA PIK3CA ERBB2 PTEN MET EGFR | 10% 8% 4% 4% 4% | 5% 6% 4% 1% 2% |
| MSI-High | 2/106 (2%) | 0/77 (0%) |
| Mean TMB (mut/Mb) | 2.4 | 3.9 |
| Median TMB (mut/Mb) | 3.6 | 2.6 |
| TMB>10 mut/Mb | 14 (10%) | 4 (4%) |
| TMB>20 mut/Mb | 4 (3%) | 1 (1%) |
| PD-L1 IHC ≥1% Positive | 2/11 (18%) | 1/18 (6%) |
Conclusions
URAC and NRAC have similar GA/tumor and absence of biomarkers predictive of IO response. However, gender frequencies differ as do GA in genes associated with their histogenesis such as TERT and APC. Significant potential treatments for both URAC and NURAC targeting PIK3CA and ERBB2 indicate that CGP has potential to personalize the care of patients suffering from these rare forms of bladder cancer.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Foundation Medicine Inc.
Funding
Foundation Medicine Inc.
Disclosure
P. Grivas: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Clovis Oncology; Advisory/Consultancy: Driver, Inc.; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Exelixis; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy: Genzyme; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: HERON; Advisory/Consultancy: Janssen; Advisory/Consultancy: Merck; Advisory/Consultancy: Mirati Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: QED Therapeutics; Advisory/Consultancy: Roche; Advisory/Consultancy: Seattle Genetics; Research grant/Funding (institution): Debiopharm Group; Research grant/Funding (institution): Immunomedics. A. Necchi: Advisory/Consultancy, Shareholder/Stockholder/Stock options, Full/Part-time employment, Non-remunerated activity/ies: Bayer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self): Foundation Medicine; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck/Merck Sharp&Dohme; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Incyte; Advisory/Consultancy, Travel/Accommodation/Expenses: Rainier Therapeutics; Advisory/Consultancy: Seattle Genetics/Astellas. J. Elvin: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.. J-A. Vergilio: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. D.I. Lin: Full/Part-time employment: Foundation Medicine Inc.. E. Williams: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. M. Hiemenz: Full/Part-time employment: Foundation Medicine Inc. J. Tse: Full/Part-time employment: Foundation Medicine Inc. M. Lechpammer: Full/Part-time employment: Foundation Medicine Inc. J.K. Killian: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.. S. Ramkissoon: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. E. Severson: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.; Full/Part-time employment: Partners Healthcare. A. Hemmerich: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. R. Huang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.; Licensing/Royalties, patents: Roche. D. Duncan: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. N.A. Danziger: Full/Part-time employment: Foundation Medicine Inc. J.S. Ross: Leadership role, Research grant/Funding (self), Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.; Advisory/Consultancy: Celsius Therapeutics. All other authors have declared no conflicts of interest.