Molecular profiling of infiltrating urothelial carcinoma of the bladder.

Abstract

311 Background: Infiltrating urothelial carcinoma (UC) is the most common variant of urinary bladder cancer. The prognosis for muscle infiltrating or metastatic UC of the bladder is poor with no major advances made in the last 20 years. We investigated a large cohort of such patients for specific genetic/biomarker alterations and compared them to other, less common urothelial malignancies. Methods: We reviewed 602 cases; 518 cases (86%) were locally advanced or metastatic UCs of the bladder and the remaining 84 cases (14%) were non-bladder UCs. Multiple methodologies for optimal assessment of biomarker expression (Caris Molecular Intelligence, Caris Life Sciences, Phoenix, AZ) were employed: Mutation analysis (Next-generation sequencing, Sanger, pyrosequencing, qPCR, RFLP), in-situ hybridization (fluorescent and chromogenic), immunohistochemistry, and RNA fragment analysis. Results: Bladder UC showed slightly higher rates of HER2/neu gene amplification (12% in bladder vs. 6% non-bladder, p=0.32) and EGFR gene amplification (22% vs. 12%, p=0.25). HER2/neu and EGFR protein expressions were more common in the bladder than in non-bladder sites (10% vs. 1%, p=0.03, and 77% vs. 60%, p=0.5, respectively). Pathogenic mutations in HER2/neu and EGFR were rare. Although c-Kit and c-Met receptor kinases were more frequently overexpressed in bladder than in non-bladder cancers (10% vs. 6% and 25% vs. 8%, respectively), activating mutations were also rare. PIK3CA and/or PTEN mutations were more frequently observed in non-bladder (27%) than in bladder UCs (21%). Non-bladder UC harbored high FGFR3 gene mutation (33%), which was not observed in any of the UC of the bladder (p=0.02). TP53 gene mutations were frequently identified in both bladder and in non-bladder cancers (49% vs. 27%, respectively, p=0.15), while KRAS was frequently mutated in the bladder adenocarcinomas (56%, p<0.001). Other therapeutically targetable biomarkers over-expressed in bladder UC compared to non-bladder UC included androgen receptor (16% vs. 8%, p=0.07) and MGMT (63% vs. 47%). Conclusions: Comprehensive molecular profiling of urothelial carcinoma identifies a number of potentially actionable targets, which can be managed by the novel treatment modalities.