Background: An integrative analysis was conducted to identify genomic alterations and mutational status on the gene pathway level that could predict OS in pts with urothelial cancers (UC) treated with platinum chemotherapy. Methods: DNA was extracted from FFPE samples from invasive UC and screened for mutations and CNAs. Of those, complete clinical data was available from 85 pts. Mutations were analyzed by a mass-spectrometry based genotyping platform (Oncomap v3) and genomic imbalances were detected by comparative genomic hybridization (CGH) analysis. Regions with threshold of log² ratio ≥0.4, or ≤ -0.3 were defined as either having copy number gain or loss with significant CNAs determined using a GISTIC analysis.To better define the co-occurrence pattern of mutations and CNAs, we grouped genes into 3 core signal transduction pathways: 1) TP53 pathway; 2) RTK-RAS-RAF pathway including ERBB2, FGFR3, MET, FGFR1, KRAS BRAF, RAF1 and NF1; 3) PI3K/AKT pathway including PTEN, PIK3CA, AKT1, TSC1 and MTOR. OS was measured from treatment to time of death or censored. Cox regression was used to assess pathways abnormalities and mutations with outcome. Results: 35 out of 94 samples (41%) platinum treated pts with advanced UT, harbored mutations on at least 1 gene, mainly TP53 (16%), PIK3CA (9%), FGFR3 (2%), HRAS/KRAS (5%) and CTNNB1 (1%). 66%of pts had some sort of CNA. PI3K/AKT was the most affected pathway and was associated with shorter overall survival (hazard ratio (HR) 2.3, 95% CI: 1.3-4.2). There was no significant association between mutational status and OS. PIK3CA/AKT pathway alteration (mutations +CNV) may have the greatest impact on OS (p=0.055). Over-expression of CTNNB1 (p=0.0008) and PIK3CA (p=0.02) was associated with decreased OS. Among other individual genomic alterations, TP53 mutations (p=0.07) ,mTOR gain (p=0.07) and PTEN over expression (p=0.08) were marginally significant negative impact on OS. Conclusions: Our results suggest that targeted therapies focusing on the PIK3CA pathway alterations can generate the greatest impact in the overall patient population of metastatic UC.