Alterations in the PI3K/Akt signaling pathway and association with outcome in invasive high-grade urothelial cancer (UC).

Abstract

277 Background: Activating mutations in PIK3CA have been associated with improved outcomes in patients (pts) with breast cancer (Kalinsky, Clin Cancer Res 2009). Molecular profiling of invasive high-grade UC demonstrates that PI3K/Akt pathway alterations occur in up to 15% of cases. The prognostic value of PI3K/Akt pathway alterations in invasive UC is unknown. Methods: Clinically annotated archival frozen surgical specimens from 95 pts (94 cystectomies, 1 nephroureterectomy) with high-grade invasive UC were genotyped for mutations in all coding exons of PIK3CA, PIK3R1, TSC1, PTEN and the AKT isoforms using high-throughput Sanger sequencing. Copy number alterations were examined using an Agilent 1M oligonucleotide array. Clinical variables including time to recurrence (TTR) and overall survival (OS) were correlated with the presence of mutations or copy number events in PIK3CA, PIK3R1, TSC1, PTEN and the AKT isoforms. Results: Specimens from 95 pts (71 M; 24 F) with a median age of 71 years (41-88) were evaluated. 34 (36%) received neoadjuvant chemotherapy and 75 (79%) were prior smokers. 4 pts (4%) had Stage 0, 11 (12%) had Stage I, 15 (16%) had Stage II, 33 (35%) had Stage III and 32 (34%) had Stage IV disease at surgery. The median follow-up was 31.5 months. Alterations (mutations or copy number gains/losses) in PI3K/Akt signaling pathway genes were identified in 26 (27%) specimens and were associated with a trend toward longer TTR, hazard ratio 0.53 (95%CI 0.24, 1.14) (p=0.08). Conclusions: Alterations in PI3K/Akt signaling in pts with invasive UC may be associated with an improvement in outcome similar to that observed in breast cancer. Further analysis in a large independent tumor set is ongoing.