Abstract 3203: Oncogenic pathways analysis and survival outcome in advanced serous ovarian cancer

Abstract

Abstract INTRODUCTION AND OBJECTIVES: Ovarian cancer is the leading cause of mortality among gynecological cancers. Identification of relevant pathways may contribute in individualization of treatment strategies. The objective of this study was to relate cellular pathway activation to survival outcome. Since survival is studied, a selection was made of patients with advanced stages of serous papillary carcinoma with uniform treatment to detect differences without histology-, stage- and treatment- induced biases. MATERIAL AND METHODS: Two publicly available microarray datasets of advanced stage (III and IV) ovarian cancer samples (N=165, N=125) were analyzed for oncogenic pathways (AKT, BetaCatenin, E2F1, EGFR, ER, HER2, MYC, INFa, IFNg, p53, p63, PI3K, PR, RAS, SRC, STAT3, TNFa, TGFb, VEGFA) (Gatza et al. PNAS 2010, Hu et al. BMC Med 2009). These pathway gene signatures were correlated with survival outcome and 3 prognostic gene signatures (Wound Response Signature WHR, Genomic Grade Index GGI and the Invasiveness Gene Signature IGS). RESULTS AND DISCUSSION: Although the WHR, GGI, and IGS have shown prognostic value in breast cancer and other malignancies, these three prognostic signatures showed opposite survival outcome in this selected population of advanced serous papillary carcinomas. Patients with a higher genomic grade had a better survival outcome than lower genomic grade tumors. Since proliferation genes seems to be the driving force within these prognostic signatures, this observation is concordant with earlier findings that tumors with high proliferation index are more chemosensitive. We furthermore show that an activated BetaCatenin, RAS and p63 pathway was associated with favorable survival outcome in both datasets (p<0.05) displaying the predictive value of combination carboplatinum-taxane chemotherapy. Furthermore these oncogenic pathways were significantly correlated with IGS, WHR and GGI (p<0.001), suggesting that these pathways contribute to chemosensitivity. These data are in line with findings of recent clinical findings that inhibition of farnesyltransferase (and downstream RAS pathway) in combination with carbotaxol in first line was not beneficial or even significantly inferior to carbotaxol alone. CONCLUSIONS: Microarray analysis of two independent datasets shows that activation of the BetaCatenin, RAS and p63 oncogenic pathways were consistently of predictive value for carboplatinum-taxane chemotherapy in advanced stage serous papillary ovarian cancer. Since these pathways may contribute to proliferation and consequent chemosensitivity, these findings may be of clinical importance for designing treatment strategies. Validation studies are ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3203. doi:10.1158/1538-7445.AM2011-3203