Correlation of Co-expression of multiple IHC markers with gene expression Signature to determine PI3K pathway activation in prostate cancer / Habiba Mohamed Saleh Elfandy ; Supervised Hoda Abdelraouf Ismail , Massimo Loda , Asmaa Ibrahim Salama

Thesis (Ph.D.) - Cairo University - National Cancer Institute - Department of Oncology-Pathology

Introduction: Phosphatidylinositol 3-kinase (PI3K) pathway is an oncogenic pathway linked to prostate cancer progression and therapy resistance. The predictive biomarker that could capture PI3K activity to inform therapy in archival tissue material is still lacking. Material and methods: Here we described the application of multiplexed immunofluorescent panel to quantitatively evaluate in situ cellular level of PTEN, pS6 and STMN1 expression aiming to predict the activity of PI3K signaling pathway. We evaluated the multiplexed panel in primary prostate cancer cohort (n=775) with a median follow-up of 13.4 years. Then, we generated 7-tier scores of the PI3K activity by combining the averaged staining intensity of PTEN, pS6 and STMN1. We investigated their association of the dichotomized scores (active PI3K and inactive PI3K) with clinicopathologic factors (PSA level, Ki67, Gleason Score, stage and tumor lethality). Then, we tested the association of activation score with the gene expression profile. Results: Our results show an increase in Ki67 proliferation index with the increase in the PI3K activation scores (r= 0.86, 95% confidence interval [CI], 0.3{u2013}0.98; p=0.013). In univariate analysis, tumors with PI3K high were more likely to develop lethal disease (47.89% vs 35.8%; Odds ratio [OR], 1.95; 95%CI, 1.19- 3.2; p= 0.0075). No association was observed between PI3K activation scores and Gleason score or tumor stage. Reduced PTEN expression was correlated with tumor stage, cribriform morphology and Gleason score. STMN1 and pS6 high scores are associated with Increased tumor proliferation

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