DOI: 10.6084/m9.figshare.7951703
title: The mTOR downstream regulator (p-4EBP1) is a novel independent prognostic marker in ovarian cancer

description: Ovarian cancer is associated with the highest mortality rate among gynaecologic malignancies. There is a need to refine the classification of ovarian cancer and identify novel targets. The mammalian target of rapamycin (mTOR) pathway has a crucial role in the pathogenesis and progression of ovarian cancer. This study aims to investigate the prognostic role of p-mTOR and its major downstream effectors p-4EBP1 (eukaryotic initiation factor 4E-binding protein 1) and p-P70S6K (ribosomal protein S6 kinase) in ovarian cancer. p-mTOR, p-4EBP1 and p-P70S6K protein expression was assessed on 195 consecutive ovarian epithelial cancers and correlated to clinicopathological features and survival. We found that high cytoplasmic expression of p-4EBP1 and p-P70S6K was associated with a serous type carcinoma (<i>p</i> = .005) and an advanced FIGO stage (<i>p</i> = .012), respectively. Univariate outcome analysis showed an inverse association between a high expression of p-4EBP1 expression and overall ovarian cancer survival (OS; <i>p</i> = .005) and progression-free survival (PFS; <i>p</i> = .005). p-P70S6K showed an inverse association with PFS (<i>p</i> = .001). Multivariate analyses indicated that p-4EBP1 was an independent predictor of both OS and PFS (<i>p</i> = .016 and <i>p</i> = .041, respectively). Therefore, we concluded that p-4EBP1 high protein expression is an independent predictor of outcome in ovarian cancer patients. Therefore, it could be used as a potential biomarker for prognostic stratification and treatment decisions.Impact statement<b>What is already known on this subject?</b> The mammalian target of rapamycin (mTOR) pathway has a crucial role in the pathogenesis and progression of ovarian cancer. To-date, very limited knowledge is known about the importance of mTOR major downstream effectors p-4EBP1 (eukaryotic initiation factor 4E-binding protein 1) and p-P70S6K (ribosomal protein S6 kinase) in ovarian cancer.<b>What do the results of this study add?</b> In this study, we have provided further evidence of the adverse prognostic behaviour associated with the positive expression of p-mTOR and its major downstream effectors. Moreover and by performing multivariate analysis, we for the first time have proved that p-4EBP1 is an independent predictor of clinical outcome in ovarian cancer.<b>What are the implications of these findings for clinical practice and/or further research?</b> p-4EBP1 could be used as a potential biomarker for prognostic stratification and treatment decisions in ovarian cancer management. <b>What is already known on this subject?</b> The mammalian target of rapamycin (mTOR) pathway has a crucial role in the pathogenesis and progression of ovarian cancer. To-date, very limited knowledge is known about the importance of mTOR major downstream effectors p-4EBP1 (eukaryotic initiation factor 4E-binding protein 1) and p-P70S6K (ribosomal protein S6 kinase) in ovarian cancer. <b>What do the results of this study add?</b> In this study, we have provided further evidence of the adverse prognostic behaviour associated with the positive expression of p-mTOR and its major downstream effectors. Moreover and by performing multivariate analysis, we for the first time have proved that p-4EBP1 is an independent predictor of clinical outcome in ovarian cancer. <b>What are the implications of these findings for clinical practice and/or further research?</b> p-4EBP1 could be used as a potential biomarker for prognostic stratification and treatment decisions in ovarian cancer management.