Oxford Classic-defined EMT risk stratification of High Grade Serous Ovarian cancer for guiding treatment decisions

Abstract Purpose: The association between epithelial to mesenchymal transition in High Grade Serous Ovarian Cancer (HGSOC) and poor prognosis is known. However, molecularly defining a subset of tumours that reproducibly associates with poor prognosis has been an elusive goal in this disease. A molecular signature that can robustly identify patients with poor prognosis and guide treatment decisions, including surgical strategy and targeted therapies, can improve survival rates. Experimental Design: We carried out RNA sequencing of 139 tumour samples (Brescia cohort), an external validation on 362 and 126 patients from the Scottish and Garsed cohort, respectively; and meta-analysis of 1023 tumours to develop clinically useful risk groups. Identification of therapeutic targets was carried out by transcriptomic analyses of FLOW-sorted tumour epithelial cells from fresh tumours and multiplex IF assessment of tissue sections. Results: In this study we have validated the prognostic strength of the OxC-EMT in three independent patient cohorts- Brescia [HR=3.6 (95% CI=1.59-7.97), p=1.99e-03], Scottish [HR=1.71 (95% CI=1.08-2.70), p=2.23e-02] and Garsed [Kruskal-Wallis p=0.00071]. OxC-based risk-stratification of HGSOC can robustly identify poor risk patients with a 5-year median survival for OxC-EMT-high and OxC-EMT-low risk groups of 13% and 50%, respectively (95%CI: 7.1%-23.5% vs. 36.1%-69.3%) in the Brescia cohort. Further analysis of the risk groups suggests that an alternate surgical strategy and a combination therapy involving EMT targeting drugs and immunomodulators could elicit improved clinical response in poor risk patients. Conclusions: This study provides a clinically useful risk stratification strategy for HGSOC as well as targeted treatment options for high-risk patients.