Benvenuto G, Todeschini P, Paracchini L, et al. - Given the general sensitivity of high-grade serous ovarian cancer (HGS-EOCs) to front-line platinum (Pt)-based chemotherapy but the existing evidence of relapse with a progressive resistant disease in most patients at an advanced stage, researchers intended to generate clinical or molecular data to recognize primary resistant cases at diagnosis. From two independent tumor tissue collections, experts retrospectively picked HGS-EOC biopsies from 105 Pt-sensitive (Pt-s) and 89 Pt-resistant (Pt-r) patients. The discrimination of Pt-s from Pt-r cases was allowed by 131 mRNAs and five miRNAs belonging to distinct functionally associated molecular pathways. Using orthogonal approaches (SI signature), they validated 17 out of 23 selected elements. Since resistance to Pt was found to be related to a short progression-free survival (PFS) and overall survival (OS), the prognostic role of the SI signature was evaluated, and 14 genes related to PFS and OS, in multivariate analyses (SII signature). In a third extensive cohort, experts validated the SII signature for its prognostic value. The expression profiles of SDF2L1, PPP1R12A and PRKG1 genes (SIII signature) were identified as independent prognostic biomarkers of Pt-response and survival. Overall, a prognostic molecular signature was defined on the basis of the integrated expression profile of three genes which had never been related to the clinical result of HGS-EOC. The consequences of this may be early recognition, at the time of diagnosis, of patients for whom standard chemotherapy would not be greatly beneficial, and therefore, are eligible for new investigational approaches.