title: Development and validation of a microRNA-based signature (MiROvaR) to predict early relapse or progression of epithelial ovarian cancer: a cohort study.
abstract: Risk of relapse or progression remains high in the treatment of most patients with epithelial ovarian cancer, and development of a molecular predictor could be a valuable tool for stratification of patients by risk. We aimed to develop a microRNA (miRNA)-based molecular classifier that can predict risk of progression or relapse in patients with epithelial ovarian cancer.
  
  
  
  We analysed miRNA expression profiles in three cohorts of samples collected at diagnosis. We used 179 samples from a Multicenter Italian Trial in Ovarian cancer trial (cohort OC179) to develop the model and 263 samples from two cancer centres (cohort OC263) and 452 samples from The Cancer Genome Atlas epithelial ovarian cancer series (cohort OC452) to validate the model. The primary clinical endpoint was progression-free survival, and we adapted a semi-supervised prediction method to the miRNA expression profile of OC179 to identify miRNAs that predict risk of progression. We assessed the independent prognostic role of the model using multivariable analysis with a Cox regression model.
  
  
  
  We identified 35 miRNAs that predicted risk of progression or relapse and used them to create a prognostic model, the 35-miRNA-based predictor of Risk of Ovarian Cancer Relapse or progression (MiROvaR). MiROvaR was able to classify patients in OC179 into a high-risk group (89 patients; median progression-free survival 18 months [95% CI 15-22]) and a low-risk group (90 patients; median progression-free survival 38 months [24-not estimable]; hazard ratio [HR] 1·85 [1·29-2·64], p=0·00082). MiROvaR was a significant predictor of progression in the two validation sets (OC263 HR 3·16, 95% CI 2·33-4·29, p<0·0001; OC452 HR 1·39, 95% CI 1·11-1·74, p=0·0047) and maintained its independent prognostic effect when adjusted for relevant clinical covariates using multivariable analyses (OC179: adjusted HR 1·48, 95% CI 1·03-2·13, p=0·036; OC263: adjusted HR 3·09 [2·24-4·28], p<0·0001; and OC452: HR 1·41 [1·11-1·79], p=0·0047).
  
  
  
  MiROvaR is a potential predictor of epithelial ovarian cancer progression and has prognostic value independent of relevant clinical covariates. MiROvaR warrants further investigation for the development of a clinical-grade prognostic assay.
  
  
  
  AIRC and CARIPLO Foundation.
authors.affiliation: Molecular Therapies Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Bagnoli
authors.affiliation: Functional Genomics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.affiliation: Functional Genomic Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G Pascale", IRCCS, Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Califano
authors.affiliation: Surgical Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G Pascale", IRCCS, Naples, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Losito
authors.affiliation: Clinical Trials Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G Pascale", IRCCS, Naples, Italy.
authors.forename: Massimo Di
authors.initials: MD
authors.lastname: Maio
authors.affiliation: Unit of Gynaecological Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Raspagliesi
authors.affiliation: Anatomic Pathology 1 Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Carcangiu
authors.affiliation: Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico, Istituto Ricovero e Cura Carattere Scientifico (CRO-IRCCS), Aviano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Toffoli
authors.affiliation: Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico, Istituto Ricovero e Cura Carattere Scientifico (CRO-IRCCS), Aviano, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Cecchin
authors.affiliation: Medical Oncology C, Centro di Riferimento Oncologico, Istituto Ricovero e Cura Carattere Scientifico (CRO-IRCCS), Aviano, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sorio
authors.affiliation: Unit of Pathology, Centro di Riferimento Oncologico, Istituto Ricovero e Cura Carattere Scientifico (CRO-IRCCS), Aviano, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Canzonieri
authors.affiliation: Functional Genomic Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G Pascale", IRCCS, Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Russo
authors.affiliation: Surgical Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G Pascale", IRCCS, Naples, Italy.
authors.forename: Giosué
authors.initials: G
authors.lastname: Scognamiglio
authors.affiliation: Functional Genomic Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G Pascale", IRCCS, Naples, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Chiappetta
authors.affiliation: Division of Experimental Oncology 2, Centro di Riferimento Oncologico, Istituto Ricovero e Cura Carattere Scientifico (CRO-IRCCS), Aviano, Italy.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
authors.affiliation: Unit of Gynaecological Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Lorusso
authors.affiliation: Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.affiliation: Department of Human Pathology, Division of Gynecologic Pathology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Zannoni
authors.affiliation: Division of Medical Oncology 1, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Savarese
authors.affiliation: Division of Pathology, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: Mariantonia
authors.initials: M
authors.lastname: Carosi
authors.affiliation: Department of Obstetrics and Gynecology, Azienda Ospedaliera Cannizzaro, Catania, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Scollo
authors.affiliation: Medical Oncology Unit Ospedale S Giovanni Calibita Fatebenefratelli, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Breda
authors.affiliation: Medical Oncology Unit Ospedale S Chiara, Trento, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Murgia
authors.affiliation: Clinical Trials Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G Pascale", IRCCS, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Perrone
authors.affiliation: Department of Urogynaecological Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G Pascale", IRCCS, Naples, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Pignata
authors.affiliation: Functional Genomics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Loris
authors.initials: L
authors.lastname: De Cecco
authors.affiliation: Molecular Therapies Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: delia.mezzanzanica@istitutotumori.mi.it.
authors.forename: Delia
authors.initials: D
authors.lastname: Mezzanzanica
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D015331:Cohort Studies; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D011379:Prognosis; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs