title: Identification of high-grade serous ovarian cancer miRNA species associated with survival and drug response in patients receiving neoadjuvant chemotherapy: a retrospective longitudinal analysis using matched tumor biopsies.
abstract: BACKGROUND
  Neoadjuvant chemotherapy (NACT) has been recognized as a reliable therapeutic strategy in patients with unresectable advanced epithelial ovarian cancer (EOC). The molecular events leading to platinum (Pt) response in NACT settings have hitherto not been explored. In the present work, longitudinal changes of miRNA expression profile were investigated to identify miRNA families with prognostic role in high-grade serous EOC patients who received the NACT regimen.
  
  
  METHODS
  One hundred sixty-four matched tumor biopsies taken at initial laparoscopic evaluation and at interval-debulking surgery (IDS) after four courses of Pt-based therapy were selected from 82 stage IIIC-IV high-grade serous-EOC patients that were judged unsuitable for complete primary debulking and subjected the NACT protocol. miRNA profiling by microarray, real-time PCR and immuno-histochemical staining for Smad2 phosphorylation (P-Smad2) were used for data analysis.
  
  
  RESULTS
  Analysis revealed that 369 miRNAs were differentially expressed in matched biopsies (referred to as DEMs). DEMs were not scattered across the genome, but clustered into families: miR-199, let-7, miR-30, miR-181 and miR-29. Multivariate analysis showed that miR-199a-3p, miR-199a-5p, miR-181a-5p and let-7g-5p associated with overall and progression-free survival (P < 0.05); miR-199a-3p, miR-199a-5p and miR-181a-5p associated with residual tumor volume and Pt-free interval (P < 0.05). Immuno-histochemical staining confirmed an enrichment of P-Smad2, a marker of transforming growth factor-β activation, in tumors from patients with shorter PFS and OS, and with high levels of expression of miR-181a-5p (P < 0.05). Kaplan-Meier curves plotting concomitant expression of P-Smad2 and miR-181a-5p show significant differences in PFS and OS compared with those depicting the expression of each biomarker alone (P < 0.001).
  
  
  CONCLUSIONS
  This study describes several miRNA families with a prognostic role in the NACT setting. It also confirms that concomitant analysis of P-Smad2 and miR-181a-5p in surgical samples may be capable of identifying those ovarian cancer patients with poor outcome and little chance of response to Pt-based NACT.
authors.affiliation: Department of Obstetrics and Gynaecology, Division of Gynaecologic Oncology.
authors.forename: M
authors.initials: M
authors.lastname: Petrillo
authors.affiliation: Department of Human Pathology, Catholic University of the Sacred Heart, Rome.
authors.forename: G F
authors.initials: GF
authors.lastname: Zannoni
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Beltrame
authors.affiliation: Department of Human Pathology, Catholic University of the Sacred Heart, Rome.
authors.forename: E
authors.initials: E
authors.lastname: Martinelli
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: DiFeo
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Paracchini
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Craparotta
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Mannarino
authors.affiliation: Department of Obstetrics and Gynaecology, Division of Gynaecologic Oncology.
authors.forename: G
authors.initials: G
authors.lastname: Vizzielli
authors.affiliation: Department of Obstetrics and Gynaecology, Division of Gynaecologic Oncology.
authors.forename: G
authors.initials: G
authors.lastname: Scambia
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy maurizio.dincalci@marionegri.it.
authors.forename: M
authors.initials: M
authors.lastname: D'Incalci
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Romualdi
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Marchini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D001706:Biopsy; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D051899:Smad2 Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; C497782:SMAD2 protein, human; D051899:Smad2 Protein
keywords: high-grade serous ovarian cancer; longitudinal matched tumor biopsies analysis; miR-181a-5p; neoadjuvant chemotherapy