title: Nibrin is a marker of clinical outcome in patients with advanced serous ovarian cancer treated in the phase III OVA-301 trial.
abstract: OBJECTIVE
  This study investigated the relationship between 13 proteins involved in DNA damage and the outcomes of patients with recurrent ovarian cancer (ROC).
  
  
  METHODS
  Immunohistochemistry staining was performed in 114 diagnostic samples from patients with serous ROC who participated in the OVA-301 study, which compared pegylated liposomal doxorubicin (PLD) with a combination of trabectedin plus PLD. Percentage of positive cells for every marker was calculated and correlated with overall response rate (ORR), progression-free survival (PFS) and overall survival (OS).
  
  
  RESULTS
  A statistically significant correlation between high levels of nibrin and lower ORR (P=0.03), shorter PFS (P=0.007) and shorter OS (P=0.01) was observed. After stratification, in patients with platinum-sensitive disease treated with the combination of trabectedin plus PLD, high levels of nibrin correlated with lower ORR (P=0.01) and shorter PFS (P=0.02). A better clinical outcome (ORR, PFS and OS) was also associated to low levels of CHK2 in trabectedin plus PLD treated patients. No correlations were found in PLD-treated patients. According to the results of a multivariate analysis, there was a statistically significant correlation between high nibrin (P=0.001) and low BRCA2 levels (P=0.03) and a worse PFS, and between high nibrin levels and a worse OS (P=0.006).
  
  
  CONCLUSIONS
  Our results indicate that high nibrin expression seems to be associated with a worse clinical outcome in serous ROC, particularly in patients treated with the combination trabectedin plus PLD. Prospective studies to determine clinical usefulness of nibrin as a possible biomarker in other series of patients with ROC are warranted.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, 500 W. Thomas Road, Suite 600, Phoenix, AZ 85013, USA. Electronic address: Bradley.Monk@DignityHealth.org.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Monk
authors.affiliation: Section of Medicine, Drug Development Unit, The Royal Marsden Hospital NHS Foundation Trust, Downs Road SM2 5PT, Sutton, UK. Electronic address: Stan.Kaye@rmh.nhs.uk.
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Kaye
authors.affiliation: Department of Medical Oncology, Valencian Institute of Oncology and GEICO, C/Prof Baguena, 19, 46009 Valencia, Spain. Electronic address: apoveda@fivo.org.
authors.forename: Andrés
authors.initials: A
authors.lastname: Poveda
authors.affiliation: Division of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 161 Fort Washington Avenue, New York, NY 10032, USA. Electronic address: th2135@cumc.columbia.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Herzog
authors.affiliation: PharmaMar, S.A., Avenida de los Reyes 1, P.I. La Mina Norte, Colmenar Viejo, 28770 (Madrid) Spain. Electronic address: maracil@pharmamar.com.
authors.forename: Miguel
authors.initials: M
authors.lastname: Aracil
authors.affiliation: PharmaMar, S.A., Avenida de los Reyes 1, P.I. La Mina Norte, Colmenar Viejo, 28770 (Madrid) Spain. Electronic address: anieto@pharmamar.com.
authors.forename: Antonio
authors.initials: A
authors.lastname: Nieto
authors.affiliation: PharmaMar, S.A., Avenida de los Reyes 1, P.I. La Mina Norte, Colmenar Viejo, 28770 (Madrid) Spain. Electronic address: nbadri@pharmamar.com.
authors.forename: Nadia
authors.initials: N
authors.lastname: Badri
authors.affiliation: Janssen Research & Development, LLC, 920 Rt 202 Raritan, NJ 08869, USA. Electronic address: TParekh1@ITS.JNJ.COM.
authors.forename: Trilok V
authors.initials: TV
authors.lastname: Parekh
authors.affiliation: PharmaMar, S.A., Avenida de los Reyes 1, P.I. La Mina Norte, Colmenar Viejo, 28770 (Madrid) Spain. Electronic address: atanovic@pharmamar.com.
authors.forename: Adnan
authors.initials: A
authors.lastname: Tanović
authors.affiliation: PharmaMar, S.A., Avenida de los Reyes 1, P.I. La Mina Norte, Colmenar Viejo, 28770 (Madrid) Spain. Electronic address: cgalmarini@pharmamar.com.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Galmarini
mesh_terms: D015415:Biomarkers; D018797:Cell Cycle Proteins / Q000032:analysis*; D018284:Cystadenocarcinoma, Serous / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality; D004149:Dioxoles / Q000627:therapeutic use; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000401:mortality; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000032:analysis*; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011092:Polyethylene Glycols / Q000627:therapeutic use; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use; D000077606:Trabectedin; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D018797:Cell Cycle Proteins; D004149:Dioxoles; C112156:NBN protein, human; D009687:Nuclear Proteins; D044005:Tetrahydroisoquinolines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000077606:Trabectedin
keywords: Molecular marker; Nibrin; Ovarian cancer; Trabectedin