title: ERCC1-positive circulating tumor cells in the blood of ovarian cancer patients as a predictive biomarker for platinum resistance.
abstract: BACKGROUND
  Platinum resistance constitutes one of the most recognized clinical challenges for ovarian cancer. Notably, the detection of the primary tumor-based excision repair cross-complementation group 1 (ERCC1) protein by immunohistochemistry was recently shown to be inaccurate for the prediction of platinum resistance. On the basis of the previous finding that circulating tumor cells (CTC) in the blood of ovarian cancer patients are prognostically significant, and given our hypothesis that the negative prognostic impact of CTC may arise from a cellular phenotype associated with platinum resistance, we asked whether expression of the excision repair cross-complementation group 1 (ERCC1) gene in the form of the ERCC1 transcript in CTC may be a suitable blood-based biomarker for platinum resistance.
  
  
  METHODS
  The presence of CTC was analyzed by immunomagnetic CTC enrichment (n = 143 patients) targeting the epithelial epitopes epithelial cell adhesion molecule (EPCAM) (also known as GA733-2) and mucin 1, cell surface associated (MUC1), followed by multiplex reverse-transcription PCR to detect the transcripts EPCAM, MUC1, and mucin 16, cell surface associated (MUC16) (also known as CA125), including ERCC1 transcripts in a separate approach. ERCC1 expression in primary tumors was comparatively assessed by immunohistochemistry, using the antibody 8F1.
  
  
  RESULTS
  At primary diagnosis, the presence of CTC was observed in 14% of patients and constituted an independent predictor of overall survival (OS) (P = 0.041). ERCC1-positive CTC (ERCC1(+)CTC) were observed in 8% of patients and constituted an independent predictor, not only for OS but also for progression-free survival (PFS) (P = 0.026 and P = 0.009, respectively). More interestingly, we discovered the presence of ERCC1(+)CTC at primary diagnosis to be likewise an independent predictor of platinum resistance (P = 0.010), whereas ERCC1 expression in corresponding primary tumor tissue predicted neither platinum resistance nor prognosis.
  
  
  CONCLUSIONS
  The presence of ERCC1(+)CTC can serve as a blood-based diagnostic biomarker for predicting platinum resistance at primary diagnosis of ovarian cancer.
authors.affiliation: Department of Gynecology and Obstetrics, West German Cancer Center, University Hospital of Essen, Essen, Germany; Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany; jan.kuhlmann@uniklinikum-dresden.de.
authors.forename: Jan Dominik
authors.initials: JD
authors.lastname: Kuhlmann
authors.affiliation: Department of Gynecology and Obstetrics, West German Cancer Center, University Hospital of Essen, Essen, Germany; Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Pauline
authors.initials: P
authors.lastname: Wimberger
authors.affiliation: German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pathology and Neuropathology, University Hospital of Essen, Essen, Germany;
authors.forename: Agnes
authors.initials: A
authors.lastname: Bankfalvi
authors.affiliation: Acomed Statistics, Leipzig, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Keller
authors.affiliation: Department of Pathology and Neuropathology, University Hospital of Essen, Essen, Germany;
authors.forename: Sarah
authors.initials: S
authors.lastname: Schöler
authors.affiliation: Department of Gynecology and Obstetrics, West German Cancer Center, University Hospital of Essen, Essen, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Bahriye
authors.initials: B
authors.lastname: Aktas
authors.affiliation: Department of Gynecology and Obstetrics, West German Cancer Center, University Hospital of Essen, Essen, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Paul
authors.initials: P
authors.lastname: Buderath
authors.affiliation: Adnagen AG, Langenhagen, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hauch
authors.affiliation: Department of Pathology and Neuropathology, University Hospital of Essen, Essen, Germany;
authors.forename: Friedrich
authors.initials: F
authors.lastname: Otterbach
authors.affiliation: Department of Gynecology and Obstetrics, West German Cancer Center, University Hospital of Essen, Essen, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Rainer
authors.initials: R
authors.lastname: Kimmig
authors.affiliation: Department of Gynecology and Obstetrics, West German Cancer Center, University Hospital of Essen, Essen, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Sabine
authors.initials: S
authors.lastname: Kasimir-Bauer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D004268:DNA-Binding Proteins / Q000235:genetics*; D003627:Data Interpretation, Statistical; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017671:Platinum Compounds / Q000008:administration & dosage / Q000627:therapeutic use; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D017671:Platinum Compounds; C071447:ERCC1 protein, human; D004720:Endonucleases