title: Serum human epididymal protein 4 (HE4) as biomarker for the differentiation between epithelial ovarian cancer and ovarian metastases of gastrointestinal origin.
abstract: OBJECTIVE
  About 5-15% of all malignant ovarian tumors are metastases from other malignancies such as gastrointestinal tumors, breast cancer or melanoma. Also other gynecological tumors can metastasize to the ovaries. It is crucial to differentiate between primary epithelial ovarian cancer (EOC) and ovarian metastases because different treatment is required. The clinical value of human epididymal secretory protein 4 (HE4) as a serum biomarker in primary ovarian cancer has been established. The use of HE4 in the differentiation between primary ovarian cancer and ovarian metastases from other malignancies has never been investigated.
  
  
  METHODS
  HE4, CA125 and CEA were measured in 192 patients with EOC (n=147) or ovarian metastases (n=40). Univariate and multivariate logistic regression analyses were done. Sensitivity, specificity and area under the curve (AUC) were calculated for all markers and ratios hereof using receiver operating characteristics methodology.
  
  
  RESULTS
  Median serum HE4 concentration was significantly higher in patients with EOC compared to patients with ovarian metastases (431 pmol/L vs 68 pmol/L, p<0.001). HE4 and CEA were independent factors in differentiating between EOC and ovarian metastases (both p<0.001) while CA125 was not (p=0.33). The HE4(2.5)/CEA ratio demonstrated the highest discriminative value (ROC-AUC 0.94) compared to HE4, CEA, CA125 or CA125/CEA ratio (0.88, 0.78, 0.80 and 0.89 respectively) and showed a specificity of 82.5% at set sensitivity of 90% in discriminating EOC from ovarian metastases.
  
  
  CONCLUSIONS
  HE4 can be used in combination with CEA to make the distinction between EOC and ovarian metastases from gastrointestinal origin.
authors.affiliation: Department of Gynecologic Oncology, Center for Gynecologic Oncology Amsterdam, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address: a.stiekema@nki.nl.
authors.forename: A
authors.initials: A
authors.lastname: Stiekema
authors.affiliation: Department of Gynecologic Oncology, Center for Gynecologic Oncology Amsterdam, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Q J A J
authors.initials: QJ
authors.lastname: Boldingh
authors.affiliation: Department of Clinical Chemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: Korse
authors.affiliation: Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: van der Noort
authors.affiliation: Department of Gastroenterology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Boot
authors.affiliation: Department of Gynecologic Oncology, Center for Gynecologic Oncology Amsterdam, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: W J
authors.initials: WJ
authors.lastname: van Driel
authors.affiliation: Department of Gynecologic Oncology, Center for Gynecologic Oncology Amsterdam, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: G G
authors.initials: GG
authors.lastname: Kenter
authors.affiliation: Department of Gynecologic Oncology, Center for Gynecologic Oncology Amsterdam, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: C A R
authors.initials: CA
authors.lastname: Lok
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000175:diagnosis / Q000556:secondary*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood*; D018394:CA-125 Antigen / Q000097:blood; D002272:Carcinoembryonic Antigen / Q000097:blood; D000077216:Carcinoma, Ovarian Epithelial; D015331:Cohort Studies; D003937:Diagnosis, Differential; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000175:diagnosis / Q000473:pathology*; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D015999:Multivariate Analysis; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000175:diagnosis*; D010051:Ovarian Neoplasms / Q000097:blood / Q000175:diagnosis / Q000556:secondary*; D011506:Proteins / Q000378:metabolism*; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D000081102:WAP Four-Disulfide Core Domain Protein 2
chemical_list: D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D002272:Carcinoembryonic Antigen; D011506:Proteins; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human
keywords: CA125; CEA; Epithelial ovarian cancer; HE4; Ovarian metastases