title: A novel diagnostic index combining HE4, CA125 and age may improve triage of women with suspected ovarian cancer - An international multicenter study in women with an ovarian mass.
abstract: OBJECTIVE
  To develop and validate a biomarker-based index to optimize referral and diagnosis of patients with suspected ovarian cancer. Furthermore, to compare this new index with the Risk of Malignancy Index (RMI) and Risk of Ovarian Malignancy Algorithm (ROMA).
  
  
  METHODS
  A training study, consisting of patients with benign ovarian disease (n=809) and ovarian cancer (n=246), was used to develop the Copenhagen Index (CPH-I) utilizing the variables serum HE4, serum CA125 and patient age. Eight international studies provided the validation population; comprising 1060 patients with benign ovarian masses and 550 patients with ovarian cancer.
  
  
  RESULTS
  Overall, 2665 patients were included. CPH-I was highly significant in discriminating benign from malignant ovarian disease. At the defined cut-off of 0.070 for CPH-I the sensitivity and specificity were 95.0% and 78.4% respectively in the training cohort and 82.0% and 88.4% in the validation cohort. Comparison of CPH-I, ROMA and RMI demonstrated area-under-curve (AUC) at 0.960, 0.954 and 0.959 respectively in the training study and 0.951, 0.953 and 0.935 respectively in the validation study. Using a sensitivity of 95.0%, the specificities for CPH-I, ROMA and RMI in the training cohort were 78.4%, 71.7% and 81.5% respectively, and in the validation cohort 67.3%, 70.7% and 69.5% respectively.
  
  
  CONCLUSIONS
  All three indices perform well at the clinically relevant sensitivity of 95%, but CPH-I, unlike RMI and ROMA, is independent of ultrasound and menopausal status, and may provide a simple index to optimize referral of women with suspected ovarian cancer.
authors.affiliation: Department of Pathology, Molecular Unit, Herlev University Hospital, University of Copenhagen, Herlev, Denmark; Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address: mona.aarenstrup.karlsen@regionh.dk.
authors.forename: Mona A
authors.initials: MA
authors.lastname: Karlsen
authors.affiliation: Department of Pathology, Molecular Unit, Herlev University Hospital, University of Copenhagen, Herlev, Denmark.
authors.forename: Estrid V S
authors.initials: EV
authors.lastname: Høgdall
authors.affiliation: Finsen Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ib J
authors.initials: IJ
authors.lastname: Christensen
authors.affiliation: Department of Obstetrics and Gynecology, Skåne University Hospital, Lund, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Borgfeldt
authors.affiliation: Department of Obstetrics and Gynecology, Skåne University Hospital, Lund, Sweden.
authors.forename: Grigorios
authors.initials: G
authors.lastname: Kalapotharakos
authors.affiliation: Department of Laboratory Medicine, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Zdrazilova-Dubska
authors.affiliation: Department of Gynecologic Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Chovanec
authors.affiliation: Department of Gynecologic Oncology, Center for Gynecologic Oncology Amsterdam, Antoni van Leeuwenhoek Hospital, The Netherlands.
authors.forename: Christianne A R
authors.initials: CA
authors.lastname: Lok
authors.affiliation: Department of Gynecologic Oncology, Center for Gynecologic Oncology Amsterdam, Antoni van Leeuwenhoek Hospital, The Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Stiekema
authors.affiliation: Department of Gynecology and Obstetrics, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Irene
authors.initials: I
authors.lastname: Mutz-Dehbalaie
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK; Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, UK.
authors.forename: Adam N
authors.initials: AN
authors.lastname: Rosenthal
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Moore
authors.affiliation: Abbott Diagnostics, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Schodin
authors.affiliation: Department of Obstetrics and Gynecology, MCU-FDT Medical Foundation, Philippines.
authors.forename: Walfrido W
authors.initials: WW
authors.lastname: Sumpaico
authors.affiliation: Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Sundfeldt
authors.affiliation: Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Björg
authors.initials: B
authors.lastname: Kristjansdottir
authors.affiliation: Gynecologic Oncology Unit, La Paz University Hospital, Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Zapardiel
authors.affiliation: Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Claus K
authors.initials: CK
authors.lastname: Høgdall
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000097:blood*; D018394:CA-125 Antigen / Q000097:blood*; D015331:Cohort Studies; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000097:blood*; D008875:Middle Aged; D015233:Models, Statistical; D015999:Multivariate Analysis; D010049:Ovarian Diseases / Q000097:blood / Q000175:diagnosis / Q000473:pathology; D010051:Ovarian Neoplasms / Q000097:blood* / Q000175:diagnosis* / Q000473:pathology; D011446:Prospective Studies; D011506:Proteins / Q000378:metabolism*; D012720:Severity of Illness Index; D000081102:WAP Four-Disulfide Core Domain Protein 2; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; C451759:MUC16 protein, human; D008565:Membrane Proteins; D011506:Proteins; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human
keywords: Age; Biomarkers; CA125; CPH-I; Copenhagen Index; HE4; Ovarian cancer; Tumor markers