Elsevier

Gynecologic Oncology

Volume 138, Issue 3, September 2015, Pages 640-646
Gynecologic Oncology

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

https://doi.org/10.1016/j.ygyno.2015.06.021Get rights and content

Highlights

  • The Copenhagen Index differentiates benign and malignant ovarian masses.

  • The Copenhagen Index may optimize referral of women with suspected ovarian cancer.

  • The Copenhagen Index is a simple index based on age, CA125 and HE4.

Abstract

Aim

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).

Patients and 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-offof 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.

Conclusion

All three indices perform well at the clinically relevant sensitivityof 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.

Introduction

Correct referral of patients with an ovarian mass of potential malignant nature is a necessity to optimize treatment and prognosis of patients with ovarian cancer (OC). Benign ovarian masses can be managed at local gynecologic departments, while suspected OC should be treated by a multidisciplinary team at a tertiary center. The treatment of OC patients by trained specialists in gynecologic oncology has been shown to enhance overall survival [1], [2], [3], [4], [5].

In Denmark, as well as in several other countries, the Risk of Malignancy Index (RMI) consisting of serum cancer antigen 125 (CA125) level, specific ultrasound findings and menopausal status is the standard method of detecting patients at high risk of OC [6]. Because the RMI depends on the result of an ultrasound examination, only gynecologists or other trained ultrasonographers can refer directly to tertiary centers resulting in increased costs and potential diagnostic delay.

Human Epididymis Protein 4 (HE4) performs as well as serum CA125 in differentiating OC from benign ovarian disease and shows an additive effect when combined [7], [8], [9]. The Risk Of Malignancy Algorithm (ROMA), based on serum CA125 level, serum HE4 level and menopausal status, has been demonstrated to distinguish OC from benign ovarian masses as well as the ultrasound dependent RMI at a set specificity (SP) (75%) [10]. However, divergent results have been reported from other centers in the validation of ROMA [11], [12], [13], [14], [15], [16], [17], [18], [19]. All three variables in ROMA are easy to obtain from visit at the general practitioner. It is therefore less time and resource consuming compared to RMI. However, menopausal status can be a clinical challenge due to varying definitions (different age limits, no menstrual bleed for more than one year, serum follicle-stimulating hormone (FSH) levels etc.). In contrast, age is an easy obtainable and reproducible variable. Furthermore, serum HE4 level steadily increases with age with no sudden increase at the time of the menopause [20], [21], [22]; hence age might improve the performance of an index utilizing serum HE4 level.

The primary aim of this study was to develop the Copenhagen Index (CPH-I), an index based on serum CA125, serum HE4 and age, to improve referral of patients with suspected OC to a tertiary center. The secondary aim was to validate the CPH-I in an international multicenter study, and to compare the CPH-I with the two established diagnostic indices ROMA and RMI.

Section snippets

Patients and methods

This study was a prospective, multicenter study with use of archived blood samples. Local ethics committees approved the local protocol for each recruitment center.

The REMARK guidelines [23] were followed to the extent possible for diagnostic biomarkers.

Results

Overall, 2665 patients were included from nine independent studies. The distribution in all studies is presented in Table 1. Table 2 demonstrates the median and range for HE4, CA125 and age.

Discussion

Numerous efforts have been made to develop an index to differentiate OC from benign ovarian disease. In particular, an index that discriminates early stage OC from benign ovarian disease is desirable due to the poor prognosis when OC has spread beyond the ovaries. The RMI is widely used for diagnostic purpose and has been demonstrated to distinguish OC from benign ovarian masses with a SN of 92% and a SP of 82% (cut-off = 200) when used in a tertiary center [27]. Other ultrasound-based prediction

Conflict of interest

Beth Schodin is employed by Abbott Laboratories and has stocks in the company.

Adam Rosenthal has received honoraria from Fujirebio Diagnostics for lecturing at conferences on topics not involving HE4.

Karin Sundfeldt was a member of an advisory board at one occasion (June 2012) for Fujirebio Inc.

Acknowledgments

We thank all eight international collaborative study groups for collecting and analyzing blood samples, registering clinical data and kindly sharing their results in order to validate the Copenhagen Index.

The Asian data were a part of the AsiaPac study, including patients from six Asian centers, and the authors kindly thank the following:

  • Karen KL Chan, Department of Obstetrics and Gynecology, University of Hong Kong, Hong Kong; Chi-An Chen, Department of Obstetrics and Gynecology, National

References (33)

  • S. Kondalsamy-Chennakesavan et al.

    Differentiating stage 1 epithelial ovarian cancer from benign ovarian tumours using a combination of tumour markers HE4, CA125, and CEA and patient's age

    Gynecol. Oncol.

    (2013)
  • A. Stiekema et al.

    Serum human epididymal protein 4 (HE4) as biomarker for the differentiation between epithelial ovarian cancer and ovarian metastases of gastrointestinal origin

    Gynecol. Oncol.

    (2015)
  • C.C. Earle et al.

    Effect of surgeon specialty on processes of care and outcomes for ovarian cancer patients

    J. Natl. Cancer Inst.

    (2006)
  • T. Paulsen et al.

    Improved short-term survival for advanced ovarian, tubal, and peritoneal cancer patients operated at teaching hospitals

    Int. J. Gynecol. Cancer

    (2006)
  • C.L. Fago-Olsen et al.

    Centralized treatment of advanced stages of ovarian cancer improves survival: a nationwide Danish survey

    Acta Obstet. Gynecol. Scand.

    (2011)
  • Retningslinier for visitation, diagnostik og kontrol af epithelial ovarie-, tuba- og primær peritonealcancer samt borderlinetumorer [database on the Internet]

    (2009)
  • Cited by (0)

    View full text