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
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
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