No benefit from combining HE4 and CA125 as ovarian tumor markers in a clinical setting
Research Highlights
► HE4 has a higher sensitivity and specificity in detecting ovarian borderline tumors and early FIGO stage epithelial ovarian and tubal cancers. ► HE4 by itself is equivalent to ROMA ► There is no benefit of measuring both HE4 and CA125 in a clinical setting except in a premenopausal patient with high CA125 and complex pelvic mass, where HE4 could help to detect endometriosis.
Introduction
Since its introduction CA125 has been the only clinically useful tumor marker for the detection of epithelial ovarian cancers (EOC) [1]. At present, the overall five-year survival for patients with EOC is 40% due to 75% of patients being diagnosed as advanced stage disease. In the absence of early detection markers, the risk of malignancy index (RMI) is currently being used in combination with CA125 [2]. Its fast and easy calculation enables gynecologists to triage patients with probable EOC to specialized gynecological oncology centers [3].
As combined tumor markers might detect a larger fraction of early FIGO stage EOC, several efforts have been undertaken to identify adjuncts to CA125 [4], [5], [6], [7]. HE4 (Human Epididymis 4) has evolved as a promising marker identified during the genomic era [8] with several studies reporting elevated mRNA expression of HE4 in various subtypes of EOC [5], [6], [7], [9], [10], [11] prompting investigations on its usefulness as a new tumor marker [10], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]. Whilst no study has examined the predictive value of HE4 within RMI, a recent publication has proposed a new risk of malignancy algorithm (ROMA) which combines a logarithmical formula of HE4 levels with the menopausal status [19].
With the increasing clinical availability of HE4, our aim was to define the clinical benefit gained by adding it to the present panel of ovarian tumor markers. We measured the detection efficacy of HE4 compared to CA125 within various risk indices with the aim to identify clear benefits compared to existing clinical alternatives. This is therefore the first study which measured and compared not only individual HE4 and CA125 detection rates within various gynecological cancers but also their combination alone and in two clinically available risk models, RMI and ROMA.
Section snippets
ELISA
Patients admitted to the University Hospital Zurich were prospectively included after giving informed consent in accordance with ethical regulations (SPUK, Canton of Zurich, Switzerland). Patients with a history of cancer or autoimmune diseases were excluded. Three major patient groups were evaluated: 1. proven healthy patients based on normal findings during surgery due to false ultrasonic abnormalities or therapeutic procedures like tubal ligation; 2. abnormalities/benign diseases diagnosed
Results
Our cohort consisted of 160 patients divided into three independent sub-groups, (1) thirty-three healthy controls, (2) seventy-one patients with benign diseases, and (3) fifty-six tumor patients. The benign cohort consisted of cystadenomas (n = 32), teratomas (n = 12) and endometriomas (n = 20) whilst the tumor cohort incorporated patients with ovarian and peritoneal borderline tumors (n = 8), endometrial cancers (n = 5), adenocarcinoma of ovarian (n = 29), tubal (n = 6) and peritoneal (n = 5) origin and
Conclusion
Emerging from the genomic era, HE is the most prominent and second commercially available tumor marker for EOC. Recent studies observed a better diagnostic performance of HE4 compared to CA125 (Table 4), however, it is difficult to directly compare these publications because the detection threshold has been variable and cancer sensitivity and specificity was measured either in relation to benign diseases or healthy controls (Table 4). We ensured that only individuals with proven negative
Conflict of interest statement
This work was partially funded by Fujirebio Diagnostics, Goteborg, Sweden (VHS). None of the other authors declare a conflict of interest.
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These authors contributed equally.