Elsevier

Gynecologic Oncology

Volume 121, Issue 3, 1 June 2011, Pages 487-491
Gynecologic Oncology

No benefit from combining HE4 and CA125 as ovarian tumor markers in a clinical setting

https://doi.org/10.1016/j.ygyno.2011.02.022Get rights and content

Abstract

Objective

About 70% of epithelial ovarian cancer patients (EOC) are diagnosed at advanced stage with a five-year survival rate of only 30%. Whilst CA125 detects peritoneally-spread disease, it has limited sensitivity for early cancers, many of which are potentially curable.

Methods

We compared the new commercially available tumor marker HE4 with CA125 individually, in combination, within the risk of malignancy index (RMI) and the newly defined risk of malignancy algorithm (ROMA). Our prospectively-collected cohort of 160 patients consisted of healthy controls, benign diseases, and borderline tumors/adenocarcinomas of ovarian, tubal, peritoneal and endometrial origin. HE4 and CA125 were measured in serum using standardized ELISA.

Results

Both markers showed similar diagnostic performance in the detection of EOC at clinically defined thresholds (CA125 35 U/ml; HE4 70 pM) but HE4 was not elevated in endometriosis. Comparison of non-malignant diagnoses (n = 71) versus early stage ovarian and tubal cancers (n = 19) revealed that HE4 and ROMA displayed the best diagnostic performance (AUC 0.86/0.87, specificity 85.9%/87.3% and sensitivity 78.9%/78.9%, respectively). Whilst RMICA125 detects peritoneal cancer better than all other models (AUC 0.99, specificity 97.2%, sensitivity 80.0%), there is no other detection benefit from RMI compared to HE4 alone or included in ROMA.

Conclusions

The major advantage of HE4 lies in its specificity and improved detection of borderline tumors and early stage ovarian and tubal cancers. HE4 is superior to CA125 with or without RMI and ROMA indices. However, we see no benefit from combining both markers in clinical practice.

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.

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