Background

The Human epididymis protein 4 (HE4) [High quality immunoassay] (hereafter referred to as “HE4 test”), is a tumor marker test utilized for diagnosing ovarian cancer in patients suspected of having the disease, particularly those presenting with a pelvic mass. During the New Health Technology Assessment in 2014, this test was assessed to be a safe and effective adjunct to the cancer antigen 125 (CA125) test in diagnosing ovarian cancer. Following this assessment, the HE4 test was included as a selective benefit item in healthcare, necessitating an 80% patient co-payment and more than five years have passed since the conformity assessment cycle.

Based on a reassessment conformity review by the Clinical Advisory Board and a priority review by the Committee of Health Technology Reassessment, it was determined that the HE4 test should be verified by health technology reassessment because it, along with the CA125 test, commonly uses the Risk of Ovarian Malignancy Algorithm (ROMA) and is known to be a test with high sensitivity and specificity. The purpose of this reassessment was to re-evaluate the clinical safety and effectiveness of the HE4 test and to substantiate its role in the efficient use of public health resources.

Methods

To assess the safety and effectiveness of the HE4 test, a systematic review was conducted. The methodology for this review was determined by the “HE4 test subcommittee” (hereafter referred to as the “Subcommittee”). This Subcommittee, composed of five members, two with expertise in laboratory medicine, two from obstetrics/gynecology, and one from evidence-based medicine, focused on a key question, “Is the HE4 test clinically safe and effective for diagnosing ovarian cancer in suspected patients with a pelvic mass?” In practical clinical settings, the HE4 test is used in tandem with the CA125 test to differentiate between benign and malignant tumors in patients with high CA125 levels. The assessment involved diagnosing ovarian cancer using the ROMA, which incorporates both HE4 and CA125 levels. The assessment involved diagnosing ovarian cancer using the ROMA, which incorporated both HE4 and CA125 levels. Additionally, HE4 levels were monitored post-diagnosis to observe the treatment course and check for the recurrence of ovarian cancer. The assessment included ROMA as a part of the intervention process, but comparisons between the health outcomes of the HE4 test and ROMA were not considered, in line with the assessment's objective.

For the literature review, three international and five domestic databases were searched based on the key question. The articles were independently screened and selected by two reviewers according to specific inclusion and exclusion criteria. In cases of disagreement, a third reviewer was consulted to reach a consensus. The risk of bias (RoB) in the selected studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Data extraction was conducted using a predetermined format. The RoB assessment and data extraction processes were independently carried out by the two reviewers, with any disagreements resolved through discussion. For the assessment of diagnostic accuracy, a meta-analysis was performed using STATA/MP 14.2. Due to the variability in reported health outcomes, a qualitative review was conducted for evaluating the effectiveness of the HE4 test in identifying the treatment course and recurrence of ovarian cancer.

Results 

In the comprehensive assessment of the HE4 test's safety and effectiveness, a total of 46 studies were analyzed, all conducted outside of Korea. These studies encompassed a population of 13,093 patients suspected of having ovarian cancer, each presenting with either a pelvic mass or an adnexal tumor confirmed through physical examination or ultrasonography. Of these patients, histopathological findings identified 3,989 individuals (30.5%) with malignant tumors and 9,104 (69.5%) with benign tumors. Various methodologies were employed in these studies to perform the HE4 test, including enzyme-linked immunosorbent assay (11 studies), chemiluminescence microparticle immunoassay (14 studies), and electrochemiluminescent immunoassay (20 studies). Notably, one study, which reported on the treatment course and recurrence, did not specify the test method used. In terms of the RoB assessment, it was found that the RoB was high in 50% of the studies (23 studies) in the patient selection domain. Concerns about applicability were also high in 15.2% of these studies (2 studies). Furthermore, the RoB was high in 28.3% of the studies (13 studies) with high applicability concerns in 41.3% (18 studies) in the index test domain. Both the RoB and concern about applicability were low in the reference standard domain, and the RoB was low in 97.8% of the studies (45 studies) in the flow and timing domain.  

Safety

Regarding the safety of the HE4 test, it was assessed based on any test-related adverse events (AEs). However, it was noted that none of the studies reported such adverse events, indicating a lack of specific data concerning the direct safety implications of the HE4 test.

Effectiveness 

The effectiveness of the HE4 test was assessed based on its diagnostic accuracy, effectiveness in monitoring the treatment course, and detecting recurrence, all in comparison to the CA125 test. 

Diagnostic accuracy was reported in 40 studies, categorizing the patients as all patients (32 studies), pre-menopausal patients (21 studies), and menopausal patients (19 studies). The diagnostic accuracy of the ROMA was reported in 31 studies. The results showed that the HE4 test had a pooled sensitivity, pooled specificity, and pooled area under the curve (AUC) of 0.75(95% confidence interval [CI] 0.71–0.78), 0.95 (95% CI 0.92–0.97), and 0.90 (95% CI 0.87–0.92), respectively, among all patients (9,838 patients in 32 studies); 0.69 (95% CI 0.63–0.75), 0.95 (95% CI 0.92–0.97), and 0.89 (95% CI 0.86–0.91), respectively, among pre-menopausal patients (5,014 patients in 21 studies); and 0.78 (95% CI 0.72–0.83), 0.96 (95% CI 0.92–0.98), and 0.92 (95% CI 0.90–0.94), respectively, among menopausal patients (3,079 patients in 19 studies). The HE4 test exhibited lower pooled sensitivity and higher pooled specificity compared to the CA125 test in all patient groups. Additionally, no statistically significant differences were observed in the pooled sensitivity and pooled specificity of the HE4 test between the periods before and after the new health technology assessment in 2014.

For ROMA, the pooled sensitivity, pooled specificity, and pooled AUC were 0.8495% CI 0.80–0.87), 0.86 (95% CI 0.82–0.90), and 0.91 (95% CI 0.88–0.93), respectively, among all patients (7,645 patients in 24 studies); 0.77 (95% CI 0.70–0.83), 0.90 (95% CI 0.86–0.93), and 0.91 (95% CI 0.88–0.93), respectively, among pre-menopausal patients (4,724 patients in 19 studies); and 0.89 (95% CI 0.84–0.92), 0.90 (95% CI 0.86–0.92), and 0.95 (95% CI 0.93–0.97), respectively, among menopausal patients (2,840 patients in 18 studies). ROMA demonstrated higher pooled sensitivity and pooled specificity than the CA125 test among all patients and menopausal patients. Among pre-menopausal patients, ROMA showed lower pooled sensitivity and higher pooled specificity than the CA125 test. Similar to the HE4 test, there were no statistically significant differences in the pooled sensitivity and pooled specificity of ROMA between the periods before and after the 2014 health technology assessment.

Regarding the treatment course and recurrence, seven studies reported on these aspects. They compared the diagnostic accuracy of the HE4 test in cases where ovarian cancer recurrence or metastasis was suspected (3 studies) and observed changes in HE4 level and clinical features after cytoreductive surgery or chemotherapy (5 studies) in comparison to the CA125 test. For the diagnosis of ovarian cancer recurrence or metastasis, the HE4 test demonstrated a sensitivity range of 0.70–0.88 and specificity range of 0.92–1.00, which were higher than those of the CA125 test (sensitivity: 0.35–0.78 and specificity: 0.59–0.87). In comparing clinical features and changes in HE4 and CA125 levels after cytoreductive surgery or chemotherapy, it was noted that both HE4 and CA125 levels reduced to the normal range after primary cytoreductive surgery. Furthermore, both HE4 and CA125 levels increased above threshold levels before or concurrently with the recurrence or metastasis findings in patients with recurrence or metastasis during the post-treatment follow-up period. Of the two markers, the HE4 level tended to increase approximately 3-8 months earlier than the CA125 level.

Conclusions and recommendations

The Subcommittee conducted a thorough evaluation of the HE4 test, synthesizing the current evidence available in the literature to gauge its safety and efficacy. 

Despite the absence of studies specifically reporting AEs associated with the HE4 test, the Subcommittee concluded that the test is generally safe. This determination is rooted in the fact that the HE4 test is an in vitro blood assay, which inherently carries minimal risk to patients, aside from the standard blood collection procedure. Regarding effectiveness, the HE4 test demonstrated a slightly lower sensitivity compared to the CA125 test. However, its sensitivity levels were deemed clinically acceptable. Notably, the HE4 test exhibited superior specificity relative to the CA125 test. Based on these findings, the Subcommittee advocated for the combined use of HE4 and CA125 tests in the diagnosis of ovarian cancer in patients presenting with a pelvic mass, affirming the enhanced diagnostic efficacy of this approach.

Furthermore, the Subcommittee highlighted the clinical utility of the HE4 test in the post-treatment monitoring phase, particularly in the detection of recurrence or metastasis in ovarian cancer cases. It was observed that the levels of HE4 in the blood exhibit a more pronounced increase compared to CA125 levels in instances of cancer recurrence or metastasis. 

In the fifth session of the Committee of Health Technology Reassessment in 2023 (on May 12, 2023), definitive conclusions were drawn regarding the HE4 test, informed by the Subcommittee's findings and in alignment with Article 4-10 of the Guidelines for Management of Health Technology Reassessment. The Committee of Health Technology Reassessment “recommended” the employment of the HE4 test as an auxiliary diagnostic tool alongside the CA125 test in the identification of ovarian cancer in suspected patients with a pelvic mass. This is based on a comprehensive evaluation of the test's clinical safety, efficacy, and other pertinent assessment criteria, particularly within the context of clinical practice in Korea (Grade of recommendation: Recommended).

Keywords: Ovarian tumor, Human epididymis protein 4, HE4, Diagnosis of ovarian cancer, Add-on test