HE4 in the Diagnostic Approach of Endometrial Cancer in Patients with Postmenopausal Bleeding, the METRODEC Protocol: Protocol for a Multicenter Prospective Study

Abstract

Background: Endometrial cancer is the most common pelvic gynecological cancer in France. The most frequent symptom is post-menopausal bleeding and is one of the primary reasons for consultation in gynecological emergencies. The treatment is very codified and consists of a surgical intervention for anatomopathological analysis. The latter is frequently reassuring. These interventions are often performed in mild situations and there is currently no element to be sufficiently reassuring to avoid surgery. This study aims to explore the sensitivity of an innovative marker: Human Epididymis 4 (HE4) in the diagnosis approach of endometrial cancer in case of postmenopausal bleedings. Methods: This is a prospective multicenter diagnostic study with three centers involved. Inclusion criteria are any patient with post-menopausal bleeding who is to undergo hysteroscopy, endometrial biopsy, or endometrial resection. In accordance with the recommendations for the management of post-menopausal bleedings, the medical conduct consists of performing a clinical examination, an ultrasound and, in general, even in case of paraclinical examination reassuring, an anatomopathological analysis. This pathological analysis can be obtained in several ways: biopsy, hysteroscopy-curettage (which is the most frequently performed surgery), and hysterectomy. Our protocol consists of taking a blood sample from each woman who will undergo one of the interventions mentioned above. The dosage of HE4 and CA125 requires the withdrawal of an additional heparinized tube during the preoperative assessment usually performed. This research is therefore classified as non-interventional. The primary outcome is to evaluate the sensitivity of the HE4 marker in patients with postmenopausal bleeding in the diagnosis of endometrial cancer. The secondary outcomes are other parameters (specificity, VPP, VPN) of HE4, Evaluating the diagnostic capabilities of the CA125 marker alone and associated with HE4, as well as those of the REM and REM-B algorithms. We aim to include 100 patients over a period of one year in three centers. Discussion: As of now, there is no biological marker used in routine practice in the diagnosis of endometrial cancer. The ultimate goal of HE4 in endometrial cancer is to avoid surgery for those who are identified as non-sick. This study is the precursor of others for use in routine practice, HE4 would represent a great help to diagnosis if our study demonstrates it as reliable in the management of these patients and avoid many unnecessary and risky surgeries.

HE4 as a Biomarker for Endometrial Cancer

“…Third, the studies use different control groups, making comparison challenging. Future multicentre studies are awaited which will look at serum HE4 as a diagnostic biomarker prospectively [ 34 ]. Table 1 summarises the cut-off values for HE4 used in different studies for the diagnosis of EC and their performance.…”

HE4 Tissue Expression as A Putative Prognostic Marker in Low-Risk/Low-Grade Endometrioid Endometrial Cancer: A Review

“…In 2021, Degez et al [ 73 ] published the proposal to conduct a non-interventional prospective multicenter study designed to better define the diagnostic possibilities offered by plasma CA125 and HE4 assay in a selected population such as that of women with abnormal uterine bleeding. The authors decided to evaluate the sensitivity of HE4 as a priority.…”

“…They expect to recruit 100 patients over 12 months in three participating centers in France. Plasma CA125 and HE4 concentrations are expected to be measured in a single reference laboratory using an automated analyzer based on electrochemiluminescence immunoassay [ 73 ].…”

Knockdown of HE4 suppresses tumor growth and invasiveness in lung adenocarcinoma through regulation of EGFR signaling

“…HE4 is a glycosylation protein [ 16 ], mainly located in the cell membrane and cytoplasm, and can also be detected in the perinuclear region [ 17 ]. Various studies have shown that HE4 functions as one biomarker in different cancers, including ovarian cancer [ 18 ], lung cancer [ 19 , 20 ], endometrial cancer [ 21 ], and breast cancer [ 22 ]. In addition, increasing evidence suggests that HE4 regulates cell proliferation and metastasis in ovarian cancers.…”