HE4 is a novel tissue marker for therapy response and progestin resistance in medium- and low-risk endometrial hyperplasia

Abstract

Background:The aim of the present study was to investigate whether changes in the tissue expression of human epididymis-specific protein 4 (HE4) could predict therapy resistance and relapse after progestin hormone therapy for medium- and low-risk endometrial hyperplasia.Methods:Endometrial biopsies were obtained from women participating in a multicentre RCT performed according to the CONSORT guidelines; the women were randomly assigned to either LNG-IUS; 10 mg of oral medroxyprogesterone acetate (MPA) administered for 10 days per cycle; or 10 mg of oral MPA administered daily for 6 months. Of the 153 women who completed therapy, 141 had adequate material for immunohistochemistry in pre- and post-treatment biopsies. An antibody to HE4 (clone 12A2 monoclonal IgG1 antibody, Fujirebio Diagnostics, Inc.) was used for the immunohistochemical staining of the pre- and post-treatment biopsies from each participant. The expression of HE4 staining was evaluated by the histological score (H-score) using light microscopy.Results:Changes in the expression of HE4 (H-score) during therapy were related to the therapy group (P<0.001) and therapy response (P<0.001) of the individuals but could not predict relapse (P>0.05). Changes in the intracellular bodies were shown to predict both the therapy response (P=0.038) and relapse (P=0.014).Conclusions:Changes in the expression of HE4 during progestin therapy regimens can predict therapy response or indicate progestin resistance for medium- and low-risk endometrial hyperplasia.

Baseline Serum HE4 But Not Tissue HE4 Expression Predicts Response to the Levonorgestrel-Releasing Intrauterine System in Atypical Hyperplasia and Early Stage Endometrial Cancer

“…The strengths of this study are that the design was prospective, and patients were selected consecutively, which minimised bias. In addition, 68% of AH/Stage Ia EEC patients responded to the LNG-IUS by 12 months, with AH showing a higher response rate compared to Stage I EEC, similar to previous studies [7][8][9][10][11] supporting that the sample is representative of the background patient population. Baseline serum HE4 was also positively associated with patient age, BMI, menopause, in agreement with previous studies [17,18,[22][23][24]30,31].…”

“…This supports a recent study that showed that serum HE4 and tissue HE4 expression in paired samples displayed a low concordance, and serum HE4 was recommended as a more precise method of clinically measuring HE4 compared to tissue expression [20]. The fact that changes in tissue HE4 expression from baseline were not predictive of LNG-IUS response or resistance contrasts with a recent study by Orbo et al 2016 [10]. They showed that a higher proportion of responders to progestogen therapy for hyperplasia (with or without atypia) had reduced tissue HE4 expression between baseline and 6 months compared to non-responders.…”

“…Studies have shown that oral progestogens can reverse AH and Stage Ia EEC in 70-75% patients by 12 months [2][3][4][5][6]. Further studies have shown that the levonorgestrel-releasing intrauterine system (LNG-IUS) produces fewer systemic side effects and regression rates of 84-100% in AH [7][8][9][10][11] and 68% in stage I EEC [12]. This has led to increased use of the LNG-IUS compared to oral progestogens as a conservative therapy.…”

“…This has sparked interest in HE4 as a potential tissue and serum biomarker for predicting and monitoring therapy response to progestogens. A recent study found that changes in HE4 tissue expression predicted response to oral and intrauterine progestogens in endometrial hyperplasia (with and without atypia), such that a greater proportion of responders achieved a reduction in HE4 tissue expression compared to non-responders [10].…”

Identification and characterization of endometrial carcinoma with tumor markers HE4 and CA125 in serum and endometrial tissue samples

“…Localized EC treatment consists of hysterectomy and double adnexectomy. Moreover, the identification of those patients that should undergo a pelvic and/or para-aortic lymphadenectomy depends on several parameters ( 16 , 17 , 18 , 19 ).…”