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

Roya Behrouzi,Y Louise Wan,Katie Stocking,Chloe E Barr,James Bolton,Abigail E Derbyshire,Zoe Maskell,Rhona J Mcvey,Philip W Pemberton,Neil A J Ryan,Emma J Crosbie

doi:10.3390/cancers12020276

Abstract

The levonorgestrel-releasing intrauterine system (LNG-IUS) is a conservative management option for atypical hyperplasia (AH) and low grade early stage endometrial cancer (EEC), but around 1 in 3 patients fail to respond to treatment. The aim of this study was to investigate if serum and/or tissue HE4 expression could predict response to LNG-IUS therapy. Patients with AH or presumed Stage I EEC had serum and endometrial samples taken at baseline and at 3-month intervals over 12 months post-insertion of LNG-IUS. 74 patients were recruited and baseline demographics recorded. Of 57 patients for whom response was histologically determinable, 39 (68%) were responders and 18 (32%) non-responders. Mean baseline serum HE4 was significantly lower in responders (62.1 ± 1.1 pM, 95% confidence interval (CI) 52.7–73.2), compared to non-responders (125.6 ± 1.3 pM, 95% CI 74.5–211.7, p = 0.014), including when considering age, BMI, menopausal status, smoking status, and histological grade as covariables (p = 0.005). Baseline tissue HE4 expression was not significantly different in responders compared to non-responders (p = 0.999). Responders showed a significant mean reduction (−9.8 ± 3.4%, 95% CI −16.7 to −2.8%, p = 0.008) in serum HE4 between baseline and 3 months (p = 0.008), whereas non-responders showed no significant change (p = 0.676). Neither responders nor non-responders showed a significant percentage change in serum HE4 from baseline beyond 3 months (p > 0.05). Change in serum HE4 between baseline and 3 and 6 months and tissue HE4 tissue expression between baseline and 3, 6, and 12 months was not significantly different in responders compared to non-responders (p > 0.05). This study suggests that baseline serum HE4, but not baseline tissue HE4 expression, is independently predictive of response to the LNG-IUS and could be used to guide management decisions.

Highlights

Endometrial carcinoma (EC) is the most common gynaecological malignancy and frequently presents at an early stage
This study suggests that serum Human epididymis protein 4 (HE4) is an independent predictive biomarker for response to levonorgestrel-releasing intrauterine system (LNG-IUS) treatment in patients with atypical hyperplasia (AH) and Stage Ia endometrial cancer (EEC)
This study suggests that baseline serum HE4, but not tissue HE4 expression, is a predictive biomarker for response to LNG-IUS treatment in stage Ia EEC and AH, and higher levels of serum

Summary

Introduction

Endometrial carcinoma (EC) is the most common gynaecological malignancy and frequently presents at an early stage. 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. Since up to a third of patients do not respond to LNG-IUS treatment, there is a demand for biomarkers that could be used to predict and/or monitor therapy response

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