Human epididymis protein 4 (HE4) has shown promising utility as a prognostic biomarker in endometrial cancer. Increased serum HE4 levels may be associated with deeper myometrial invasion, extrauterine disease and poorer prognosis.

To evaluate the use of serum HE4 level, compared to and alongside other investigations, to accurately guide management in apparent early‐stage endometrial cancer.

Materials and Methods
This is a single‐site prospective study of 100 patients with histologically confirmed endometrial cancer. All patients underwent preoperative measurements of HE4 and CA125 levels and a preoperative magnetic resonance imaging (MRI) to assess the depth of invasion, nodal status and tumour size. Correlation was sought between serum HE4 level, CA125 level, MRI findings and intra‐operative frozen section with tumour type, grade and stage.

While both median HE4 and CA125 levels were higher with worsening clinicopathological features, serum HE4 level showed a more consistent association with high‐risk features. Patients with a low‐grade biopsy preoperatively and a low HE4 level (<70 pmol/L) demonstrated an 86.8% likelihood of having low‐risk disease on final histopathology. In comparison, preoperative MRI or intraoperative frozen section alongside a low‐grade biopsy demonstrated a similar likelihood of 86.2 and 87.7%, respectively. Conclusions When used in conjunction with an initial low‐grade endometrial biopsy, serum HE4 level demonstrated a similar likelihood to both preoperative MRI and intraoperative frozen section in identifying low‐risk disease on final histopathology. As a triaging tool this may be significant given that a preoperative, serum‐based assay would likely be the least invasive, least resource‐intensive and most cost‐effective approach.