Introduction/Background Endometrial cancer is the commonest gynaecological malignancy. Molecular classification informs prognosis, however markers that further risk-stratify intermediate groups are needed. Serum cancer antigen-125 (CA125) and human epididymis-4 (HE4) show promise as prognostic markers. The aim of this study was to evaluate the association between serum CA125, HE4 and endometrial cancer survival outcomes when stratified by molecular subgroup.

Methodology Pre-treatment serum CA125 and HE4 levels were measured and endometrial tumours classified according to WHO molecular classification. The relationship between biomarkers and survival was evaluated using Kaplan-Meier analysis and multivariable cox regression.

Results Overall, 327 women were included, with POLE status available for 216. Tumours were POLE-mutant (5%), p53-abnormal (11%), MMR-deficient (30%) and NSMP (54%). Median follow up was 50 months (IQR 30–60), during which 42 (13%) recurred and 71 (21%) women died. CA125≥35U/mL was independently associated with overall mortality [aHR=2.42 (95%CI:1.45–4.06), p=0.001), cancer specific death [aHR=2.00 (95%CI:1.04–3.87), p=0.04] and recurrence [aHR=2.69 (95%CI:1.38–5.27), p=0.004]. When stratified by molecular subgroup, CA125≥35U/mL and HE4≥150pmol/L were prognostic of overall survival in MMR-deficient [CA125: aHR=4.92 (95%CI:1.74–13.89), p=0.003 and HE4: aHR=4.03 (95%CI:1.34–12.11), p=0.01] and NSMP subgroups [CA125: aHR=3.72 (95%CI:1.30–10.67), p=0.01)].

Conclusion CA125 and HE4 may risk-stratify those at intermediate risk of recurrence and death. Evaluation in a larger population is required.