Serum CA125 levels in the context of ProMisE molecular classification provides pre-operative prognostic information that can direct endometrial cancer management.

Objective: Previous research suggests serum CA125 reflects extra-uterine disease in patients with endometrial carcinoma (EC). Our objective was to determine if CA125 can identify patients with extra-uterine and/or nodal metastases, the association of this biomarker with EC molecular subtype, and to explore an optimal cutoff in this context.

Methods: We assessed the association of CA125 levels with clinicopathologic and outcomes data on a cohort of 1107 molecularly classified EC.

Results: Abnormal CA125 (>35kU/L) was associated with higher stage and lymph node metastases (LNM) in all EC and in each molecular subtype on univariate (p < 0.01) and multivariate (p < 0.05) analyses. POLEmut had the lowest median CA125 level and proportion of CA125 abnormal patients, and p53abn the highest proportion (p < 0.001). CA125 > 35 kU/L had a sensitivity of 0.82, specificity 0.53, positive-predictive-value 0.92, and negative-predictive-value 0.31 for LNM, with similar values for stage>I. CA125 > 35 kU/L was associated with worse overall (OS), disease-specific (DSS), and progression-free survival (PFS) in all EC, p53abn (OS, DSS, PFS), NSMP (OS, DSS), and MMRd (OS, DSS) subtypes. CA125 > 35 kU/L demonstrated a relative risk (RR) of 2.50 with presence of stage III/IV disease (p < 0.001) and RR 18.4 for the presence of synchronous endometrial and ovarian carcinomas (SEOC)/co-existing adnexal malignancies (CAM) (p < 0.001). An exploratory cut point, optimized for correlation with DSS (CA125 > 24 kU/L) show similar association with clinical parameters and survival outcome.

Conclusions: CA125 levels are associated with molecular subtype, stage>I disease, and SEOC/CAM. CA125 remains a useful clinical tool in the triage of EC in the era of molecular classification.