The challenge of molecular stratification in No Specific Molecular Profile endometrial cancer.

Objective: In this study, we aimed to evaluate the prognostic impact of molecular alterations beyond those included in the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), in order to identify biomarkers that could improve prognostic stratification within the No Specific Molecular Profile (NSMP) subgroup of endometrial cancers.

Methods: This systematic review and meta-analysis was conducted according to PRISMA guidelines. We searched PubMed, Scopus and Web of Science for studies published up to December 2024. We included prospective and retrospective studies assessing the prognostic impact of molecular alterations not included in the ProMisE classification, reporting outcomes as hazard ratios (HRs). The primary outcome was progression-free survival (PFS), and the secondary outcome was overall survival (OS), analyzed in both the overall endometrial cancer population and specifically within the NSMP subgroup.

Results: A total of 19 studies met the inclusion criteria and were included in the final analysis: 17 retrospective and 2 prospective, all observational in design. L1CAM overexpression and ER loss were identified as unfavorable prognostic factors in the overall endometrial cancer population (PFS HR 3.44 [2.57, 4.59; 95 % CI] and 3.13 [2.45, 4.00; 95 % CI], respectively) and within the NSMP subgroup (PFS HR 3.34 [2.05, 5.44; 95 % CI] and 3.14 [2.00, 4.91; 95 % CI], respectively). ARID1A mutation showed a negative prognostic impact limited to NSMPs (PFS HR 2.35 [1.09, 5.06; 95 % CI]). Conversely, β-catenin/CTNNB1 and PIK3CA/PTEN mutations did not demonstrate consistent prognostic significance in either group.

Conclusions: These findings underscore the potential of ER loss and L1CAM overexpression as prognostic markers within the NSMP subgroup, supporting more personalized adjuvant strategies. Further research is needed to clarify the prognostic role of other alterations, such as ARID1A, specifically within NSMP tumors. PROSPERO registration number: CRD420250654207.