Prognostic role of immunohistochemical and molecular markers in no specific molecular profile endometrial cancer: a systematic review and meta-analysis

Objective: No specific molecular profile (NSMP) endometrial cancer represents nearly half of the diagnoses, characterized by significant molecular heterogeneity and intermediate recurrence and survival outcomes. Currently, no immunohistochemical or molecular markers are established in guidelines to improve prognosis estimation and personalize treatment in NSMP endometrial cancer. This systematic review and meta-analysis aimed to evaluate the prognostic significance of potential immunohistochemical and molecular surrogate markers in NSMP endometrial cancers. Data sources: This systematic review and meta-analysis adhered to PRISMA guidelines and was registered with PROSPERO (CRD42024601035). A comprehensive literature search was conducted using Scopus, PubMed/MEDLINE, ScienceDirect, and the Cochrane Library (January 1994-December 2024). Study eligibility criteria: Studies assessing the prognostic roles of L1CAM, CTNNB1, ARID1A, estrogen receptor (ER), progesterone receptor (PR), and STATHMIN expression or mutation status in NSMP endometrial cancers were included. Study appraisal and synthesis methods: Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS) and the Quality in Prognosis Studies (QUIPS) tool for risk of bias in prognostic studies. Certainty of evidence for each outcome was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Hazard ratios (HR) for recurrence and survival were calculated using random- or fixed-effects models depending on heterogeneity. Results: Fourteen retrospective studies including 4,654 NSMP endometrial cancers were analysed. L1CAM overexpression significantly predicted higher recurrence (HR=3.42, 95% CI:1.86-6.29; p<0.001) and worse survival (HR=4.31, 95% CI:2.62-7.09; p<0.001). ER positivity correlated significantly with reduced recurrence risk (HR=0.37, 95% CI:0.26-0.53) and improved survival (HR=0.22, 95% CI:0.17-0.29). Loss of PR expression was associated with increased recurrence and poorer survival outcomes. Conversely, ARID1A and CTNNB1 mutations and STATHMIN1 overexpression did not significantly impact recurrence or survival outcomes. Conclusions: L1CAM overexpression, ER positivity, and PR status demonstrate significant prognostic relevance in NSMP endometrial cancer, warranting consideration as potential markers for improving patient management, including fertility-sparing approach.