Prognostic Relevance of Molecular Classification in Endometrial Cancer: Insights From a South African Cohort
PURPOSE
Geographical and racial diversity may influence endometrial cancer (EC) prognosis, yet its impact remains underexplored. In South Africa (SA), the rising incidence of EC underscores the need to investigate potential biologic differences. Molecular classification of EC offers valuable prognostic insights that could help address disparities and improve care. This study evaluated the prevalence and prognostic significance of molecular subtypes in a South African high-intermediate and high-risk EC cohort.
MATERIALS AND METHODS
We included 133 patients with high-intermediate and high-risk EC diagnosed in SA between January 2017 and December 2021. Clinical, demographic (including self-identified race), and follow-up data were collected. Central pathology review assessed histotype, grade, lymphovascular space invasion, and International Federation of Gynecology and Obstetrics 2009 stage. Molecular subtyping followed the WHO 2020 algorithm using targeted next-generation sequencing and immunohistochemistry for p53, mismatch repair (MMR) proteins, and ER. Shallow whole-genome sequencing (sWGS) assessed genome-wide copy number alterations.
RESULTS
Among 131 patients with complete molecular classification, the most common subtype was p53-abnormal (p53abn, n = 71; 54.2%), followed by MMR-deficient (MMRd, n = 30; 22.9%), no specific molecular profile (NSMP, n = 21; 16.0%), and
POLE
-ultramutated (
POLE
mut, n = 9; 6.9%). Nonendometrioid EC (NEEC) predominated (n = 82; 61.7%). High-grade endometrioid EC and NEEC were more frequent in non-White patients (
P
= .030). Molecular subtypes were significantly associated with overall recurrence (
P
= .029), with no recurrences in
POLE
mut ECs and the worst outcomes in p53abn ECs. sWGS revealed higher CN burdens in p53abn ECs, with recurrent focal alterations involving
CCNE1
amplification and
RB1
loss.
CONCLUSION
To our knowledge, this study is the first to demonstrate the prognostic value of EC molecular classification in a South African cohort. These findings support the global relevance of molecular EC subtyping. The urgent need for access to molecular diagnostics or cost-effective alternatives in resource-limited settings is highlighted.
