FRα expression in advanced endometrial carcinoma: Clinicopathological, molecular, and prognosis correlates

Abstract

Background

Advanced endometrial carcinoma (EC) is a therapeutic challenge with limited treatment options. Folate receptor alpha (FRα)-targeted antibody-drug conjugates (ADCs) are being explored for EC treatment. However, the molecular profiles of FRα-expressing ECs remain understudied. This study aims to evaluate FRα expression in advanced EC and its associations with clinicopathological features, molecular alterations, and prognosis value.

Methods

We analyzed a cohort of 111 advanced ECs from our institution (PUMCH). We used immunohistochemistry (IHC) to quantify FRα expression and next-generation sequencing (NGS) to determine genomic mutations. In parallel, a cohort from the TCGA database was included as an external cohort for validation.

Results

In the PUMCH cohort, 21 out of 111 (18.9 %) cases were graded as FRα-high. FRα-high ECs were significantly associated with aggressive histotypes and the p53abn molecular subtype. A significant correlation between FRα and CA125 was demonstrated at the protein level in the PUMCH cohort and the RNA level in the TCGA cohort. Molecularly, FRα-high ECs were more often associated with TP53 mutations, while FRα-low ECs were characterized by PTEN mutations. In survival analysis, high FRα expression was closely correlated with poor outcomes, especially in Stage III ECs. Additionally, FRα could significantly stratify prognosis within a limited cohort of mismatch repair-deficient (MMR-d) ECs.

Conclusion

FRα positivity in advanced ECs corresponds with a unique molecular landscape, particularly the p53abn subgroup. The prognostic value of FRα in advanced ECs, especially in MMR-d ECs, warrants clinical attention.