Prognosis Stratification Tools in Early-Stage Endometrial Cancer: Could We Improve Their Accuracy?

Abstract

There are three prognostic stratification tools used for endometrial cancer: ESMO-ESGO-ESTRO 2016, ProMisE, and ESGO-ESTRO-ESP 2020. However, these methods are not sufficiently accurate to address prognosis. The aim of this study was to investigate whether the integration of molecular classification and other biomarkers could be used to improve the prognosis stratification in early-stage endometrial cancer. Relapse-free and overall survival of each classifier were analyzed, and the c-index was employed to assess accuracy. Other biomarkers were explored to improve the precision of risk classifiers. We analyzed 293 patients. A comparison between the three classifiers showed an improved accuracy in ESGO-ESTRO-ESP 2020 when RFS was evaluated (c-index = 0.78), although we did not find broad differences between intermediate prognostic groups. Prognosis of these patients was better stratified with the incorporation of CTNNB1 status to the 2020 classifier (c-index 0.81), with statistically significant and clinically relevant differences in 5-year RFS: 93.9% for low risk, 79.1% for intermediate merged group/CTNNB1 wild type, and 42.7% for high risk (including patients with CTNNB1 mutation). The incorporation of molecular classification in risk stratification resulted in better discriminatory capability, which could be improved even further with the addition of CTNNB1 mutational evaluation.

Morules But Not Squamous Differentiation are a Reliable Indicator of CTNNB1 (β-catenin) Mutations in Endometrial Carcinoma and Precancers

“…20 Endometrial cancers with CTNNB1 (β-catenin) mutations are a biologically distinct subgroup of endometrial cancers with an increased risk of recurrence and poorer prognosis. [21][22][23][24] Most CTNNB1 mutations cause alteration of phosphorylation site residues within exon 3 of CTNNB1, which in turn leads to defective proteasomal degradation, increased β-catenin protein levels, and abnormal localization to the nucleus. 25 Nuclear β-catenin staining has been found to have high specificity and sensitivity for CTNNB1 mutations in EEC, 21,26,27 although in some cases the area with aberrant nuclear staining can be focal.…”

“…β-catenin (encoded by the CTNNB1 locus), is a key factor in canonical Wnt signaling, and is one of the most frequently mutated genes in endometrial carcinoma, with an ∼50% mutation rate in mismatch repair-proficient, copy number low endometrial cancers 20. Endometrial cancers with CTNNB1 (β-catenin) mutations are a biologically distinct subgroup of endometrial cancers with an increased risk of recurrence and poorer prognosis 21–24. Most CTNNB1 mutations cause alteration of phosphorylation site residues within exon 3 of CTNNB1 , which in turn leads to defective proteasomal degradation, increased β-catenin protein levels, and abnormal localization to the nucleus 25.…”