Clinicopathologic evaluation of CTNNB1 gene mutations in high-intermediate risk endometrial cancer

Objectives: CTNNB1 mutations convey increased risk of recurrence in low risk endometrioid endometrial cancers. However, sub-analyses of high-intermediate risk (HIR) endometrioid endometrial cancers in other cohorts have not demonstrated a clearly increased recurrence risk and have often been equivocal. The objective of this study is to perform a clinicopathologic evaluation of patients with HIR endometrioid endometrial cancer in relation to CTNNB1 mutational status. Methods: A single-institution chart review of patients diagnosed with endometrioid endometrial cancer between 2006 and 2018 was undertaken. Patients were classified as HIR according to GOG249 criteria. Mutational status was determined by Sanger sequencing of exon 3 of the CTNNB1 gene in primary tumor specimens. Immunohistochemical (IHC) analysis of B-catenin was performed to evaluate for the presence of nuclear staining. Factors associated with recurrence were assessed by logistic regression; recurrence-free (RFS) and overall survival (OS) were assessed by Kaplan-Meier survival analysis. Results: 93 cases of HIR endometrioid endometrial cancer were identified, of which 23 (24.7%) were CTNNB1 mutant and 70 (75.3%) were wild type. Median follow-up was 59.7 months. Recurrence occurred in 14/93 (15.1%) patients. Recurrence rates were not significantly different between patients with CTNNB1 mutant and wild type tumors (13.0% vs. 15.9%, p=0.76). In both univariable and multivariable analyses, RFS and OS were not significantly different (RFS HR 0.88, p=0.85, 95% CI 0.24 - 3.17; OS HR 0.20, p=0.12, 95% CI 0.03 - 1.54). Predicted oncogenic mutations comprised 87% of all identified mutations and were present in 100% of recurrent tumors and 85% of non-recurrent tumors (p=0.47). Nuclear B-catenin expression by IHC demonstrated a sensitivity of 87% and a specificity of 83% for CTNNB1 mutations. Conclusions: CTNNB1 mutations have a prevalence of 25% in HIR endometrioid endometrial cancer. In this single institution retrospective study, there were no differences in RFS or OS in patients with CTNNB1 mutant compared to wild-type tumors.