Molecular characteristics and clinicopathology of CTNNB1-mutated endometrial cancer: Implications for fertility-sparing management in young women

BACKGROUND: The incidence rate of endometrial cancer (EC) is increasing among young women who require fertility preservation. The identification of molecular biomarkers can improve clinical outcomes in these patients. This study evaluated the role of CTNNB1 mutations in EC and whether the CTNNB1 gene can serve as a molecular marker in fertility-sparing management. METHODS: Retrospective cohorts of patients with pathologically confirmed EC were included in the study. The molecular landscape and TCGA-based molecular classification were analyzed through targeted next-generation sequencing and immunohistochemistry. The clinicopathological and molecular characteristics of CTNNB1-mutated and CTNNB1-wild-type patients were assessed. For young patient who received fertility-sparing treatment (FST), the responses to progestin treatment were evaluated. RESULTS: CTNNB1 mutations were significantly more common in the age group ≤ 40 years than in the age group > 40 years, indicating that CTNNB1 had a significant role in young patients with EC seeking fertility preservation. Most cases carrying CTNNB1 mutations were in the no specific molecular profile group. The most frequent CTNNB1 hotspot mutations were Ser37Phe on exon3 (16.13%). Moreover, CTNNB1 mutations were significantly associated with higher rates of endometrioid EC (p = 0.0001) and earlier stages (FIGO I or II) than the absence of mutations (p = 0.0457). Nonetheless, there were no significant differences in other pathological risk factors between the mutant and wild-type groups. The immunohistochemical expression of β-catenin can be used as a surrogate for CTNNB1 mutation status; nonetheless, specificity was associated with the frequency of CTNNB1 mutations. Patients with CTNNB1 mutations showed poor response to progestin treatment, possibly because of the reduced expression of progesterone receptors since the nuclear expression of β-catenin in the endometrium was negatively correlated with progesterone receptor expression. CONCLUSIONS: CTNNB1 status in EC can help predict the response to fertility-sparing treatment, allowing early stratification and risk assignment.