Clinical and molecular heterogeneity in advanced-stage POLE-mutated endometrial carcinoma: a focus on aggressive...

The POLE-mutated molecular subtype of endometrial carcinoma is characterized by an ultramutated genomic profile, high tumor mutational burden, and a favorable prognosis. The clinical behavior of advanced-stage POLE-mutated endometrial carcinoma remains poorly defined due to its rarity. While most cases retain an indolent course, emerging evidence suggests that a subset may develop aggressive disease, including atypical metastatic patterns such as brain dissemination.

A multi-center retrospective analysis was performed on 14 patients with advanced (International Federation of Gynecology and Obstetrics Stage III-IV) POLE-mutated endometrial carcinoma. Data on the clinico-pathological characteristics and treatment outcomes were collected.

The cohort consisted exclusively of high-grade tumors (100% Grade 3), with the majority being endometrioid (86.7%). Lymphovascular space invasion was ubiquitous (100%). The detected POLE mutations were: p.V411L (37%), p.P286A (14%), p.S459F (14%), p.G433A (7%), p.M444L (7%), p.S297P (7%), p.P286R (14%). Most tumors were mismatch repair-proficient (64%) and p53 wild-type (79%). Co-mutations in the PI3K/AKT pathway were detected in 29% of cases, while 43% of patients harbored at least one additional oncogenic driver. Data were interpreted according to variant allele frequency, in order to differentiate biologically relevant clonal alterations from subclonal or passenger events. Three patients (21%) underwent surgery followed by adjuvant radiotherapy and chemotherapy, three (21%) received surgery followed by chemotherapy alone, and four (29%) were treated with surgery alone; treatment data were unavailable for one patient (7%). One patient (7%) presented with brain metastases at diagnosis.

This study provides a detailed descriptive characterization of a rare endometrial carcinoma patient population and highlights the emergence of atypical metastatic patterns, including cerebral involvement. Although observed in a very limited number of cases, the recurrent identification of the V411L variant among patients with advanced disease raises hypotheses and requires validation in larger cohorts. These findings underscore the need for nuanced risk stratification that goes beyond POLE mutation status alone.