Clinical Report: Advanced POLE-Mutated Endometrial Carcinoma Characteristics and Outcomes

Overview

This retrospective study of 14 patients with advanced-stage POLE-mutated endometrial carcinoma reveals a predominance of high-grade endometrioid tumors with frequent lymphovascular invasion. While most cases maintain an indolent course, a subset exhibits aggressive behavior including atypical metastases such as brain involvement, highlighting heterogeneity within this molecular subtype.

Background

POLE-mutated endometrial carcinomas are characterized by ultramutated genomic profiles and typically favorable prognoses due to robust anti-tumor immune responses. These tumors are usually high-grade and endometrioid, with a high tumor mutational burden. Although international guidelines recommend therapy de-escalation based on early-stage data, the clinical behavior of advanced-stage POLE-mutated tumors remains poorly defined. Emerging evidence suggests that some advanced cases may develop aggressive disease with unusual metastatic patterns, necessitating further characterization.

Data Highlights

Key Findings

• All advanced POLE-mutated tumors were high-grade (Grade 3) with predominantly endometrioid histology (86.7%).
• Lymphovascular space invasion was present in all cases, indicating aggressive pathological features despite typical favorable prognosis.
• The p.V411L POLE mutation was the most frequent variant (37%) among advanced cases, suggesting a possible association with disease progression.
• Most tumors were mismatch repair-proficient (64%) and p53 wild-type (79%), consistent with typical POLE-mutated profiles.
• Co-occurring oncogenic mutations, including PI3K/AKT pathway alterations, were identified in a substantial subset (29%-43%), potentially contributing to heterogeneous clinical behavior.
• Atypical metastatic patterns were observed, including brain metastases at diagnosis in one patient (7%), highlighting the potential for aggressive disease in this subgroup.

Clinical Implications

Clinicians should recognize that advanced-stage POLE-mutated endometrial carcinomas, while generally associated with favorable outcomes, can exhibit aggressive features and atypical metastases. Molecular profiling beyond POLE mutation status, including assessment of co-occurring mutations and specific POLE variants such as p.V411L, may inform risk stratification and guide personalized treatment decisions. Careful surveillance for unusual metastatic sites, including the brain, may be warranted in select patients.

Conclusion

This study underscores the clinical and molecular heterogeneity of advanced POLE-mutated endometrial carcinoma, challenging the assumption of uniformly indolent behavior. Further research in larger cohorts is needed to validate these findings and refine prognostic models for this rare but clinically significant subgroup.

References

1. The Cancer Genome Atlas Research Network 2013 -- Integrated genomic characterization of endometrial carcinoma
2. ESGO/ESTRO/ESP Guidelines 2021 -- Management of endometrial carcinoma
3. MITO POLE END Study 2024 -- Diverse Clinical and Molecular Characteristics of Advanced POLE-Mutated Endometrial Carcinoma