Which molecular subgroup is associated with the most favorable prognosis in endometrioid endometrial carcinoma?

POLE-Mutated Subgroup Confers the Best Prognosis in Endometrioid Endometrial Carcinoma

The POLE-mutated (POLEmut) molecular subgroup demonstrates the most favorable prognosis among all endometrial carcinoma molecular subtypes, with excellent overall survival, disease-specific survival, and progression-free survival, independent of grade, stage, or treatment modality. 1, 2

Molecular Subgroup Prognostic Hierarchy

The four molecular subgroups of endometrial carcinoma demonstrate distinct prognostic outcomes in the following order 1:

• POLEmut (POLE ultramutated): Excellent prognosis 1, 2
• dMMR (MSI-high/hypermutated): Intermediate prognosis 1
• NSMP (no specific molecular profile): Intermediate prognosis 1
• p53-aberrant (copy number high): Poor prognosis 1

Evidence Supporting POLE-Mutated Superior Prognosis

Survival Outcomes

POLEmut tumors demonstrate the best clinical outcomes across all survival metrics 1, 2:

• Disease-specific survival: HR 0.41 for POLEmut versus other subtypes 1
• Progression-free survival: HR 0.23 for POLEmut versus other subtypes 1
• Overall survival: HR 0.90 for POLEmut versus other subtypes 1

Meta-analyses consolidating thousands of patients confirm these findings, with POLEmut showing disease-specific survival HR of 0.408 and progression-free survival HR of 0.231 3, 4.

Biological Basis for Favorable Prognosis

The exceptional prognosis of POLEmut tumors stems from their unique molecular characteristics 1, 2:

• Ultra-high mutational burden: >100 mutations/megabase, creating the highest neoantigen load (median 8,342 predicted neoantigens per sample versus 541 for MSI and 70.5 for microsatellite stable tumors) 1, 2
• Robust immune infiltration: Highest degrees of CD8+ T cell infiltration with prominent tumor-infiltrating lymphocytes and tertiary lymphoid structures 1, 2
• Very low somatic copy-number alterations: Genomic stability despite high mutation rate 2

Clinical-Pathological Features of POLEmut Tumors

Paradoxical High-Grade Presentation

POLEmut tumors frequently present with aggressive histologic features that belie their excellent prognosis 2, 3:

• High-grade histology: 51-62% are grade 3 endometrioid carcinomas 1, 2
• Early stage at diagnosis: 89-92% present at FIGO stage I-II 1, 2, 3
• Limited myometrial invasion: Significantly associated with <50% myometrial invasion (OR 1.48-1.77) 5, 3
• Reduced lymph node metastases: OR 0.202 for lymph node involvement 3

Diagnostic Identification

POLEmut status is identified through specific hotspot mutations in the exonuclease domain 1, 2:

• Pathogenic mutations: P286R, V411L, S297F, A456P, S459F 1, 2
• Testing method: NGS, Sanger sequencing, or targeted hotspot analysis 1
• Hierarchical priority: POLE testing takes precedence in the diagnostic algorithm, performed before MMR and p53 assessment 1, 2

Treatment Implications Based on Molecular Classification

POLEmut: Treatment De-escalation

All stage I-II POLEmut cancers are classified as low-risk regardless of grade, myometrial invasion, or lymphovascular space invasion 1, 6, 2:

• Observation after surgery is appropriate for stage I-II POLEmut tumors following patient counseling 1, 2
• Adjuvant radiation or chemotherapy are not routinely recommended, even with high-grade features 6, 2
• De-escalation trials ongoing: PORTEC-4a is evaluating safety of omitting adjuvant therapy 2

Contrast with p53-Aberrant: Treatment Escalation

The p53-aberrant subgroup requires the opposite approach 1, 6:

• Poorest prognosis independent of stage, histology, or treatment 1
• Chemotherapy addition required regardless of early stage 6
• High-risk classification for all p53-aberrant tumors with myometrial invasion 1

Critical Clinical Pitfalls to Avoid

Do Not Rely on Histology Alone

A high-grade endometrioid carcinoma may be POLEmut (excellent prognosis) or p53-aberrant (poor prognosis)—molecular testing is essential to distinguish these fundamentally different entities 2:

• Traditional grade 3 endometrioid histology encompasses both best-prognosis (POLEmut) and worst-prognosis (p53-aberrant) molecular subtypes 1
• Molecular classification supersedes histologic grading for risk stratification and treatment decisions 6

Mandatory Testing for All Cases

Molecular testing must be performed on all endometrial cancer specimens, regardless of histological type or apparent low-risk features 6, 2:

• Even early-stage, low-grade tumors require molecular classification 6
• The resulting molecular subgroup fundamentally alters therapeutic decisions 2
• Underutilization of molecular testing leads to inappropriate over-treatment of POLEmut patients and under-treatment of p53-aberrant patients 1

Follow Hierarchical Testing Order

The diagnostic algorithm must follow POLE → MMR → p53 sequence to avoid misclassification 1, 2:

• POLE status overrides any other molecular category (e.g., a tumor may be both POLEmut and MSI-high, but is classified as POLEmut) 2
• Testing p53 before excluding POLE mutation can lead to incorrect risk stratification 2

Frequency and Population Distribution

POLEmut tumors comprise a small but clinically significant subset 1, 2:

• Overall prevalence: 5-15% of all endometrial carcinomas 1, 2
• In high-grade endometrioid: Approximately 15% 2
• In type I (endometrioid): 8.22% 5
• In type II (non-endometrioid): 0.93% 5

Patients with POLEmut tumors tend to be younger with lower body mass index and earlier disease onset compared to other molecular subtypes 1, 2.