What is the role of molecular typing in guiding treatment decisions for patients with endometrial cancer?

Molecular Typing in Endometrial Cancer

Molecular classification should be performed on all endometrial cancer specimens regardless of histological type using immunohistochemistry for p53 and MMR proteins (MLH1, PMS2, MSH2, MSH6) combined with POLE hotspot sequencing, as this directly guides risk stratification and adjuvant treatment decisions that impact survival. 1

The Four Molecular Subgroups and Their Clinical Implications

The molecular classification identifies four distinct prognostic groups that supersede traditional histology-based risk assessment 1:

POLEmut (POLE ultramutated)

• Prevalence: 5-15% of cases 1
• Diagnostic test: NGS/Sanger sequencing for hotspot mutations (P286R, V411L, S297F, A456P, S459F) 1
• Prognosis: Excellent, even with high-grade histology 1
• Treatment impact: Stage I/II POLEmut cancers are classified as low-risk and require no adjuvant treatment, representing a major de-escalation opportunity 1
• Key feature: >100 mutations/megabase with prominent tumor-infiltrating lymphocytes 1

dMMR (Mismatch Repair Deficient/MSI)

• Prevalence: 25-30% of cases 1
• Diagnostic test: IHC for MLH1, PMS2, MSH2, MSH6 (loss of one or more proteins indicates deficiency) 1
• Prognosis: Intermediate 1
• Treatment impact: Eligible for immunotherapy (pembrolizumab) in advanced/recurrent disease, as 20-30% of advanced endometrial cancers have this profile 2
• Associated features: Often endometrioid histology with substantial LVSI, higher BMI, Lynch syndrome association 1

NSMP (No Specific Molecular Profile)

• Prevalence: 30-40% of cases 1
• Diagnostic test: Absence of POLE mutation, intact MMR, and wild-type p53 1
• Prognosis: Intermediate 1
• Treatment impact: Risk stratification depends heavily on traditional clinicopathological factors (stage, grade, LVSI) 1
• Key features: Mostly low-grade endometrioid with diffuse ER/PgR expression, notable absence of TILs 1

p53-aberrant (p53-mutant)

• Prevalence: 5-15% of cases 1
• Diagnostic test: p53 IHC (acceptable surrogate for TP53 mutation status in MMR-proficient, POLE wild-type cases) 1
• Prognosis: Poor, regardless of histology 1
• Treatment impact: Greatest benefit from adjuvant chemotherapy addition, including serous cancers and significant portions of carcinosarcomas 1
• Clinical features: Advanced stage at presentation, lower BMI, high cytonuclear atypia, low TILs 1

Diagnostic Algorithm Implementation

The testing sequence follows a hierarchical approach 1:

1. First: POLE hotspot sequencing (if pathogenic variant found, classify as POLEmut regardless of other findings)
2. Second: MMR IHC (if deficient, classify as dMMR)
3. Third: p53 IHC on MMR-proficient, POLE wild-type cases (if aberrant, classify as p53-aberrant)
4. Fourth: Remaining cases classified as NSMP

This algorithm applies to all histological subtypes including carcinosarcomas 1.

Risk Stratification Based on Molecular Classification

The integrated molecular-clinicopathological risk groups directly determine adjuvant therapy 1:

Low-Risk (No Adjuvant Treatment)

• Stage IA (G1-G2) endometrioid with dMMR or NSMP and no/focal LVSI 1
• All stage I/II POLEmut cancers (even stage III POLEmut may be considered low-risk) 1

High-Risk (Requires Intensive Adjuvant Therapy)

• All stages with p53-aberrant and myometrial invasion 1
• All stages with serous or undifferentiated carcinoma including carcinosarcoma with myometrial invasion 1
• All stage III-IVA with no residual tumor, regardless of histology or molecular subtype 1

Critical Pitfalls to Avoid

Conflicting results: When IHC and molecular testing disagree (e.g., MLH1 loss by IHC but MSS by NGS), prioritize the molecular sequencing result, as IHC can show false positives 3. One study found 3/45 cases classified as MSI-H by IHC were MSS by NGS 3.

p53 interpretation: p53 IHC showing missense mutations may not correlate with functional p53 abnormality; sequencing confirmation is preferred in ambiguous cases 3.

Substantial vs. focal LVSI: This distinction critically impacts risk classification—substantial LVSI upgrades dMMR/NSMP cases to high-intermediate risk even in stage I disease 1.

Transition phase documentation: Cases without complete molecular classification should be designated as "EC not-otherwise-specified (EC-NOS)" with specification of which classification system was used 1.

Impact on Treatment Decisions

De-escalation: POLEmut patients can avoid unnecessary adjuvant radiation/chemotherapy despite high-grade features, preventing overtreatment 1.

Escalation: p53-aberrant cases require chemotherapy addition regardless of early stage, preventing undertreatment 1.

Immunotherapy eligibility: dMMR status identifies patients eligible for pembrolizumab in advanced/recurrent disease, representing the first tissue-agnostic FDA approval applicable to endometrial cancer 2.

Clinical trial stratification: The PORTEC-4a trial is actively using molecular classification to guide adjuvant treatment decisions, validating this approach prospectively 1.

The molecular classification represents a paradigm shift from histology-driven to biology-driven treatment decisions, with direct impact on morbidity through treatment de-escalation in favorable subtypes and mortality reduction through intensification in high-risk molecular profiles 1.