How does molecular subtype and current FIGO (International Federation of Gynecology and Obstetrics) staging influence adjuvant therapy decisions in patients with endometrial carcinoma?

Molecular Classification and FIGO Staging in Endometrial Carcinoma: Impact on Adjuvant Therapy Decisions

Molecular classification significantly impacts adjuvant therapy decisions in endometrial carcinoma and should be integrated with FIGO staging to guide treatment, with p53abn tumors requiring more aggressive therapy regardless of stage, while POLEmut tumors may need less intensive treatment even with higher risk features. 1

Risk Stratification Framework

The current approach to risk stratification in endometrial carcinoma integrates:

1. FIGO Staging - anatomical extent of disease
2. Histopathological Features - grade, histological type, LVSI
3. Molecular Classification - POLEmut, MMRd, NSMP, p53abn

Current Risk Groups (ESMO/ESGO/ESTRO Consensus)

Risk Group	Description
Low	Stage I endometrioid, grade 1-2, <50% myometrial invasion, LVSI negative
Intermediate	Stage I endometrioid, grade 1-2, ≥50% myometrial invasion, LVSI negative
High-intermediate	Stage I endometrioid, grade 3, <50% myometrial invasion, regardless of LVSI status; or Stage I endometrioid, grade 1-2, LVSI unequivocally positive, regardless of depth of invasion
High	Stage I endometrioid, grade 3, ≥50% myometrial invasion, regardless of LVSI; Stage II; Stage III endometrioid with no residual disease; Non-endometrioid histology
Advanced	Stage III with residual disease and stage IVA
Metastatic	Stage IVB

2

Molecular Classification Impact on Adjuvant Therapy

The molecular classification divides endometrial cancer into four distinct prognostic subgroups:

1. POLEmut (POLE ultramutated) - Excellent prognosis
2. MMRd (Mismatch repair deficient) - Intermediate prognosis
3. NSMP (Non-specific molecular profile) - Variable prognosis
4. p53abn (TP53 mutated) - Poor prognosis

Key Treatment Implications by Molecular Subtype:

POLEmut Tumors

• Even with high-risk features: Consider de-escalation of adjuvant therapy
• Stage I: Observation may be appropriate regardless of other risk factors
• Higher stages: May still benefit from less intensive adjuvant therapy

MMRd Tumors

• High-intermediate risk: Adjuvant brachytherapy recommended
• High risk: Adjuvant EBRT recommended
• Important finding: No significant survival benefit from adding chemotherapy to radiation therapy, even in high-risk or advanced disease 1

NSMP Tumors

• Follow standard risk-based recommendations according to FIGO stage and other risk factors
• Adjuvant therapy decisions similar to conventional risk stratification

p53abn Tumors

• Require more aggressive therapy regardless of stage
• Stage I: Consider adjuvant chemotherapy plus radiation
• All stages: Significantly improved disease-specific survival with combined chemoradiation compared to radiation alone 1
• Even in early-stage disease: Benefit from chemotherapy addition, including non-serous histotypes

Adjuvant Therapy Algorithm Based on Integrated Classification

Stage I Disease:

1. Low Risk (Stage IA, Grade 1-2, LVSI negative, non-p53abn)

   • No adjuvant therapy 2
   • If POLEmut: No adjuvant therapy regardless of other factors

2. Intermediate Risk (Stage IB, Grade 1-2, LVSI negative)

   • If surgical nodal staging performed and negative: Consider observation or vaginal brachytherapy
   • If no surgical nodal staging: Vaginal brachytherapy
   • If POLEmut: Consider observation

3. High-Intermediate Risk

   • If surgical nodal staging performed and negative:
     • Adjuvant brachytherapy recommended to decrease vaginal recurrence
     • If p53abn: Consider adding chemotherapy
   • If no surgical nodal staging:
     • LVSI positive: Adjuvant EBRT recommended
     • Grade 3, LVSI negative: Adjuvant brachytherapy
     • If p53abn: Consider adding chemotherapy regardless of LVSI status 1

4. High Risk (Stage IB, Grade 3 or non-endometrioid)

   • Adjuvant EBRT recommended
   • If p53abn: Add chemotherapy
   • If POLEmut: Consider de-escalation to brachytherapy alone

Stage II Disease:

• Standard approach: Pelvic EBRT and vaginal brachytherapy
• If grade 1-2, <50% myometrial invasion, negative LVSI, complete surgical staging: Brachytherapy alone
• If p53abn: Add chemotherapy regardless of other factors
• If POLEmut: Consider de-escalation to brachytherapy alone

Stage III Disease:

• Standard approach: Combined chemotherapy and radiation therapy
• If p53abn: Prioritize platinum-based chemotherapy with sequential radiation
• If MMRd: Radiation therapy may be prioritized over chemotherapy 1
• If POLEmut with no residual disease: Consider less intensive adjuvant therapy

Clinical Implications and Pitfalls

Important Considerations:

1. Complete molecular classification is strongly recommended for all endometrial cancers to guide adjuvant therapy decisions 3

2. p53abn status is a critical determinant of adjuvant therapy needs, even in early-stage disease 1

3. POLEmut status may allow de-escalation of therapy even in the presence of other high-risk features

4. MMRd tumors may not benefit from chemotherapy addition to radiation therapy, an important consideration when weighing toxicity 1

5. Grade 3 tumors with LVSI have particularly high recurrence risk and may benefit from combined modality treatment, especially if p53abn 4

Common Pitfalls to Avoid:

1. Relying solely on FIGO staging without considering molecular classification

2. Undertreatment of p53abn tumors in early stages due to favorable conventional risk factors

3. Overtreatment of POLEmut tumors that have excellent prognosis despite high-risk features

4. Applying chemotherapy uniformly across all high-risk patients without considering molecular subtype

5. Failing to consider LVSI status which significantly impacts recurrence risk, especially in intermediate-risk disease

The integration of molecular classification with traditional FIGO staging provides a more personalized approach to adjuvant therapy decisions in endometrial carcinoma, with potential to improve outcomes while avoiding unnecessary treatment toxicity.