First-Line Treatment in Advanced Endometrial Carcinoma

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📉 Disease Overview

Median Age at Diagnosis: 60–65 years 🧓

Metastatic at Presentation: 5–15% 🚨

Common Metastatic Sites:

Lungs: 40% 🫁

Lymph Nodes: 30% 🧬

Liver: 20% ❤️

Bones: 10%

Median Overall Survival (OS): 12–18 months ⏳

Median Progression-Free Survival (PFS): 5–6 months 📉

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🔬 Histological and Molecular Profiling

Histological Subtypes (WHO Classification):

Endometrioid Adenocarcinoma (Grade 1–3) 🧬

Serous Carcinoma 🚨

Clear Cell Carcinoma

Carcinosarcoma (MMMT)

Undifferentiated/Dedifferentiated Carcinoma

Essential Molecular Testing:

Mismatch Repair (MMR) IHC: MLH1, PMS2, MSH2, MSH6

Microsatellite Instability (MSI) Testing

Estrogen Receptor (ER) & Progesterone Receptor (PR) Status

HER2 Testing (IHC/FISH): Serous/Carcinosarcoma tumors

PD-L1 IHC (Optional)

p53 IHC (Optional)

POLE Mutation Testing (Optional)

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💉 First-Line Systemic Therapy Options

Chemotherapy-Based Regimens:

1. Carboplatin + Paclitaxel (CP) – GOG-209 Trial

Comparison: CP vs. TAP (Paclitaxel, Doxorubicin, Cisplatin)

Outcome: CP was non-inferior to TAP

Median PFS (Carbo + Pacli): 13 months ⏳

Median OS (Carbo + Pacli): 37 months ⏳

Standard of Care for advanced/recurrent endometrial cancer

2. Carboplatin + Paclitaxel + Bevacizumab (GOG-86P)

Median PFS: 13 months (not significant) ⏳

Median OS: 34 months (significant) ⏳

3. Carboplatin + Paclitaxel + Pembrolizumab (NRG-GY018)

PFS HR (dMMR): 0.3 📉

PFS HR (pMMR): 0.54 📉

Median PFS (pMMR): 13 months ⏳

Median OS (pMMR): 28 months ⏳

Maintenance: Pembrolizumab every 6 weeks for 2 years 🛡️

4. Dostarlimab + Carboplatin/Paclitaxel (RUBY/ENGOT-EN6/GOG3031)

PFS HR (dMMR): 0.3 📉

PFS HR (pMMR): 0.8 📉

Overall OS HR: 0.69 (significant) 📉

Maintenance: Dostarlimab for 3 years 🛡️

5. Carboplatin + Paclitaxel + Trastuzumab (HER2-positive)

Median PFS: 13 months ⏳

Median OS: 24 months ⏳

6. Durvalumab + Chemotherapy ± Olaparib (DUO-E Trial)

PFS HR (Durvalumab): 0.71 📉

PFS HR (Durvalumab + Olaparib): 0.55 📉

Median PFS (Durvalumab): 10.0 months ⏳

OS HR (dMMR): 0.4 📉

7. Atezolizumab + Chemotherapy (AtTEnd Trial)

Median PFS: 10 months ⏳

Median OS: 38 months ⏳

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🔪 Surgical Cytoreduction

Stage IVB Intra-abdominal Disease:

Complete Cytoreduction (CRS): Median OS = 48 months ⏳

Optimal Cytoreduction (OCR, <1 cm residual): Median OS = 24 months ⏳

Neoadjuvant chemotherapy (NACT) considered if OCR is feasible.

Note: Data is retrospective 🏥

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💊 Hormonal Therapy

Indicated for:

Low-grade, indolent, endometrioid histology 🌿

Hormone receptor-positive (HR+) tumors 💊

Low-volume disease, especially in elderly/frail patients 👵

Key Trial Data (GOG-119):

Regimen: Daily Tamoxifen (40mg )+ alternate weekly MPA ( 200mg)

ORR: 27% 📈

Median PFS: 2.7 months ⏳

Median OS: 14 months ⏳

Other Hormonal Agents:

Progestins: Medroxyprogesterone acetate, Megestrol acetate

Aromatase Inhibitors: Letrozole, Anastrozole

Tamoxifen (Selective Estrogen Receptor Modulator)

Fulvestrant (Estrogen Receptor Degrader)

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📝 Final Insights

🔍 Optimized Treatment Approach

1. dMMR/MSI-H Tumors:

Preferred: Chemotherapy + Immunotherapy (Pembrolizumab/Dostarlimab/Durvalumab/Atezolizumab) 🛡️

Benefit: Significant OS and PFS improvement ⏳✅

2. pMMR/MSS Tumors:

Preferred: Chemotherapy (CP) ± Immunotherapy (PFS benefit only) 💉

3. HER2-Positive Tumors:

Preferred: Chemotherapy + Trastuzumab 🎯

4. Low-Volume, HR-Positive Tumors:

Preferred: Hormonal Therapy (Letrozole, Megestrol, Tamoxifen) 💊

5. Surgical option in intra abdominal mets (Stage IVB):

Preferred: Cytoreduction (if feasible) with NACT consideration 🏥