Teaching pack: Endometrial cancer

Endometrial cancer is the most common gynaecologic cancer in high-income countries (~420,000 cases a year worldwide) and one of the few cancers whose incidence and mortality are rising, driven by obesity, diabetes, and an ageing population. Most cases are low-grade endometrioid tumours found at stage I because of postmenopausal bleeding, and are cured by hysterectomy; a minority (serous, clear-cell, carcinosarcoma, and other p53-abnormal tumours) behave like high-grade ovarian cancer and account for most deaths. Since 2013, four molecular classes (POLE-mutated, mismatch-repair deficient, p53-abnormal, no specific molecular profile) have replaced histology as the primary prognostic and predictive framework.

The standard of care for early disease is minimally invasive hysterectomy with sentinel lymph node mapping, and adjuvant therapy scaled to risk: observation or vaginal brachytherapy for low and intermediate risk, pelvic radiotherapy or chemoradiation plus chemotherapy for high risk (PORTEC-3), with molecular class increasingly steering choices and fertility-sparing progestin therapy available for young women with the earliest tumours. Advanced and recurrent disease changed in 2023: three phase 3 trials (RUBY, NRG-GY018, DUO-E) established chemotherapy plus a PD-1/PD-L1 antibody as first-line standard, with dramatic benefit in dMMR tumours and a survival gain in the whole population (RUBY, OS 44.6 vs 28.2 months). Lenvatinib plus pembrolizumab (KEYNOTE-775) remains the second-line option for mismatch-repair-proficient disease, and trastuzumab deruxtecan is approved for HER2 IHC 3+ tumours.

• IO-chemotherapy first line with OS benefit in dMMR and beyond.
• Chemotherapy plus PD-1/PD-L1 blockade is first-line standard for advanced disease, with a 16-month overall survival gain in RUBY and a 72% reduction in progression risk in dMMR tumours.
• Molecular classification (POLE, MMR, p53) is part of routine diagnosis and is beginning to direct adjuvant therapy.
• Sentinel lymph node mapping has replaced full lymphadenectomy, cutting lymphoedema without missing metastases.
• Lenvatinib plus pembrolizumab gives an 18-month median survival in pMMR disease after platinum, where PD-1 alone barely worked.
• HER2 IHC 3+ disease has an approved ADC (T-DXd) with an 85% response rate.

1. 1971Progestins approved for advanced endometrial cancer
2. 1983Bokhman's type I / type II model
3. 2009LAP2: laparoscopic hysterectomy equivalent to open surgery
4. 2010PORTEC-2: vaginal brachytherapy replaces pelvic radiation for intermediate risk
5. 2013TCGA molecular classification
6. 2013TCGA defines four molecular classes
7. 2017FIRES: sentinel node mapping validated; pembrolizumab approved for MSI-H tumours
8. 2018PORTEC-3: chemoradiation plus chemotherapy for high-risk disease
9. 2019Lenvatinib + pembrolizumab accelerated approval (KEYNOTE-146)
10. 2021KEYNOTE-775: lenvatinib + pembrolizumab OS benefit; dostarlimab approved for dMMR recurrence (GARNET); molecular classification enters ESGO guidelines

• Sacituzumab tirumotecan (product)
• Puxitatug samrotecan (product)
• Rinatabart sesutecan (product)
• RAINFOL-01 (Rina-S) (trial)
• Luveltamab tazevibulin (product)
• Trastuzumab deruxtecan (product)
• Molecular-class-directed adjuvant therapy in endometrial cancer (idea)
• HER2 ADCs as standard for HER2-positive serous endometrial cancer (idea)
• Letrozole (and other aromatase inhibitors) (product)
• Abemaciclib (product)
• WEE1 (target)
• MRD / molecular residual disease testing (technology)

• PORTEC-3 (phase 3, n=660): Overall survival at 5 years: 81.4% vs 76.1%, HR 0.7
• RUBY / ENGOT-EN6 / GOG-3031 (phase 3, n=494): Progression-free survival at 24 months (dMMR/MSI-H): 61.4% vs 15.7%, HR 0.28
• KEYNOTE-775 / Study 309 (phase 3, n=827): Overall survival (all comers): 18.3 months vs 11.4 months, HR 0.62
• NRG-GY018 / KEYNOTE-868 (phase 3, n=816): Progression-free survival (dMMR): pending
• DUO-E / GOG-3041 / ENGOT-EN10 (phase 3, n=718): Progression-free survival (dMMR, durvalumab): pending
• DESTINY-PanTumor02 (phase 2, n=267): Objective response rate, endometrial cohort: 57.5% vs 84.6%

• p53-abnormal disease behaves like serous ovarian.
• Obesity-driven incidence rising.
• Incidence and mortality are rising, and Black women in the US die at nearly twice the rate of white women, driven by more p53-abnormal tumours and later diagnosis.
• p53-abnormal and carcinosarcoma histologies still relapse frequently despite chemoradiation; no subtype-specific therapy is approved beyond HER2.
• Immunotherapy benefit in pMMR disease is modest and biomarkers to select pMMR responders are lacking.
• Optimal adjuvant strategy by molecular class is unproven prospectively until RAINBO and PORTEC-4a report.

1. What does 'triple-negative' mean in breast cancer?
   Answer

   The tumour lacks the three receptors other breast cancers can be treated through: oestrogen receptor, progesterone receptor, and HER2 (IHC 0-1+ or 2+/ISH-negative).
2. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
3. Why does trastuzumab deruxtecan work in 'HER2-low' breast cancers that older HER2 drugs ignored?
   Answer

   Its cleavable linker releases a membrane-permeable topoisomerase-I payload (DXd) at high DAR, so a small amount of HER2 is enough to deliver drug and the payload diffuses to kill neighbouring cells (bystander effect); HER2-low is a delivery address, not a driver. DESTINY-Breast04 and -06 proved it.
4. What questions should someone newly diagnosed with triple-negative breast cancer ask before surgery?
   Answer

   Whether chemo-immunotherapy before surgery (KEYNOTE-522) is planned and why; germline BRCA testing; PD-L1 and HER2-low status; TIL score; clinical trial options; fertility preservation; breast-conserving versus mastectomy and sentinel node approach; what response (pCR/RCB) will mean for treatment afterwards.
5. Which CDK4/6 inhibitors are approved after surgery for early hormone-positive breast cancer, and on what trials?
   Answer

   Abemaciclib (monarchE, high-risk node-positive) and ribociclib (NATALEE, stage II-III including node-negative).
6. In what setting did T-DXd move into early-stage HER2-positive breast cancer in 2026?
   Answer

   Neoadjuvant (DESTINY-Breast11, T-DXd followed by THP, pCR 67.3% vs 56.3%) and post-neoadjuvant residual disease (DESTINY-Breast05, beating T-DM1), both approved Q2 2026.

• Wikipedia: https://en.wikipedia.org/wiki/Endometrial_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1473
• Guideline: https://www.esgo.org/guidelines/endometrial-cancer-guidelines/