What is the recommended treatment for a patient with Stage 1a cancer, positive peritoneal washings, and mixed Mismatch Repair (MMR) deficiency?

Treatment Recommendation for Stage IA Endometrial Cancer with Positive Peritoneal Washings and MMR Deficiency

For Stage IA endometrial cancer with positive peritoneal washings and MMR deficiency, immunotherapy with pembrolizumab, dostarlimab, or nivolumab should be the primary treatment approach, as MMR-deficient tumors demonstrate exceptional response to PD-1 inhibitors and may derive limited or no benefit from traditional chemotherapy.

Primary Treatment Strategy

Immunotherapy as First-Line Treatment

• Immunotherapy is strongly recommended as the initial approach for dMMR/MSI-H tumors across cancer types, with PD-1 inhibitors demonstrating superior outcomes compared to conventional chemotherapy 1
• Pembrolizumab, dostarlimab, or nivolumab are all appropriate first-line options for dMMR/MSI-H endometrial cancer 1
• Dostarlimab achieved 100% clinical complete response rates in locally advanced rectal cancer with dMMR status, with zero progression or recurrence at 2024 data analysis, demonstrating the remarkable efficacy of immunotherapy in MMR-deficient tumors 1

Why Avoid Traditional Chemotherapy in dMMR Tumors

• dMMR tumors show significantly reduced response to traditional chemotherapy, with response rates of only 5% versus 44% in MMR-proficient tumors 2
• Preclinical studies demonstrate that dMMR colorectal cancer cell lines are at least 18-fold more resistant to 5-fluorouracil than pMMR cell lines 2
• The chemotoxicity induced by 5-FU treatment is partially mediated by the MMR pathway itself; when this pathway is deficient, the mechanism of chemotherapy action is compromised 2
• In advanced stage endometrial cancer, patients with intact MMR showed improved progression-free survival with adjuvant chemotherapy (p=0.031), while those with defective MMR may receive less benefit 3

Clinical Context: Positive Peritoneal Washings

Prognostic Significance

• Positive peritoneal washings in Stage IA disease traditionally upstages patients and indicates higher risk for recurrence
• However, MMR deficiency itself is associated with better overall survival and progression-free survival in endometrial cancer patients receiving adjuvant therapy 4
• Women with MMR-deficient endometrial cancers who receive adjuvant therapy have lower recurrence rates (5.9 per 100 person-years) compared to MMR-proficient cancers (10.7 per 100 person-years) 4

Treatment Algorithm for This Specific Scenario

1. Confirm MMR deficiency status using immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 proteins 3
2. Initiate immunotherapy with pembrolizumab, dostarlimab, or nivolumab as first-line treatment 1
3. Continue immunotherapy per FDA-approved duration and monitor for clinical complete response 1
4. Assess response at 6 months using appropriate imaging (MRI, PET/CT) and clinical evaluation 1

Important Caveats and Pitfalls

When Chemotherapy Might Still Be Considered

• If rapid tumor downstaging is urgently needed (e.g., symptomatic disease burden), chemotherapy with or without monoclonal antibodies may be preferable over immunotherapy in selected cases, as 29.4% of patients on pembrolizumab had primary progressive disease versus 12.3% on chemotherapy 2
• For patients who fail immunotherapy (20-30% of dMMR patients do not respond), combination chemotherapy regimens may be considered as second-line treatment 2

Radiation Therapy Considerations

• Subgroups of patients with non-endometrioid endometrial cancer and defective MMR may have improved survival after adjuvant radiotherapy 3
• There was significant increase in overall survival (p=0.003) and progression-free survival (p=0.004) in those with MMR-deficient, non-endometrioid tumors treated with teletherapy 3
• However, for Stage IA disease with positive washings, the role of radiation remains uncertain and should be weighed against immunotherapy benefits

Mixed MMR Status Interpretation

• The term "mixed MMR deficient" requires clarification—if this refers to heterogeneous expression patterns, the tumor should be classified based on the most deficient component
• Both endometrial and any synchronous ovarian tumors typically show the same MMR expression status 5
• If any MMR protein is absent on immunohistochemistry, the tumor should be classified as dMMR and treated accordingly 3

Monitoring and Follow-up

• No grade 3 or higher adverse events were reported with dostarlimab monotherapy in dMMR tumors, indicating excellent tolerability 1
• Regular surveillance imaging and clinical assessment should be performed every 3-6 months during the first 2 years
• Immune-related adverse events should be monitored and managed according to standard immunotherapy protocols