Yes, MMR/MSI Testing is Essential and Should Be Performed Immediately
MMR/MSI status must be evaluated in all patients with stage II colon cancer, including those with high pre-operative CEA and potential high-risk features, as it fundamentally determines whether adjuvant chemotherapy should be offered and guides treatment selection. 1
Why MMR Status is Critical in This Clinical Scenario
Prognostic and Predictive Impact
MMR status serves dual roles that directly impact your treatment decision:
- Prognostic marker: dMMR/MSI-H tumors have inherently better outcomes than pMMR/MSS tumors in stage II disease 1
- Predictive marker: dMMR/MSI-H status predicts lack of benefit (and potential harm) from fluoropyrimidine-only adjuvant chemotherapy 1
Treatment Algorithm Based on MMR Status
For dMMR/MSI-H tumors:
- Fluoropyrimidine-only chemotherapy is NOT recommended (strong recommendation, moderate evidence) 1
- Poor differentiation is NOT considered a high-risk feature in dMMR tumors 1
- Exception: If T4 tumor and/or other high-risk features present (excluding poor differentiation), oxaliplatin-containing chemotherapy may be considered through shared decision-making 1
- Recent data from 2026 suggests that dMMR patients with specific high-risk features (particularly T4 or perineural invasion) may derive survival benefit from adjuvant chemotherapy 2, 3
For pMMR/MSS tumors:
- Standard risk stratification applies using conventional high-risk features 1
- Adjuvant chemotherapy improves outcomes in patients with high-risk features 4, 5
- CEA >5 ng/mL is an independent prognostic factor in this population 6
Important Clinical Caveats
The dMMR Paradox in Imaging
Be aware that dMMR right-sided colon cancers are more likely to be overstaged on preoperative CT scans (OR 1.551,95% CI 1.210-1.989) 6. This means:
- Radiologic lymph node involvement may overestimate true pathologic stage
- Don't let CT findings alone drive you toward neoadjuvant treatment without tissue confirmation
- Overstaged dMMR patients actually have better prognosis than their imaging suggests 6
Emerging Evidence on High-Risk dMMR Disease
The most recent 2026 data challenges older dogma:
- High-risk stage II dMMR patients (particularly those with T4 or perineural invasion) showed improved 5-year RFS (94.0% vs 83.7%, p=0.001) and OS (98.3% vs 89.0%, p=0.001) with adjuvant chemotherapy 2
- Perineural invasion emerged as a particularly important independent predictor (HR 3.581 for RFS, HR 4.968 for OS) 2
- Poorly differentiated histology in dMMR tumors may identify a subset benefiting from adjuvant treatment 3
Practical Implementation
Order MMR testing now via:
- Immunohistochemistry for MLH1, MSH2, MSH6, PMS2 proteins, OR
- PCR-based MSI testing
- Consider NGS panel (preferred by NCCN for metastatic disease) if resources allow 7
Do not proceed with treatment decisions until MMR status is known, as the treatment recommendation fundamentally differs based on this biomarker. The high pre-operative CEA and potential high-risk features you mention are relevant for pMMR tumors but have different implications in dMMR disease.