Is MMR (Mismatch Repair) testing recommended for a patient with stage II A colon cancer who has undergone a sigmoidectomy?

MMR Testing in Stage II Colon Cancer

Yes, MMR (Mismatch Repair) testing is strongly recommended for all patients with stage II colon cancer, including those who have undergone sigmoidectomy. This testing is essential for both prognostic assessment and treatment decision-making regarding adjuvant chemotherapy 1, 2.

Why MMR Testing is Critical in Stage II Disease

MMR status fundamentally changes treatment recommendations and prognosis in stage II colon cancer. The evidence demonstrates that:

• MSI-H/dMMR tumors occur in approximately 22% of stage II colon cancers, making this a common and clinically significant finding 1
• Patients with dMMR tumors have approximately half the recurrence risk compared to proficient MMR (pMMR) tumors, with recurrence rates of 11% versus 26% 1
• dMMR status is associated with significantly improved survival outcomes, with hazard ratios of 0.64 for overall survival and 0.59 for disease-free survival 3

Impact on Treatment Decisions

For dMMR/MSI-H Stage II Disease

Observation without adjuvant chemotherapy is recommended for most stage II dMMR patients 1, 4. The rationale includes:

• Fluoropyrimidine-based chemotherapy may be detrimental or provide no benefit in dMMR stage II disease 1
• Multiple studies show patients with MSI-H tumors who received 5-FU adjuvant therapy had lower 5-year survival rates than those undergoing surgery alone 1
• The ASCO guideline states there is very low-quality evidence showing uncertainty whether adjuvant chemotherapy improves or worsens outcomes for dMMR patients, with considerable heterogeneity 1

Exception: For high-risk stage II dMMR patients (T4 tumors, <12 lymph nodes examined, bowel obstruction, perforation), combination chemotherapy may be considered, though the benefit remains uncertain 1, 4

For pMMR/MSS Stage II Disease

MMR testing identifies the 80% of patients with pMMR tumors who may benefit from adjuvant chemotherapy, particularly those with high-risk features 1. These patients showed:

• Significantly improved overall survival with adjuvant chemotherapy (HR 0.31,95% CI 0.18-0.52) 1
• Improved 2-year recurrence rates with fluoropyrimidine treatment (OR 0.59,95% CI 0.45-0.77) 1

Testing Methodology

Both immunohistochemistry (IHC) and PCR-based MSI analysis are acceptable methods 2, 5. The approach should include:

• IHC evaluation of four MMR proteins (MLH1, MSH2, MSH6, PMS2), with loss of any protein indicating dMMR 2, 6
• Moderate concordance exists between IHC and PCR methods (Kappa test), suggesting both should ideally be performed for reliable clinical decisions 6, 5
• PMS2 deficiency is the most frequent deficiency among MMR proteins in Chinese populations 6

Additional Clinical Implications

MMR testing has implications beyond adjuvant chemotherapy decisions:

• Identifies Lynch syndrome risk (2-4% of colon cancers), requiring genetic counseling and surveillance 1, 2
• Predicts response to immune checkpoint inhibitors in metastatic disease, with pembrolizumab approved for MSI-H/dMMR colorectal cancer 2, 7
• Grade 3-4 differentiation is NOT considered a high-risk feature in MSI-H stage II disease 1

Common Pitfalls to Avoid

• Do not assume distal colon tumors require MMR testing routinely—defective MMR is rare in distal tumors (only 3%), though your patient had a sigmoidectomy which may involve proximal sigmoid 8
• Do not use MMR status to guide oxaliplatin decisions in stage III disease—conflicting data exist and it should not influence treatment in this setting 1
• Do not recommend adjuvant bevacizumab, cetuximab, panitumumab, or irinotecan outside clinical trials regardless of MMR status 4

In summary, MMR testing should be performed on your patient's stage II colon cancer specimen before making any adjuvant therapy decisions, as it will determine whether observation alone (for dMMR) or consideration of chemotherapy (for pMMR with high-risk features) is most appropriate 1, 2.