Should mismatch repair (MMR) testing be performed in a patient with stage III colon cancer?

MMR Testing in Stage III Colon Cancer

Yes, MMR testing should be performed in all patients with stage III colon cancer, primarily to identify Lynch syndrome for family counseling and surveillance, not to guide adjuvant chemotherapy decisions. 1

Primary Rationale for Testing

Lynch syndrome identification is the critical reason to test stage III patients. 1, 2 The NCCN guidelines explicitly state that MMR testing should be considered for all patients with colorectal cancer, with particular emphasis on those under 50 years of age. 1 Approximately 18% of stage III colon cancers with dMMR harbor constitutional pathogenic variants (Lynch syndrome), which has profound implications for the patient and their family members. 3

Key Testing Indications:

• All patients under 50 years: This age cutoff meets revised Bethesda guidelines and significantly increases Lynch syndrome probability 1, 2
• Stage III disease regardless of age: For Lynch syndrome detection and family counseling 1, 4
• Prognostic information: dMMR tumors show reduced recurrence rates (22% vs 33%) and delayed time to recurrence compared to pMMR tumors 5

Critical Distinction: Stage III vs Stage II

Unlike stage II disease, MMR status does NOT change adjuvant chemotherapy recommendations in stage III colon cancer. 6 This is a common pitfall. The guidelines are explicit:

• Stage II dMMR: May have good prognosis and do not benefit from 5-FU monotherapy 1
• Stage III dMMR: Should still receive standard oxaliplatin-based chemotherapy (FOLFOX or CAPOX) regardless of MMR status 6, 7

The evidence shows that in stage III disease, 5-FU-based treatment reduced distant recurrence for dMMR tumors (11% vs 29%, P=0.011), suggesting benefit from adjuvant therapy even in dMMR cases. 5

Prognostic Nuances in Stage III

The prognostic impact of dMMR in stage III disease depends on tumor location and nodal burden. 7 A critical 2013 study analyzing 2,686 stage III patients treated with FOLFOX showed:

• Proximal dMMR tumors: Favorable outcome (HR 0.71, P=0.018) 7
• Distal dMMR tumors: Poor outcome (HR 1.71, P=0.056) 7
• N2 disease: Any survival benefit of dMMR is lost in heavily node-positive disease 7

This interaction between MMR status and tumor site was validated in an independent cohort. 7

Testing Methodology

Immunohistochemistry (IHC) for the four MMR proteins (MLH1, MSH2, MSH6, PMS2) is the highly recommended first-line test. 1, 4 IHC has 88% positive predictive value and 97% negative predictive value when used alone. 8

PCR-based MSI testing or validated NGS should be used when IHC is equivocal or unavailable. 1 Both methods are considered equivalent in clinical practice. 4

Expected Loss Patterns:

• MLH1 and PMS2 co-loss: 79% of dMMR tumors 3
• MSH2 and MSH6 co-loss: 10% of dMMR tumors 3
• Isolated MSH6 or PMS2 loss: 3-5% combined 3

Follow-up Testing Algorithm for MLH1/PMS2 Loss

When MLH1 and PMS2 loss is detected, immediately pursue BRAF V600E mutation testing and MLH1 promoter hypermethylation analysis to distinguish Lynch syndrome from sporadic cancer. 1, 2

• BRAF V600E mutation present: Strongly favors sporadic pathogenesis (found in ~75% of sporadic MLH1-silenced tumors, extremely rare in Lynch syndrome) 1, 2
• MLH1 promoter hypermethylation present: Supports somatic (non-inherited) event 2
• Both BRAF wild-type AND no hypermethylation: High suspicion for Lynch syndrome, proceed to germline testing 1, 2

Family and Surveillance Implications

If Lynch syndrome is confirmed, first-degree relatives have 50% chance of carrying the mutation and require genetic counseling. 2 MLH1 carriers face:

• 30-51% lifetime risk of endometrial cancer 2
• Requirement for colonoscopy every 1-2 years starting age 20-25 2
• 72% decrease in colorectal cancer mortality with appropriate surveillance 2

Common Pitfalls to Avoid

Do not withhold oxaliplatin-based chemotherapy in stage III disease based solely on dMMR status. 6 This is appropriate only for stage II disease considering 5-FU monotherapy. 1

Do not use immunotherapy (pembrolizumab/nivolumab) in the adjuvant setting for stage III disease. 6 These agents are FDA-approved only for metastatic MSI-H colorectal cancer, not for adjuvant treatment. 6

Do not delay testing. The turnaround time is 1-2 weeks, and testing should be performed early to allow for genetic counseling and family screening if Lynch syndrome is identified. 1