Do I need to undergo a biopsy for Microsatellite Instability (MSI) and KRAS testing before starting new therapy for my rectal cancer?

MSI and KRAS Testing Must Be Completed Before Starting Therapy for Rectal Cancer

You need to obtain tissue for MSI and KRAS testing before initiating treatment for rectal cancer, as these biomarkers fundamentally alter your treatment approach and can significantly impact mortality and quality of life outcomes. 1

Critical Biomarker Testing Requirements

Mandatory Pre-Treatment Testing

Testing for MMR status (which determines MSI) and KRAS/NRAS mutations is recommended in all patients at the time of metastatic or locally advanced rectal cancer diagnosis 1. This is a Level I, Grade A recommendation from ESMO 2023 guidelines, meaning it is based on the highest quality evidence. 1

The 2024 ASCO guidelines specifically state that immunotherapy is strongly recommended for MSI-H/dMMR rectal cancers (evidence quality: low; strength of recommendation: strong), representing a paradigm shift in treatment approach. 1

Why This Testing Cannot Wait

MSI-H/dMMR tumors (occurring in approximately 3.5-6.5% of rectal cancers) respond dramatically differently to treatment than MSS tumors: 2

• MSI-H tumors show 100% clinical complete response rates with immunotherapy alone (dostarlimab monotherapy), eliminating the need for surgery, chemotherapy, or radiation in locally advanced disease 2
• Fluoropyrimidine-based chemotherapy has historically been less effective in dMMR tumors, making standard chemoradiation potentially inferior 1, 2
• KRAS wild-type status is mandatory before using anti-EGFR monoclonal antibodies (cetuximab or panitumumab), as KRAS mutations predict non-response 1

Practical Testing Approach

For tissue acquisition: 1

• Testing can be performed on either the primary tumor or metastatic sites 1
• Fixation with 10% neutral buffered formalin for 6-48 hours is recommended 1
• Tumor cell content should be >20% after macro-dissection 1
• Next-generation sequencing panels are preferred over individual gene testing, as they can detect rare actionable mutations (NTRK, RET fusions, HER2 amplifications) 1

Testing methods: 1

• MSI can be assessed by PCR-based microsatellite analysis or immunohistochemistry for MMR proteins (MLH1, MSH2, MSH6, PMS2) 1
• KRAS/NRAS testing should include exons 2,3, and 4 1
• BRAF mutation status should be assessed simultaneously for prognostic assessment 1

Treatment Algorithm Based on Biomarker Results

If MSI-H/dMMR Detected:

First-line treatment is immunotherapy (pembrolizumab, nivolumab, or dostarlimab), NOT standard chemoradiation 1, 3, 2. This represents a complete departure from conventional treatment and offers:

• Potential for organ preservation without surgery 2
• 100% clinical complete response rates in locally advanced disease 2
• Superior progression-free and overall survival compared to chemotherapy 3

If MSS/pMMR and KRAS Wild-Type:

Standard neoadjuvant therapy options include: 1

• Total neoadjuvant therapy (TNT) with chemotherapy and radiation
• Anti-EGFR therapy (cetuximab/panitumumab) is an option in metastatic disease 1

If MSS/pMMR and KRAS Mutant:

Anti-EGFR therapy is contraindicated 1. Standard chemotherapy regimens (FOLFOX, CAPOX) with or without bevacizumab are appropriate 1.

Common Pitfalls to Avoid

Do not start fluoropyrimidine-based therapy without DPD deficiency testing, as this can cause severe, potentially fatal toxicity 1. This is a Level III, Grade A recommendation. 1

Do not assume MSI status based on clinical features alone in rectal cancer. While MSI-H is more common in proximal colon cancers, it occurs in approximately 4-6.7% of rectal cancers and cannot be reliably predicted clinically. 4, 5

Be aware that KRAS mutation status may change after neoadjuvant therapy (reported in 2 of 25 patients in one study), which is relevant if considering anti-EGFR therapy in later lines. 6

For endoscopically treated patients with limited tissue, prioritize immunohistochemistry over PCR-based MSI testing, as IHC requires less tissue. 1

Timeline Considerations

Testing typically takes 1-2 weeks for standard methods, up to 2-3 weeks for comprehensive NGS panels. 1 This brief delay is justified given that:

• Incorrect initial treatment selection (especially missing MSI-H status) can result in unnecessary surgery, radiation toxicity, and inferior outcomes 2
• The 2024 ASCO guidelines recommend assessment of complete response at 8±4 weeks after completion of neoadjuvant therapy, so a 1-2 week testing delay does not significantly impact overall treatment timeline 1

Bottom line: Obtain biopsy tissue for MSI and KRAS testing before initiating any therapy. The results will fundamentally determine whether you pursue immunotherapy (for MSI-H), standard chemoradiation, or other targeted approaches, directly impacting survival and quality of life outcomes.