What is RAS/RAF wild‑type colon cancer?

RAS/RAF Wild-Type Colon Cancer: Definition and Clinical Significance

RAS/RAF wild-type colon cancer refers to colorectal tumors that lack activating mutations in KRAS (exons 2,3, and 4), NRAS (exons 2,3, and 4), and BRAF genes—representing approximately 40-50% of metastatic colorectal cancers and identifying patients who are eligible for anti-EGFR monoclonal antibody therapy with cetuximab or panitumumab. 1

Molecular Definition and Testing Requirements

Comprehensive RAS/RAF testing must include:

• KRAS mutations in codons 12,13 (exon 2), codons 59,61 (exon 3), and codons 117,146 (exon 4) 1
• NRAS mutations in exons 2,3, and 4 (same codon positions as KRAS) 1
• BRAF V600E mutation status, which occurs in approximately 5-9% of colorectal cancers and is mutually exclusive with RAS mutations 1

The NCCN mandates that RAS mutation status be determined at diagnosis of stage IV disease, and testing must be performed in CLIA-certified laboratories on tumor tissue from either the primary tumor or metastasis. 1

Clinical Significance for Treatment Selection

Anti-EGFR therapy eligibility:

• Only patients with all RAS genes wild-type (no mutations in KRAS exons 2,3,4 or NRAS exons 2,3,4) should receive cetuximab or panitumumab 1
• The FDA specifically contraindicates panitumumab in patients with KRAS or NRAS mutation-positive disease in combination with oxaliplatin-based chemotherapy 1
• Patients with any known RAS mutation should never be treated with cetuximab or panitumumab, as these agents provide no benefit and may cause harm 1

Evidence of harm in RAS-mutant patients:

The FIRE-3 trial demonstrated that patients with RAS-mutant tumors receiving FOLFIRI plus cetuximab had significantly worse progression-free survival compared to those receiving FOLFIRI plus bevacizumab (6.1 vs 12.2 months; P=0.004), indicating cetuximab has a detrimental effect in RAS-mutant disease. 1

Prevalence and Distribution

• Approximately 40-50% of metastatic colorectal cancers are RAS wild-type (no KRAS or NRAS mutations) 1
• Among patients initially classified as KRAS exon 2 wild-type, 17% have mutations in KRAS exons 3-4 or NRAS exons 2-4, emphasizing the necessity of extended RAS testing 1
• BRAF mutations occur in 5-9% of colorectal cancers and are essentially limited to tumors without RAS mutations 1

BRAF Status in RAS Wild-Type Tumors

Even among RAS wild-type tumors, BRAF V600E mutation status affects prognosis and treatment response:

• BRAF V600E mutation confers poor prognosis regardless of treatment, with median overall survival of only 9.2 months 2
• BRAF mutations are mutually exclusive with RAS mutations for practical purposes 1
• The activated BRAF protein is constitutively active downstream of EGFR, potentially bypassing EGFR inhibition 1
• Evidence regarding BRAF as a predictive marker for anti-EGFR therapy benefit remains mixed, with some studies suggesting potential benefit in first-line settings and others showing no effect or harm 1

Testing Algorithm and Timing

The NCCN strongly recommends:

1. Perform comprehensive genotyping (KRAS/NRAS exons 2,3,4 and BRAF) at diagnosis of stage IV disease, not in a time-sensitive manner before starting treatment 1, 2
2. Testing can be performed on archived specimens from either primary tumor or metastasis, as KRAS mutations are early events with tight correlation between primary and metastatic sites 1
3. Fresh biopsies should not be obtained solely for genotyping unless archived specimens are unavailable 1

Common Pitfalls to Avoid

• Do not assume KRAS exon 2 wild-type alone is sufficient—17% of these patients harbor mutations in other RAS exons that predict non-response to anti-EGFR therapy 1
• Do not use EGFR expression by immunohistochemistry to guide cetuximab or panitumumab therapy, as EGFR status does not correlate with treatment efficacy 1
• Do not delay comprehensive molecular testing until progression on first-line therapy, as this creates time pressure when patients are clinically deteriorating 2
• Remember that even RAS wild-type status does not guarantee response—only 40-60% of RAS wild-type patients respond to anti-EGFR therapy, indicating additional resistance mechanisms exist 2