METASTATIC COLORECTAL CANCER – KRAS, NRAS AND BRAF TESTING

ANALYSIS OF CODONS 12, 13, 59, 61, 117 AND 146 OF THE KRAS GENE, CODONS 12, 13, 59 AND 61 OF THE NRAS GENE AND CODON 600 OF THE BRAF GENE

Activating somatic KRAS gene variants are found in 30-40% of colorectal tumours. These variants typically occur in codons 12, 13 (exon 2), 59, 61 (exon 3) 117 or 146 (exon 4) of the KRAS gene and result in constitutive activation of KRAS. Patients with tumours that have variants in the KRAS gene are unlikely to benefit from treatment with anti-EGFR monoclonal antibodies (e.g. cetuximab) (De Roock et al 2011 Lancet Oncol 12:594-603).

Somatic disease-causing NRAS variants are found in 2.6-5% of colorectal cancer patients. Similar to KRAS, variants in NRAS occur at codons 12, 13, 59 and 61 with variants in codon 61 being the most common. Patients with NRAS disease-causing variants have a significantly lower response rate and shorter overall survival, when they are treated with anti-EGFR monoclonal antibodies plus chemotherapy, compared to patients with no NRAS variant (De Roock et al 2010 Lancet Oncol 11:753-762; Vaughn et al 2011 Genes, Chromosomes&Cancer50:307-312).

Approximately 15% of colorectal cancers harbour BRAF codon 600 variants.  The most frequently reported BRAF variant in tumours (>95%) is the p.Val600Glu variant within the kinase activation domain.  Patients whose tumours have this variant are not likely to experience significant clinical benefit with anti-EGFR monoclonal antibodies treatment (Di Nicolantonio et al 2008 J Clin Oncol 26:5705-5712).

Recommended clinical referral criteria for RAS testing:

Patients who meet NICE guidelines (TA176): first line treatment of patients with metastatic colorectal cancer with metastases confined to the liver.

Reporting time: 5-10 working days from sample receipt.

Laboratory contact: Christopher Bowles 01392 408249 (Christopher.Bowles@nhs.net)

The laboratory participates in the United Kingdom National External Quality Assessment Service (UK NEQAS) scheme for the molecular genetic analysis of colorectal cancer.