Results: Patient with colorectal cancer and a somatic (tumour) KRAS variant

A 42-year-old woman is diagnosed with metastatic colorectal cancer. Somatic (tumour) testing via a multi-target massively parallel sequencing (sometimes called next-generation sequencing) panel reveals a pathogenic KRAS variant that is known to be oncogenic.

RAS mutations

• Activating mutations in members of the RAS family have been found in 20%–25% of human cancers.
• These mutations set proteins in a permanently activated state (GTP-bound conformation), impairing the ATPase activity.
• Deregulated RAS signalling results in increased proliferation, angiogenesis and motility, as well as decreased apoptosis.

RAS mutations in colorectal cancer

• KRAS is mutated in approximately 40% of colorectal cancer cases, mostly in exon 2 codons 12 (70%–80%) and 13 (15%–20%). The remaining mutations are mainly located in exon 3 codons 59 to 61 and in exon 4, which includes codons 117 and 146.
• Mutations in NRAS are present in approximately 3%–5% of colorectal cancer samples, particularly in exon 3 codon 61 (60%) and in exon 2 codons 12 and 13.
• The prognostic value of RAS mutations in colorectal cancer is not clear, but they are known to have a predictive role in treatment selection.

• Metastatic colorectal cancer is usually treated first line with doublet chemotherapy of 5-fluorouracil and either oxaliplatin or irinotecan.
• In patients whose cancers are wild-type for KRAS and NRAS, there is additional benefit from combining these treatments with an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (cetuximab or panitumumab).
• Identification of a somatic (tumour) pathogenic KRAS variant is a contraindication to anti-EGFR monoclonal antibodies, as patients with pathogenic variants in the RAS family have inferior outcomes with this therapy.
  • Note: The above management advice is only relevant for metastatic colorectal cancer, as anti-EGFR therapy is not indicated in the setting of localised colorectal cancer.
• The finding of a somatic (tumour) KRAS mutation is not in itself an indication to perform any constitutional (germline) genomic testing. The decision to perform constitutional genomic testing in a patient with colorectal cancer should be based on mismatch repair deficiency and microsatellite instability status and/or the patient’s family history.
  • However, a particular hotspot variant in KRAS (c.34G>T, (p.Gly12Cys), G12C), rare in sporadic colorectal cancer, has been reported to occur with increased frequency in cancers occurring within the context of MUTYH-associated polyposis (MAP) – being found in 65% of MAP-related cancers. This, in itself, is not an indication for constitutional (germline) MUTYH testing, but should prompt an assessment of polyp phenotype and family history.

For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.

For clinicians

• European Society for Medical Oncology (ESMO): Clinical practical guideline: metastatic colorectal cancer
• NHS England: National Genomic Test Directory
• OncologyPro and ESMO: RAS in colorectal cancer: ESMO biomarker factsheet

References:

• Lièvre A, Bachet JB, Le Corre D and others. ‘KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer‘. Cancer Research 2006: volume 66, issue 8, pages 3,992–3,995. DOI: 10.1158/0008-5472.CAN-06-0191
• Therkildsen C, Bergmann TK, Henrichsen-Schnack T and others. ‘The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis‘. Acta Oncologica 2014: volume 53, issue 7, pages 852–864. DOI: 10.3109/0284186X.2014.895036

For patients

• Macmillan: Targeted therapies and immunotherapies for bowel cancer