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Example clinical scenario

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

What do you need to do?

  • 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 this with an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (cetuximab or panitumumab).
  • Identification of a somatic KRAS pathogenic variant is a contraindication to anti-EGFR monoclonal antibodies, as patients with RAS-family gene pathogenic variants 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 KRAS mutation is not in itself an indication to perform any germline genomic testing. The decision to perform constitutional (germline) 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 MUTYH testing, but should prompt an assessment of polyp phenotype and family history.


For clinicians


Tagged: Colorectal cancer

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  • Last reviewed: 03/05/2022
  • Next review due: 03/05/2023
  • Authors: Dr Alison Berner
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh