Results: Patient with colorectal cancer – somatic (tumour) KRAS variant identified

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.

• 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

• ESMO: Clinical practice guidelines for metastatic colon cancer 
• NHS England: National Genomic Test Directory and eligibility criteria

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 852–64. DOI: 10.3109/0284186X.2014.895036

For patients

• Macmillan: Targeted therapies and immunotherapies for bowel cancer