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Colorectal Cancer - Predictive Testing for Anti-EGFR Therapy

0040248

KRAS Mutation Detection 0040248

Method

Polymerase Chain Reaction/Pyrosequencing

May assist in predicting response to anti-EGFR therapy in CRC

2003123

NRAS Mutation Detection by Pyrosequencing 2003123

Method

Polymerase Chain Reaction/Pyrosequencing

May assist in predicting response to anti-EGFR therapy in CRC

2002498

BRAF Codon 600 Mutation Detection by Pyrosequencing (Change effective as of 05/20/24: Refer to 3017203) 2002498

Method

Polymerase Chain Reaction/Pyrosequencing

May assist in predicting response to anti-EGFR therapy in CRC

Colorectal cancer (CRC) is the third most common cancer diagnosed in men and women in the United States (excluding skin cancers), and is the second most common cause of cancer deaths in both men and women. Two anti-EGFR monoclonal antibodies (cetuximab and panitumumab) are available for treatment of advanced CRC. KRAS, BRAF, and possibly NRAS mutations are associated with resistance to anti-EGFR therapy.

Genetics and Test Information

Gene	KRAS	NRAS	BRAF
Gene Function	GTPase-encoding gene in the RAS/RAF/MAPK pathway	GTPase-encoding gene in the RAS/RAF/MAPK pathway	Kinase-encoding gene in the RAS/RAF/MAPK pathway
Mutations	Majority of oncogenic mutations: codons 12 and 13 (>90%) Most of the remaining activating mutations: codons 61 and 146^a	Majority of activating mutations: codon 61^a Mutually exclusive with KRAS mutations in individuals with CRC Associated with relative resistance to anti-EGFR therapy	Majority of activating mutations: codon 600 Mutually exclusive with KRAS mutations in individuals with CRC
Sensitivity/ Specificity	Clinical sensitivity: activating KRAS mutations found in ~40% of CRCs Analytic sensitivity/specificity: 100%	Clinical sensitivity: oncogenic NRAS mutation found in ~3% of CRCs Analytic sensitivity/specificity: 100%	Clinical sensitivity: activating BRAF mutation found in ~10% of CRCs Analytic sensitivity/specificity: 100%
Results	Positive Oncogenic KRAS mutation detected Lack of response to therapy with antibodies targeted to EGFR is predicted Negative No oncogenic KRAS mutation detected Follow-up BRAF testing is advised prior to initiation of anti-EGFR therapy	Positive Oncogenic NRAS mutation detected Predictive of relative resistance to anti-EGFR therapy Negative No oncogenic NRAS mutation detected	Positive Oncogenic BRAF mutation detected Available data suggest resistance to anti-EGFR therapy Appears to be associated with a worse prognosis Negative No oncogenic BRAF mutation detected
Limitations	Limit of detection Pyrosequencing: 10% mutant alleles NGS: 5% mutant alleles Pyrosequencing: oncogenic mutations outside of codons 12, 13, 61 will not be detected A substantial portion of individuals with wild-type KRAS still fail to respond to anti-EGFR agents, implicating downstream mutations	Limit of detection Pyrosequencing: 10% mutant alleles NGS: 5% mutant alleles Pyrosequencing: oncogenic mutations outside of codons 12, 13, 61 will not be detected Presence or absence of mutations does not guarantee a response or lack of response to anti-EGFR therapy	Limit of detection Pyrosequencing: 10% mutant alleles NGS: 5% mutant alleles Pyrosequencing: oncogenic mutations outside of codon 600 will not be detected
^aGuidelines recommended extended RAS testing, which includes codons 12, 13, 59, 61, 117, and 146. (National Comprehensive Cancer Network, 2021).

References

NCCN - colon cancer v2.2021

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colon cancer. Version 2.2021. Updated Jan 2021; accessed Feb 2021.

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Colorectal Cancer - Predictive Testing for Anti-EGFR Therapy

Genetics and Test Information

References

NCCN - colon cancer v2.2021