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 146a
|
Majority of activating mutations: codon 61a
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 ).
|
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May assist in predicting response to anti-EGFR therapy in CRC