Colorectal Cancer - Predictive Testing for Anti-EGFR Therapy

  • Aids in therapeutic decisions for solid tumor cancers.
  • May assist in predicting response to anti-EGFR therapy in CRC.
  • Simultaneously evaluates mutations in 44 genes, including BRAF, KRAS, and NRAS; for more detailed information about this test, refer to the Solid Tumor Mutation Panel by Next Generation Sequencing Test Fact Sheet.

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

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

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 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 )

References