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KRAS Mutation Analysis

KRAS Mutation Analysis

Test Summary

KRAS Mutation Analysis

  

Clinical Use

  • Detect mutations in the KRAS gene

  • Determine eligibility for therapies targeting epidermal growth factor receptor (EGFR)

Clinical Background

Mutations in the RAS gene family (HRAS, KRAS, and NRAS) have been observed in a variety of cancers (Table 1). They are activating mutations that result in continual signal transduction, stimulating downstream signaling pathways involved in cell growth, proliferation, invasion, and metastasis.

Table 1. RAS Mutation Frequency1
Cancer Frequency, %
Adenocarcinoma

Lung

Colon

Pancreas

 

30

43

80

Thyroid cancer

Follicular

Undifferentiated

 

53

60

Myeloid disorders

MDS

AML

 

27

27

MDS, myelodysplastic syndromes; AML, acute myeloid leukemia.

The KRAS gene encodes the KRAS protein that regulates 2 such signaling pathways: PI3K/PTEN/AKT and RAF/MEK/ERK. These pathways are targets of anti-cancer drugs that are currently in development. Drugs targeting EGFR, which controls these pathways upstream from KRAS, are already available. When bound to its ligand, EGFR stimulates tyrosine kinase activity, leading to activation of KRAS and the signaling pathways.

Current therapies targeting EGFR are used to treat colorectal cancer (CRC) and non-small-cell lung cancer (NSCLC) and employ either 1) monoclonal antibodies (eg, cetuximab and panitumumab) that prevent ligand binding and EGFR activation or 2) tyrosine kinase inhibitors (eg, erlotinib) that prevent activation of the signaling pathways. However, if the signaling pathways are activated independent of EGFR, as happens when the KRAS gene is mutated, these drugs are rendered ineffective.

KRAS mutations frequently found in neoplasms include those at exon 2 (codons 12 and 13) and exon 3 (codon 61). Mutations in KRAS codons 12 and 13 have been associated with lack of response to EGFR-targeted therapies in both CRC and NSCLC patients (Table 2).2-4 The National Comprehensive Cancer Network (NCCN) recommends KRAS mutation testing before initiating EGFR-targeted therapies for CRC or NSCLC.5 NCCN further recommends alternative therapies be considered for patients with KRAS mutations.5

Quest Diagnostics can perform KRAS mutation testing on formalin-fixed, paraffin-embedded (FFPE) tumor tissue as well as bone marrow and whole blood (plasma). However, clinical studies that have assessed the impact of KRAS mutations on treatment response were based on testing tumor tissue only; therefore, the preferred sample type is FFPE tumor tissue.

Table 2. Impact of KRAS Mutations in Patients Treated with an EGFR Antagonist2-4
Therapy Treatment Response Rate Median Patient Survival

KRAS Mutation Positive

KRAS Mutation Negative

 

KRAS Mutation Positive

KRAS Mutation

Negative

Metastatic Colorectal Cancer

Cetuximab

Panitumumab

0/36 = 0%a

0/84 = 0%b

34/78 = 44%a

21/124 = 17%b

 

9 weeks (PFS)

7 weeks (PFS)

32 weeks (PFS)

12 weeks (PFS)

Advanced Non-Small-Cell Lung Cancer

Erlotinib

2/25 = 8%a

27/104 = 26%a

4.4 months (OS)

12.1 months (OS)

PFS, progression-free survival; OS, overall survival.
a Response rate includes partial and complete responders.
b Response rate includes only partial responders.

Individuals Suitable for Testing

  • Patients with CRC or NSCLC who are being considered for treatment with an EGFR antagonist

Method

  • Polymerase chain reaction (PCR) and gene sequencing

   PCR amplification of exon 2 (codons 12 and 13) and exon 3 (codon 61) of the KRAS gene

   Gene sequencing of purified products

   Computer analysis of sequencing data to determine mutation presence or absence

  • Analytical sensitivity: 20% mutant allele in the background of wild-type allele

  • Result reported: positive (homozygous or heterozygous for the mutation detected) or negative

Interpretive Information

In patients with advanced CRC or NSCLC, absence of a KRAS mutation predicts a greater likelihood of response to EGFR-targeted therapies and improved survival with such treatment. The presence of a KRAS mutation in codon 12 or 13 is associated with a high likelihood of resistance to therapies targeting EGFR (93%).6

This assay detects mutations at codons 12, 13, and 61 of the KRAS gene; polymorphisms or mutations at other locations that may be associated with drug efficacy or patient outcome will not be detected. Results should be interpreted in conjunction with other laboratory and clinical findings.

References

  1. Bos JL. RAS oncogenes in human cancer: a review. Cancer Res.1989;49:4682-4689.

  2. Lièvre A, Bachet J-B, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374-379.

  3. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626-1634.

  4. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005;25:5900-5909.

  5. NCCN Clinical Practice Guidelines in Oncology™. Colon cancer. v 2.2009. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed November 19, 2012.

  6. Linardou H, Dahabreh IJ, Kanaloupiti D, et al. Assessment of somatic k-ras mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol. 2008;9:962-972.
     

This test was developed and performance characteristics have been determined by Quest Diagnostics Nichols Institute. Performance characteristics refer to the analytical performance of the test.

Content reviewed 03/2014
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