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KRAS testing in colorectal cancer:
an overview
What is KRAS?
KRAS is a gene that encodes one of the proteins in the
epidermal growth factor receptor (EGFR) signaling
pathway
This signaling pathway is important in the development
and progression of cancer
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KRAS and the EGFR pathway

The EGFR signaling pathway is activated
in response to ligand binding to the cellsurface receptors: these ligands include
TGFα and EGF

The signaling cascade that is activated is
involved in regulating genes that control
cell cycle progression

Cell cycle progression gives rise to
tumor survival, growth and proliferation
as well as metastasis and angiogenesis

In the early part of the signaling cascade,
the protein KRAS regulates downstream
proteins involved in these effects
The KRAS protein plays a central role in tumor development,
regulating downstream proteins that are involved in
proliferation, survival, metastasis and angiogenesis
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The EGFR pathway and the importance of
KRAS status

The KRAS gene may be normal (wildtype) or mutated

Wild-type KRAS protein is active for a
short period when the EGFR is
stimulated


When KRAS is mutated the protein is
permanently turned on, even without
being triggered by EGFR-mediated
signaling


The effects of the protein are closely
controlled
The effects of KRAS that lead to
tumor growth and spread continue
unregulated
The KRAS status of a tumor may be
indicative of prognosis and predictive
of response to certain drugs
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Use of anti-EGFR antibodies to disrupt the
signaling pathway



Monoclonal antibodies against EGFR
block signaling by the receptor and inhibit
downstream events, including effects
mediated by KRAS
When KRAS is mutated and permanently
switched on, blocking EGFR will probably
not affect downstream events
 The tumor may continue to grow,
proliferate and spread
Therefore, blocking EGFR with a
monoclonal antibody will be more effective
in KRAS wild-type tumors

In metastatic CRC, up to 65% of
patients have KRAS wild-type tumors
 There are six KRAS mutations relevant
to CRC at codons 12/13: G12A, G12V,
G12D, G12C, G12S, G13D and G12R
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Biomarkers and KRAS testing

There has recently been increased interest in the role of biomarkers
in oncology, including the role of KRAS status as a biomarker in
CRC and other EGFR-associated cancers

The test for KRAS status uses standard methodology and is
performed on a sample of tumor tissue (fresh frozen or paraffinembedded) sent to a laboratory for analysis

Determining the KRAS status of a tumor helps the treating physician
to choose the most effective therapeutic approach for each
individual patient
Patients diagnosed with metastatic CRC
should be tested for KRAS status to allow
the optimum treatment strategy to be implemented
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The KRAS test

A tumor sample is taken and sent
to the laboratory – the test can use
fresh, frozen or paraffin-embedded
tissue

A pathologist confirms that the
tissue is cancerous, and a sample
of DNA is prepared for the KRAS
test

The polymerase chain reaction
(PCR) is used to amplify the DNA
and test for KRAS mutation status*
*Direct DNA sequencing can also be used
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There are commercially available PCR
assays for KRAS
 KRAS tests are based on well-established quantitative
PCR (qPCR) technology
 The probes used in this technique are specific for
KRAS mutations known to confer constitutive
activation
 The assays are highly specific
 The assays are robust and reliable
 Direct DNA sequencing can be used as an alternative
to PCR
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Benefits of KRAS testing

Knowing the KRAS status of the patient’s tumor allows treatment to
be tailored to the individual

Patients with metastatic CRC with KRAS wild-type tumors gain more
benefit when treated with agents targeted to the EGFR than patients
with KRAS mutant tumors1,2

Anti-EGFR therapies may have activity independent of KRAS status
 An lgG1 anti-EGFR monoclonal antibody has been shown to
stimulate antibody-dependent cellular cytotoxicity3
 Consequently this agent may offer some benefit in patients with
KRAS mutant tumors
Testing for KRAS status allows
a tailored treatment strategy to be implemented
1) Bokemeyer et al. ASCO Annual Meeting 2008: abstract 4000. 2) Van Cutsem et al. ASCO Annual Meeting 2008: abstract 2.
3) Kimura et al. Cancer Sci 2007;98:1275-80
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