KRAS mutation status has recently been shown to relate to outcome in metastatic colorectal (mCRC) patients treated with cetuximab as a single agent or in combination with irinotecan.  Efficacy analyses have been repeated to evaluate the influence of KRAS mutation status in first-line pts treated with FOLFIRI with or without ImClone's Erbitux (cetuximab) under controlled study conditions.  A normal KRAS gene sends a signal telling cells to divide.
The mutation is associated with uncontrolled division of tumour
cells, ie no apoptosis or programmed cell death occurs.

For most people with a normal version of the gene, known as
KRAS, adding Erbitux to chemotherapy slashed the risk
of the disease progressing by a third, according to a study presented at the annual meeting of the American Society of
Clinical Oncology
in Chicago. 

In the Erbitux study, researchers examined tissue samples
from 587 patients getting initial treatment for advanced
colorectal cancer.  About 59 percent of those with normal KRAS
responded to Erbitux plus chemotherapy, compared with 43 percent
of those who took chemotherapy alone.  Adding Erbitux didn't harm
patients carrying the mutation, though it offered no benefit.

This means that KRAS testing may end up being routinely conducted in all
colorectal cancer patients immediately after diagnosis in order to determine which targeted therapy is most suitable for patients.  Focusing EGFR treatment on the normal KRAS patients (approx. 60%) may result in a much bigger benefit, which
is clinically very important.  Clearly, there is no point in treating the 40% of the patients who do have the KRAS mutation with a drug that is unlikely to work.

Meanwhile, another EGFR inhibitor, Amgen's Vectibix (panitumumab), also wasn't effective for patients with a
KRAS mutation in a similar study presented at a cancer meeting
in January.  The drug slowed the spread of tumors for 12.3 weeks
in patients with a normal gene, compared with 7.4 weeks in those
with the mutation.

Almost 150,000 people in the U.S. will be diagnosed with
colorectal cancer in 2008, according to the American Cancer
Society.  The ability to choose a drug based on a genetic target
can help doctors treat the disease more effectively and may change the way Erbitux
competes against Genentech's Avastin,
which had sales of $3.4 billion last year.


Photo: Boulard, Y. Cognet, J.A. Fazakerley, G.V., J. Mol. Biol.
268 (1997) 331-347.

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