Colorectal Cancer Drugs Require Careful Patient Selection
Adapted from the NCI Cancer Bulletin, vol. 5/no. 12, June 10, 2008 (see the current issue).
Patients with advanced colorectal cancer who have mutant forms
of the gene KRAS in their tumors should not
receive chemotherapy plus cetuximab
(Erbitux®), because they are unlikely to benefit from the treatment and
should be spared the side effects and cost, researchers said at the
recent American Society of Clinical Oncology (ASCO) annual meeting in
Based on a growing body of evidence, including findings
presented at the meeting, several experts predicted that it will become
standard practice to test all colorectal tumors for mutations in the KRAS
gene before starting patients with advanced disease on therapies
involving cetuximab and a similar drug, panitumumab
"I believe it is now warranted to test all patients being
considered for these agents," said Dr. Gail Eckhardt of the
University of Colorado Denver, who was not involved in the research and
discussed the findings at ASCO. "Patients with KRAS
mutations should not receive cetuximab or panitumumab in [certain]
These drugs are designed to block the activity of the
epidermal growth factor receptor (EGFR) protein, which is often
overactive in colorectal cancer.
An estimated 30 to 40 percent of colorectal tumors carry KRAS
mutations, and commercial tests are available. Screening could proceed
based on the breast cancer model, where women undergo testing for
genetic characteristics of their tumors prior to treatment with trastuzumab
"KRAS is the first molecular marker for
targeted therapy in combination with standard chemotherapy as a
first-line treatment for metastatic colorectal cancer," said
Dr. Eric Van Cutsem of Gasthuisberg University Hospital in
Leuven, Belgium, at the meeting. "If we know in advance that a patient
has a KRAS mutation, then we know we don't have
to treat the patient [with these agents]."
He presented new
results from the CRYSTAL trial, which in
2007 showed that some patients with metastatic
benefited from cetuximab plus chemotherapy with respect to
progression-free survival. But not all patients benefited and given
growing interest in the KRAS gene, the
researchers went back and looked at tumor tissue from 587 of the nearly
1,200 patients in the trial.
The results were striking: Only patients with normal KRAS
genes benefited. Perhaps most important, findings from other studies
presented at the 2008 ASCO meeting,
including the OPUS
trials, support the findings from the CRYSTAL trial. Retrospective
analyses of KRAS gene status and treatment
outcomes have now been performed on 1,200 patients with advanced
colorectal cancer from separate randomized trials.
"We now have substantial evidence that mutations in KRAS
are a negative predictive marker for the use of cetuximab with
chemotherapy and for panitumumab as a single agent based on results
from a variety of trials," said Dr. Margaret Mooney of the
National Cancer Institute's Cancer
Program, who was not involved in the research.
Before the meeting, European regulators approved cetuximab
plus chemotherapy as a first-line treatment for colorectal cancer in
patients with normal KRAS. Panitumumab
is approved in Europe for treating advanced colorectal cancer, but also
only in patients with the normal KRAS gene.
Prospective studies are now needed to validate the marker.
Trials such as CRYSTAL were not designed to answer questions about
cetuximab and KRAS, and the researchers do not
have tumor tissue from all patients. These patients could provide
useful information in developing new therapies.
Dr. Eckhardt stressed the importance of communicating to
patients with KRAS mutations that current
chemotherapy regimens are effective. "Hopefully," she added, this is
"only the beginning of the era of individualized therapy for patients
with colon cancer."
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