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Markers May Help Select Patients for Adjuvant Therapy

  • James L. Abbruzzese, MD, FACP
Mar 1, 2004
Volume: 
13
Issue: 
3
  • Colorectal Cancer

PALM BEACH, Florida-Integrating
molecular biology with patient
care will require testing methods
that are feasible in routine care, reproducible,
and manufactured with good
quality assurance, according to Al B.
Benson III, MD.

Early work in colorectal cancer suggests
that such tests can be developed,
that they will improve the efficiency of
clinical trials, and that they will help
clinicians select regimens most likely
to benefit the individual patient, Dr.
Benson said at the First International
Colorectal Cancer Congress. He is director
of clinical investigations, Northwestern
University Robert H. Lurie
Comprehensive Cancer Center,
Chicago.

"At present, eligibility criteria for
clinical trials represent a generic population
that includes a high percentage
of patients who will receive no
benefit from the study treatment," Dr.
Benson said. "Targeting markers, such
as those for epidermal growth factor
receptor (EGFR) or vascular endothelial growth factor (VEGF), may help
avoid giving patients a test drug from
which they can expect only toxicity."

For a marker to become clinically
useful, it must have significant and
independent value, be validated by
clinical testing, be feasible for routine
use, be reproducible, and be widely
available with rigorous quality controls,
Dr. Benson noted. "Furthermore,
we should demonstrate that a
given result will offer benefit to the
individual patient," he said.

The list of candidates for clinically
useful markers in colorectal cancer is
long (see Tables 1 and 2). Some of
these will be markers for unfavorable
prognosis, suggesting that the patient
is a candidate for particularly aggressive
treatment. Others are predictors
of response to a specific drug such as
fluorouracil (5-FU). "These include
loss of the 18q allele in microsatellite
stable cancer, mutations of the gene
for type II receptor for TGF-β1 (TGF-
β1-RII) in cancers with microsatellite
instability (MSI), and high expres
sion of thymidylate synthase," Dr.
Benson said.

One challenge for clinical investigators
is how to help patients understand
why taking tissue samples for
marker analysis is important. "Many
trials require additional patient approval
for tissue acquisition, and recent
privacy laws in the United States
with their accompanying regulatory
processes may make it much more
difficult to obtain tissue and to establish
tissue banks," he said.

Tissue acquisition increases the cost
of conducting clinical trials, and new
funding sources will be required to
establish tissue banks and develop usable
tests for tumor markers. He said
that there is a tension between industry's
push for rapid drug development
and researchers' need for biologically
driven trials.

Multidisciplinary
collaboration
required

"This will require multidisciplinary
collaboration. In the past,
most trials did not include funding
for the pathologists and surgeons, who
will be critical for obtaining and evaluating
tissue for our biological analyses,"
Dr. Benson said.

Small uncontrolled or retrospective
correlational trials may not provide
definitive answers about the predictive
power of a molecular marker,
he said. "We must resist the temptation
to use the growing number of
commercial laboratories that market
tests for molecular and other markers,"
Dr. Benson stressed.

Trial Data

Data from ECOG patients in intergroup
trials of stage III colon cancer
patients showed that retention of the
18q allele, TGF-β1-RII, and MSI with
a TGF-β1-RII mutation were associated
with favorable outcome after 5-
FU. Five-year survival was 74% in patients
who had the 18q allele vs 50% in
those without the allele, and 74% in
those who had MSI but also had the
TGF-β mutation vs 46% in those with
MSI but no such mutation.

Dr. Benson said that clinical trial
E5202, which is now on the drawing
board for patients with stage II colon
cancer, would be the first to prospectively
evaluate presence of the 18q allele
and MSI status in tissue samples
obtained immediately after surgery.
High-risk and low-risk profiles will be
determined according to whether the
patient has microsatellite stability but
has lost the 18q allele (high risk) or has
MSI without loss of the 18q allele
(low risk).

Low-risk patients will be assigned
to observation, and Dr. Benson estimated
that survival of low-risk patients
should approach 90%. Highrisk
patients will be randomized to
5-FU/ leucovorin or to an experimental
arm that will include a targeted
therapy yet to be determined.

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