Researchers at Fred Hutchinson Cancer
Research Center have found that people with the most-aggressive form of
Barrett's esophagus, a precancerous condition that can lead to esophageal
cancer, may benefit the most from preventive therapy with aspirin,
ibuprofen and other nonsteroidal anti-inflammatory drugs, or NSAIDs. The
researchers also identified a cluster of four known cancer biomarkers, or
genetic abnormalities, in people with Barrett's that significantly
increases their risk of developing esophageal cancer.
These findings, by lead authors Patricia C. Galipeau and Xiaohong Li,
senior author Brian J. Reid, M.D., Ph.D., and colleagues in the Hutchinson
Center-based Seattle Barrett's Esophagus Program, will be published in the
Feb. 27 issue of PLoS Medicine, a freely available online journal.
Researchers from Virginia Mason Medical Center, Harvard Medical School and
The Wistar Institute collaborated on the study, which was funded by the
National Institutes of Health and the Hutchinson Center.
The researchers found that those with three or more of the cancer
biomarkers upon enrollment in the study who also used aspirin or other
NSAIDs had a 30 percent risk of esophageal cancer after 10 years, while
those with the same biomarkers who did not use NSAIDs had a 79 percent risk
of developing cancer within a decade of joining the study.
"This is the first prospective, longitudinal study in patients with
Barrett's esophagus -- or any other pre-malignant condition, for that
matter -- to link somatic genetic biomarkers for cancer-risk prediction
with candidate interventions such as NSAIDs to prevent cancer," said
Galipeau, a research technician in Reid's laboratory, which is based in the
Hutchinson Center's Human Biology Division.
The researchers also found that Barrett's patients whose esophageal
tissue had no such genetic abnormalities, or biomarkers, upon joining the
study had a 12 percent risk of developing esophageal cancer after 10 years,
whereas those with three or more of the abnormalities at baseline had a
nearly 80 percent risk of developing such cancer within a decade.
"Several studies have suggested that individual genetic abnormalities
may identify Barrett's patients who are at increased risk of progression
toward esophageal cancer, but this is the first study to evaluate the
combined contribution of genetic abnormalities for esophageal cancer-risk
prediction," said Reid, director of the Seattle Barrett's Esophagus
Program.
The study followed 243 people with Barrett's esophagus for 10 years
(189 male, 54 female, mean age 62 upon joining the study). The participants
were interviewed about their medical history, diet and medication use and
were closely monitored for signs of disease progression through regular
endoscopies and tissue biopsies.
Their Barrett's-related esophageal tissue was evaluated at the initial
study visit for a variety of known cancer biomarkers, but the genetic
abnormalities that were most strongly predictive of progression toward
cancer were:
Loss of heterozygosity (LOH) at 9p and 17p -- loss on the short arms
of chromosomes 17 and 9. Such chromosomal abnormalities inactivate tumor-
suppressor genes that are critical for controlling cell growth.
DNA content abnormalities (aneuploidy and tetraploidy) -- the
accumulation of cells with grossly abnormal amounts of DNA, which indicates
substantial genetic damage and heralds advanced progression toward cancer.
Ultimately, the researchers hope, these biomarkers one day could be
used in a clinical setting to identify which Barrett's patients are most
likely to develop esophageal cancer and therefore benefit from aggressive
cancer surveillance via endoscopy and chemoprevention with aspirin and
other NSAIDs. Galipeau and colleagues are in the process of developing such
a standardized, biomarker-based screening test. The test would evaluate DNA
from esophageal- tissue biopsies, but significantly fewer tissue samples
would need to be collected as compared to current endoscopic-surveillance
methods.
"Once such a test is available, it could be a major factor in guiding
the development of clinical trials to identify high-risk patients and
definitively determine the value of NSAIDs in preventing the progression of
Barrett's esophagus toward cancer," Reid said.
It is hypothesized that aspirin and other NSAIDs may fight cancer by
reducing chronic inflammation, which is a driving force behind the
development of many cancers and other diseases. Specifically, NSAIDs have
been shown to inhibit the production of the cyclooxygenase-2 (COX-2)
enzyme. Disruption of this pathway slows the growth of abnormal cells and
facilitates the normal process of programmed cell death, or apoptosis, both
of which can thwart cancer development. NSAIDs are also believed to
decrease proliferation of cells and decrease the growth of blood vessels
that supply blood to tumors, Reid said.
The annual incidence of esophageal cancer among Barrett's esophagus
patients is about 1 percent -- most patients never get the cancer. However,
the outlook is grim if the cancer is not diagnosed early, with an overall
survival rate of only 13.7 percent. For this reason, Barrett's patients
must undergo frequent endoscopic surveillance.
"Many Barrett's patients are subjected to overdiagnosis of risk and
overtreatment," Reid said. "These findings ultimately may help us identify
high-risk patients who truly require frequent surveillance and low-risk
patients who need no or less-frequent surveillance. For example, low-risk
patients with no biomarker abnormalities at baseline had a zero percent
cumulative risk of developing esophageal cancer for nearly eight years," he
said. "These findings also may help us determine which Barrett's patients
may benefit most from a very cost-effective, noninvasive therapy in the
form of aspirin or NSAIDs."
Currently, the recommended endoscopic screening frequency for Barrett's
esophagus ranges from once every three to six months to once every two to
three years, depending on the amount of affected tissue and the degree of
dysplasia, or cellular abnormality, detected upon examining a tissue sample
under a microscope. While cellular dysplasia is the most common method for
determining the severity, or grade, of Barrett's, several recent studies
have found that the technique is not truly predictive of cancer risk.
Longitudinal studies of high-risk Barrett's patients (as determined by
degree of cellular dysplasia) have found cancer-incidence rates ranging
from 8 percent to 59 percent. "Clearly we need a new, more consistent and
reliable way to predict risk that doesn't rely on the subjective
interpretation of a pathologist," said Reid, also a professor of
gastroenterology and medicine and an adjunct professor of genome sciences
at the University of Washington School of Medicine.
BACKGROUND INFORMATION
About Barrett's esophagus
An estimated 20 million Americans experience chronic heartburn; about 2
million of these people have Barrett's esophagus, a premalignant condition
of the tube that carries food from the mouth to the stomach.
While the condition is most prevalent in middle-aged white men, the
incidence of esophageal adenocarcinoma, the cancer associated with
Barrett's esophagus, is rising in women and African Americans.
A physician may suspect the condition is present if part of the inner
lining, or epithelium, of the esophagus is red rather than the usual light
pink. This is determined through a procedure called endoscopy, in which a
tube-like instrument is used to view the esophageal lining. A definite
diagnosis cannot be made unless small samples of the red lining are
biopsied, or removed and examined under a microscope, and found to have
cellular changes typical of this disorder.
Barrett's-related esophageal cancer strikes about 10,000 Americans a
year, and for unknown reasons, the incidence is rising faster than that of
any other cancer in the United States. Barrett's-related cancers increased
fourfold between 1973 and 2002, with a nearly fivefold increase in white
males. More than 90 percent of patients with invasive esophageal
adenocarcinoma die within five years of diagnosis.
About the Seattle Barrett's Esophagus Program
The Seattle Barrett's Esophagus Program is a multidisciplinary research
effort based at Fred Hutchinson Cancer Research Center and conducted in
collaboration with researchers at the University of Washington, The Wistar
Institute, Harvard Medical School and Virginia Mason Medical Center. The
goals of the program are to understand the biological mechanisms by which
esophageal cancer develops, to identify lifestyle and other factors that
promote or inhibit progression toward cancer, and to identify genetic
markers of increased risk so the disease can be prevented or detected
early, while it is still curable.
The Barrett's research team has shown that a systematic,
multidisciplinary approach to early cancer detection can boost the
five-year survival rate for esophageal cancer from about 10 percent to more
than 80 percent.
Other promising research findings from the Seattle team, all of which
require additional research, suggest that reducing obesity and quitting
smoking also may prevent progression of Barrett's.
For more information about the Seattle Barrett's Esophagus Program,
visit fhcrc/science/barretts. For more information about Barrett's
esophagus, visit barrettsinfo, a peer-reviewed Web site developed
by researchers at the Hutchinson Center and University of Washington that
is supported by AstraZeneca LP through an unrestricted educational-research
grant from the Ryan Hill Research Foundation, Seattle.
About Fred Hutchinson Cancer Research Center
At Fred Hutchinson Cancer Research Center our interdisciplinary teams
of world-renowned scientists and humanitarians work together to prevent,
diagnose and treat cancer. Center researchers, including three Nobel
laureates, bring a relentless pursuit and passion for health, knowledge and
hope to their work and to the world. For more information, please visit
fhcrc/.
Fred Hutchinson Cancer Research Center
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