The
humble aspirin may have just added another beneficial effect beyond its ability
to ameliorate headaches and reduce the risk of heart attacks: lowering colon
cancer risk among people with high levels of a specific type of gene.
The
extraordinary finding comes from a multi-institutional team that analyzed data
and other material from two long-term studies involving nearly 128,000
participants. The researchers found that individuals whose colons have high
levels of a specific gene product — 15-hydroxyprostaglandin dehydrogenase (15-PGDH)
RNA — dramatically reduce their chances of developing colorectal cancer by
taking aspirin. In contrast, the analgesic provides no benefit to individuals
whose colons show low levels of 15-PGDH.
The
findings appear in the April 23 edition of Science Translational Medicine. While previous trials
and prospective studies had indicated that aspirin could reduce colorectal
cancer risk, this retrospective study provides the first evidence to help
explain why aspirin benefits some people, but not others.
The
research team included researchers from Case Western Reserve University School
of Medicine, Dana Farber Cancer Institute, Harvard University, Massachusetts
General Hospital, and University Hospitals Case Medical Center.
"If
you looked at the folks from the study who had high 15-PGDH levels and took
aspirin, they cut their risk of colon cancer by half," said senior author
Sanford Markowitz, MD, PhD, Ingalls Professor of Cancer Genetics at Case
Western Reserve School of Medicine. "If you looked at the folks from the
study that were low for 15-PGDH, they did not benefit at all from taking
aspirin. These findings represent a clean Yes-No about who would benefit from
aspirin."
Funded
in part by the Entertainment Industry Foundation's National Colorectal Cancer
Research Alliance (NCCRA), the discovery represents precisely the kind of
advancement that Katie Couric and her colleagues sought when they founded the
initiative in 2000. She lost her 42-year-old husband, Jay Monahan, to colon
cancer in 1998 and has been a steadfast advocate for colon cancer prevention
efforts in the years since.
"Prevention,
early detection and effective treatments are key to conquering cancer,"
Couric said. "This finding that aspirin can prevent colon cancer in
certain individuals is an easy and cost-effective addition to our arsenal in
the fight against the second-leading cancer killer. I am proud to see this
valuable research advancing patient care for those at risk of colon cancer
resulting from NCCRA support."
According
to the American Cancer Society, colorectal cancer is the second leading cause
of cancer-related deaths in the United States, with predictions that 137,000
Americans will develop the disease and 50,000 will die from it in 2014. Thanks
to regular screenings, the death rate from colorectal cancer has dropped in the
past 20 years, and members of this research team have been dedicated to finding
additional measures to help reduce risk and ultimately eradicate the disease.
In
this latest effort, the scientists sought to build on earlier research that
indicated that regular use of non-steroidal anti-inflammatory drugs (NSAIDs),
including aspirin, reduces the chances of developing colon cancer for some
individuals, but not in all. Their question: Why? What is different between
those helped by aspirin, and those who saw no effects?
Markowitz,
also the head of the Cancer Genetics Program at the Case Comprehensive Cancer
Center and a medical oncologist at University Hospitals Case Medical Center
joined lead co-senior author Andrew T. Chan, MD, PhD, of Massachusetts General
to explore whether the presence of 15-PGDH led to different outcomes in terms
of which individuals developed colon cancer.
Their
goal: to see whether it is possible to develop a test that would help guide
physicians and patients in determining whether an aspirin regimen would be of
benefit.
The
team examined tissues of 270 colon cancer patients culled from 127,865
participants followed for over three decades in the Harvard-based Nurses'
Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Previous
reports from the Massachusetts General/Dana-Farber team indicated that
participants in these studies who regularly took aspirin had a lower risk of
colorectal cancer. In earlier research, the Case Western Reserve investigators,
along with Monica Bertagnolli, MD, of Brigham and Women's Hospital, had found
that the presence of 15-PGDH appeared to enhance the ability of celecoxib, an
anti-inflammatory medication commonly known as Celebrex, to prevent colon
tumors in mice and in 16 humans tested. But when 15-PGDH was low or not
present, celecoxib did not prevent colon tumors in mice or humans.
In
this latest study, the investigators combined forces in a much larger study to
examine whether 15-PGDH levels might also be associated with the colon
cancer-preventing benefits of aspirin, which is already taken by many
individuals and does not have the cardiovascular side effects of celecoxib .
The Massachusetts General and Dana-Farber team dissected normal colon tissue
from the pathology specimens of NHS/HPFS participants who developed colon
cancer over the studies' follow-up period. The team at Case Western Reserve
then analyzed these colon tissues to identify which among them had high or low
levels of colon 15-PGDH. The investigators at Massachusetts General and
Dana-Farber examined how the data on participants' aspirin use and levels of
15-PGDH related to the risk of colorectal cancer to address the question the
larger group had set out to answer: Were individuals who developed colorectal
cancer while taking aspirin more likely to have low or high levels of colonic
15-PGDH?
The
study is among the first examples of the type of test that could allow more
personalized decisions about treatment to prevent colorectal cancer. It also
allows those whose 15-PGDH levels indicate aspirin would have little impact to
avoid the potential gastrointestinal challenges — such as stomach ulcers — that
can accompany aspirin use.
Additional
researchers involved in the study included first authors Stephen Fink, PhD, an
instructor at Case Western Reserve; Mai Yamauchi, PhD, and Reiko Nishihara,
PhD, research fellows at Dana-Farber Cancer Institute; and senior authors
Charles S. Fuchs, MD, MPH, and Shuji Ogino, MD, PhD, MS, also from the
Dana-Farber Cancer Institute. Chan is a gastroenterologist at Massachusetts
General and Associate Professor of Medicine at Harvard Medical School.
The
researchers' next steps are two-fold: first, the development of a
cost-effective and accessible test for measuring 15-PGDH in the colon, and
second, a prospective clinical trial to further confirm these findings. Chan
and Markowitz both consider the first step well within reach of current medical
practice.
"During
a colonoscopy, a gastroenterologist could easily and safely take an additional
biopsy from the colon in individuals for whom preventive aspirin treatment
might be appropriate," Chan said. Added Markowitz, "There would be no
reason why a good hospital pathology laboratory could not establish the test for
15-PGDH."
The
study authors are also hopeful that publication of these findings will draw the
interest from funders and other researchers in developing a confirmatory
randomized, prospective clinical trial in which high-risk patients would be
identified, treated with aspirin or a placebo, depending on their 15-PGDH
levels, and monitored for development of colorectal tumors.
The
mechanisms of action in the 15-PGDH gene and in aspirin make them key players
in the colon cancer discussion. Prostaglandins promote development of colon
cancer, and aspirin helps prevent colon cancer development by preventing
prostaglandins from being generated. 15-PGDH also helps prevent colon cancer
development by catalyzing the reaction that "chews up"
prostaglandins. Markowitz refers to 15-PGDH as the body's genetic form of
aspirin. The study shows that both aspirin and 15-PGDH must work together to
effectively prevent colon cancer, with aspirin benefitting most individuals who
also have high levels of 15-PGDH.
"This study highlights the benefits of the relatively new practice
of molecular pathological epidemiology, or MPE," said co-senior author
Ogino of Dana-Farber, an Associate Professor of Pathology at Harvard Medical
School. "The molecular pathology part relates to analysis of 15-PGDH gene
expression level in normal colon to classify cancer based on molecular
pathogenesis, while the epidemiology part relates to collection and analysis of
aspirin use data in population. MPE is an integration of these analyses."
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