Aspirin Confers Long-Term Protective Effect in Lynch Syndrome Patients

Jacquelyn K. Beals, PhD

November 02, 2009

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November 2, 2009 (Honolulu, Hawaii) — A daily dose of aspirin 600 mg   can reduce the cancer burden in Lynch syndrome patients by about half, according to   research presented here at the American Society of Human Genetics 59th Annual   Meeting.

"Clearly, what we have demonstrated is an impact on mismatch repair-deficient   tumors in a very specific genetic subgroup," presenter John Burn, MD, medical   director and head of the Institute of Human Genetics, Newcastle University,   Newcastle upon Tyne, United Kingdom, told Medscape Pathology & Lab   Medicine.

These new details add to the results already reported from   this study.

The genetic subgroup consisted of carriers of hereditary nonpolyposis colorectal   cancer (HNPCC), also known as Lynch syndrome. Of the more than 150,000 cases of   colorectal cancer newly diagnosed in the United States each year, HNPCC comprises   2% to 7%. Lynch syndrome I involves familial colon cancer, whereas Lynch   syndrome II includes colorectal cancer and another cancer, often   gastrointestinal or reproductive.

HNPCC is characterized by early-onset cancers. In the current study, mean age at   recruitment was 44 years. The dysfunction in Lynch syndrome is defective DNA   mismatch repair, causing "microsatellite instability," which can be identified in   tumor specimens in the pathology laboratory.

The Colorectal Adenoma/Carcinoma Prevention Programme (CAPP), an international   project with the goal of finding ways to prevent bowel cancer, assisted by families   at genetic risk, identified more than 1000 Lynch syndrome carriers to be part of a    randomized controlled trial, at 43 centers worldwide, of aspirin as a strategy to   prevent colorectal cancer in high-risk individuals.

Most patients were assigned to 1 of 4 daily regimens: aspirin 600 mg plus   placebo; aspirin 600 mg plus Novelose (a fiber-like starch resistant to   digestive enzymes) 30 g, Novelose 30 g  plus placebo, and placebo only.   After 7 to 74 months (mean, 29 months), no significant difference was evident in   the occurrence of colonic neoplasia between aspirin-treated and placebo   patients.

Of 937 patients starting the study, 745 underwent colonoscopy and 711 were   followed beyond the end of the trial. One participant insisted on knowing the   treatment category, but no other patients or contributing clinicians were told the   assigned categories. Four years after the first assignment, 14 participants in the   aspirin-treated group and 16 in the placebo group had developed colon cancers (a   nonsignificant difference). However, over the subsequent 3 years, colon cancers   developed in 3 participants in the aspirin-treated group and in 9 in the placebo   group.

Noncolorectal cancers related to HNPCC were also reduced — relative risk   in the aspirin-treated group was 0.38 (P = .05). Aspirin had no affect   on the occurrence of adenomas during the trial, but adenomas were confirmed in 100   participants during follow-up — an equal number in the aspirin-treated and   placebo groups. The total number of colorectal cancer cases currently known stands   at 29 of those receiving placebo and 17 of those receiving aspirin.

"People at very high risk, very strong family history risk, are the ones for   whom this would be the most relevant," Dr. Burn told Medscape Pathology &   Lab Medicine. "All I can say is that, in Lynch syndrome, it seems to work, but   you have to do it for a long time." The protective effect is correlated with the   length of aspirin use during the trial. "If you put that together with the rest of   the literature, it suggests that it's not just mismatch repair, but we really do   need to do that long-term follow-up of people, ideally on different amounts of   aspirin, because that's the next big question," said Dr. Burn.

Because aspirin did not reduce the formation of adenomas, investigators wonder   whether aspirin induces apoptosis in aberrant stem calls. The next CAPP study will   compare different doses of aspirin. Although aspirin appears to work, the dosage   and length of use have not been established. During his presentation, Dr. Burn   expressed the hope that smaller doses will produce the same benefit.

Asked whether the participants might have continued their regimens after   concluding the original study, Dr. Burn said he thought it was unlikely: "This is a   relatively young population. They're not Americans, so they don't pop pills. And   they tend to pop the pills their doctors give them rather than the ones they buy   themselves. It's a very different behavior pattern," he said. "People expect to be   given their tablets by their doctor; there's much less of a culture of   self-medication," he said.

A disadvantage of long-term aspirin use is the increased risk for hemorrhage.   "It's not only [gastrointestinal] bleeds. You have hemorrhagic stroke, for   example . . . probably less of an issue on the baby aspirin than it   is on the higher dose aspirin," session comoderator David Malkin, MD, told   Medscape Pathology & Lab Medicine. Dr. Malkin is associate chief of   research (clinical), senior staff oncologist, senior scientist, and codirector of   the Cancer Genetics Program at The Hospital for Sick Children, Department of   Pediatrics, Division of Oncology, in Toronto, Ontario.

"The issue that [Dr. Burn] called the 60 million dollar question is   whether, for the general population, . . . they're able to show that   this is beyond just the Lynch syndrome effect. [If so], it would be particularly   important to figure out a way to screen individuals before presumably putting them   on aspirin."

Dr. Malkin also wondered whether the age the aspirin was started at had an   effect: Was there a greater protective effect for patients who started earlier than   for those who started later? "At what point, after the adenoma starts to develop,   is taking aspirin no longer beneficial?" Dr. Malkin asked. "I don't know if they   know that yet. But [Dr. Burn] probably has enough data from those numbers to pull   it out."

Dr. Burn reports receiving research and other grants, scholarships, or   fellowships from Bayer Corporation and Leverkusen Germany. Dr. Malkin has disclosed   no relevant financial relationships.

American Society of Human Genetics (ASHG) 59th Annual Meeting: Abstract 113.   Presented October 23, 2009.

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