National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
November 1, 2011 • Volume 8 / Number 21

Special Report

Study Shows Aspirin Reduces Colorectal Cancer in Those at High Risk

AspirinHigh doses of aspirin decreased colorectal cancer incidence in those with Lynch syndrome by nearly 60 percent.

Findings from the first large clinical trial of its kind indicate that taking high doses of aspirin daily for at least 2 years substantially reduces the risk of colorectal cancer among people at increased risk of the disease.

Conducted in the United Kingdom, the trial, dubbed CAPP2, showed a nearly 60 percent decrease in colorectal cancer incidence among men and women with hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch syndrome, who took 600 mg of aspirin daily compared to a placebo. HNPCC is an inherited condition in which mutations in certain genes substantially increase the risk of colorectal cancer as well as several other cancers. People with hereditary mutations in these genes, which are involved in a type of DNA repair process called mismatch repair, typically begin developing cancer in their 40s; approximately 15 percent of all colorectal cancers are attributed to defects in mismatch repair genes.

Published October 27 online in The Lancet, the findings update the trial's initial results, published in 2008. At that time, based on a mean follow-up of 29 months, use of daily aspirin was not found to reduce the incidence of colorectal cancer or precancerous lesions.

The updated results are based on a mean follow-up of nearly 56 months for 861 participants with HNPCC. Overall, there was a strong trend toward a reduction in colorectal cancer incidence among participants taking aspirin, but the reduction did not reach statistical significance

Among participants who took aspirin for at least 2 years (258), however, colorectal cancer incidence fell nearly 60 percent compared to that among participants who took a placebo for the same length of time. At least 2 years of aspirin use was also associated with a 55 percent reduction in other cancers associated with HNPCC, which can include stomach, ureter, biliary tract, skin (sebaceous glands), and endometrial cancers, as well as glioblastoma.

A Provocative Question: How Does Aspirin Prevent Cancer?

The accumulating evidence that aspirin and several other commonly used drugs, such as those used to treat diabetes, reduce cancer risk and mortality was strong enough that it garnered inclusion in NCI Director Dr. Harold Varmus' Provocative Questions initiative.

This particular provocative question (PQ 5) is soliciting research projects focused on elucidating the mechanisms by which aspirin and these other drugs exert anticancer effects. 

"There is broad agreement that cancer prevention is an area where we can and need to make huge strides in the coming years," said Dr. Umar. "Determining how these drugs are working is an extremely important part of that, and we encourage investigators working in this area to submit applications and to help provide answers to this important question."

"Our results, taken in conjunction with recent research, provide a basis for recommendation of aspirin chemoprevention in Lynch syndrome as a standard of care," wrote the trial's lead investigator, Dr. John Burn of Newcastle University, and his colleagues. "The optimum dose and duration of treatment remain to be established."

The findings are the latest to demonstrate aspirin's potential as a cancer prevention agent. Last year, two meta-analyses of findings from other clinical trials involving aspirin (but in which cancer incidence was not a pre-defined endpoint) showed substantial reductions in overall cancer risk and colorectal cancer risk associated with regular aspirin use for an average of 4 years.

The only other randomized trial of aspirin that had cancer incidence as a pre-specified endpoint, the Women's Health Study, did not show a reduction in overall cancer incidence or any specific cancers. Participants in that trial, however, were not at elevated risk for cancer and took only a 100 mg dose of aspirin every other day, although over a longer period than participants taking high-dose aspirin daily in CAPP2.

The continued follow-up of CAPP2 participants was a pre-specified component of the trial, the researchers explained. "This concept of delayed cancer chemoprevention was apparent in observational studies, in which protection against cancer in regular aspirin users took about 10 years to emerge," they wrote. The longer-term results, they continued, "support the hypothesis of a delayed effect of aspirin on colorectal cancer."

In an accompanying Lancet commentary, Drs. Scott Lippman and Andrew Chan, of the University of Texas M. D. Anderson Cancer Center and Harvard Medical School, respectively, agreed that the findings "provide a strong rationale for routine use of aspirin in individuals with Lynch syndrome." This should be in addition to continued "intensive cancer surveillance" with standard screening tools, they added.

With the lower incidence of other HNPCC-related cancers among trial participants taking aspirin, further research is also needed on the optimal dose and duration "that gives maximum benefits with minimal side effects" in others at elevated cancer risk, said Dr. Asad Umar of NCI's Division of Cancer Prevention.

Unlike the sporadic forms of colorectal cancer, inflammation does not appear to considerably influence cancer development in people with HNPCC, added Dr. Umar, whose research in the 1990s identified that the genetic mutations associated with this syndrome hindered key DNA repair processes in cells. The primary mechanism of action of aspirin and other nonsteroidal anti-inflammatory drugs, or NSAIDs, is to inhibit the COX1 and COX2 proteins, lynchpins in the body's inflammatory response.

"This work really suggests that, at least in people with HNPCC, aspirin may be working by a very different mechanism of action," Dr. Umar said. (See the sidebar.)

The updated findings from CAPP2 did not include any information on side effects, in particular gastrointestinal bleeding, that have been associated with aspirin and other anti-inflammatory drugs. Determining whether a lower dose could have the same cancer prevention effect will be important, Dr. Umar stressed, because it could limit any toxicity caused by either short- or long-term aspirin use for cancer prevention.

The CAPP2 research team, Dr. Burns said in a Lancet podcast, will be analyzing tumor samples from participants in the trial's aspirin and placebo arms to see if they can identify differences that can provide some insight into the mechanism. And the CAPP3 trial is being launched to test different aspirin doses in people with HNPCC.

Carmen Phillips