Aspirin may reduce the risk of colorectal cancer and researchers are studying whether it reduces the risk of other cancers.

In the United States, tens of millions of adults take aspirin to reduce their risk of heart attack or stroke. But studies over the last two decades have suggested that regular use of aspirin may have another important benefit: decreasing the risk of developing or dying from some types of cancer.

Results from some of these studies, in fact, formed the basis for guidance released in April 2016 by an influential federal advisory panel on disease prevention. The panel, the U.S. Preventive Services Task Force (USPSTF), recommended that, for some people, aspirin can be used to help reduce their risk of cardiovascular disease and colorectal cancer.

Several researchers who conducted some of the seminal studies on which the USPSTF based its guidance stressed the importance of the panel’s actions.

Writing in Nature Reviews Cancer, Andrew Chan, M.D., of Harvard Medical School, and several colleagues called the recommendation a "crucial first step in realizing a potential broader population-wide impact of aspirin use" for cancer prevention.

The USPSTF recommendations are far from sweeping, however. And researchers are continuing to investigate critical questions, including just how aspirin may reduce colorectal cancer risk and what other cancers, if any, regular use of this century-old drug may help to prevent.

The findings from these studies should help to fill an important informational void. At least one study suggests that, even before the USPSTF made its recommendations, Americans were buying in to the idea of aspirin's anticancer potential; in that 2015 study, 18% of Americans who were taking aspirin regularly said they were doing so to help prevent cancer.

Consistent Data in Colorectal Cancer

The USPSTF's recommendation on aspirin and colorectal cancer makes sense, said Ernest Hawk, M.D., division head for Cancer Prevention and Population Sciences at the University of Texas MD Anderson Cancer Center.

In published studies looking at aspirin's protective effect against cancer, the "greatest consistency" has been in colorectal cancer, Dr. Hawk explained.

For example, in the CAPP2 trial, which tested high-dose daily aspirin in individuals with Lynch syndrome—a hereditary condition that greatly increases the risk of colorectal and endometrial cancers as well as several other cancers—participants given aspirin had a 63% reduction in the relative risk of developing colorectal cancer compared with those given a placebo.

But the evidence also extends to those at average colorectal cancer risk as well. Among the most recent examples is an analysis of two large, long-running cohort studies published in June 2016 in JAMA Oncology. The study, led by Dr. Chan at Harvard, linked the use of aspirin for 6 years or longer with a 19% decreased risk of colorectal cancer and a 15% decreased risk of any type of gastrointestinal cancer.

Based on their analysis, the research team estimated that regular aspirin use could prevent nearly 11% of colorectal cancers diagnosed in the United States each year and 8% of gastrointestinal cancers.

"The data for colorectal cancer are really good," said Theodore Brasky, Ph.D., an epidemiologist at The Ohio State University Comprehensive Cancer Center whose research focuses on anti-inflammatory drugs and cancer risk.

"Certainly the observational data show that aspirin reduces colorectal cancer risk," Dr. Brasky continued. And several randomized clinical trials have shown that aspirin use "at any dose" can reduce the incidence of any polyps as well as advanced polyps, he said, both of which can be precursors to colorectal cancer.

Most Benefit, Lowest Risk

The USPSTF guidance singles out a population group who the data suggest are likely to get a net benefit with the least risk: people 50 to 59 years old who are at increased risk of cardiovascular disease.

The recommendation also advises that potential candidates should have a life expectancy of at least 10 years and not be at increased risk of bleeding (due to other health conditions or the use of other medications)—a known side effect of long-term aspirin use.

A recommendation for a treatment that covers two distinct diseases is unique, acknowledged USPSTF chair Kirsten Bibbins-Domingo, M.D., Ph.D., M.A.S., of the University of California, San Francisco. But there was a specific logic to the task force’s decision.

"We were trying to simulate how a doctor and patient make…decisions" about prevention, she said. "They don't necessarily make a separate decision for cardiovascular disease and for cancer."

The task force concluded that it did not have enough evidence to recommend for or against aspirin in those under age 50 or older than age 70 and said that the decision to use aspirin for people aged 60–69 should be an individual one.

The June 2016 Harvard study also revealed another important finding that should help to clarify a point of debate among prevention researchers, Dr. Hawk stressed: In people who had been screened for colorectal cancer, regular aspirin use produced an added reduction in risk.

"We know that with screening by any approach, there is a certain miss rate and an interval cancer rate," Dr. Hawk said. The latter refers to cancers that are diagnosed in the interval after a normal screening exam and before the next scheduled screening.

The study's findings, he said, strongly suggest that aspirin may be able to "complement colorectal cancer screening" by decreasing the risk of interval cancers.

Reduced Risk of Other Cancers?

The jury is still out on whether aspirin has a future as a way to reduce the risk of cancers other than colorectal.

Findings that regular aspirin use is associated with a reduced risk of other cancers "have been hit or miss," Dr. Hawk said. In the recent Harvard study, for instance, aspirin use was not linked with a reduced risk of the other most common cancers. There was also no overall reduction in cancer risk in the Women’s Health Study—a randomized clinical trial that tested whether every-other-day use of low-dose aspirin could reduce cancer risk in nearly 40,000 women aged 45 and over.

And for colorectal cancer prevention, there is also evidence from clinical trials and laboratory experiments to support its use. But for many other cancers, "there isn’t much supporting experimental data in humans to rely on," he said.

Even so, findings from observational studies continue to hint at aspirin’s anticancer potential beyond colorectal cancer, including those linking aspirin to a lower risk of melanoma, ovarian cancer, and pancreatic cancer.

Many studies of aspirin and cancer risk often have important limitations, Dr. Brasky said, including missing information on critical factors like aspirin dose and duration of use.

They also often lump aspirin together with other nonsteroidal anti-inflammatory drugs, or NSAIDs, like naproxen, ibuprofen, and celecoxib (Celebrex®), which have also been studied for their potential effects on colorectal cancer risk.

"These are different medicines, different chemicals," he said. "They have other effects that aren't well studied."

So while all of these drugs are part of the NSAID family and have anti-inflammatory effects, when it comes to their effect on cancer risk, he continued, "I'm not convinced, necessarily, that it's wise to study them as a single class of drugs."

Cancer Type, Biology, Both?

Another wrinkle to consider is that aspirin's protective effects against cancer may depend as much on biological factors as on cancer type. Some studies, for example, have suggested that NSAIDs like aspirin may not be as effective at preventing cancer in women as in men.

Other studies have identified other factors that may predict who is likely to benefit, factors that hint at the molecular mechanisms by which aspirin may exert its anticancer effects. Much of this work has focused on aspirin’s inhibition of the COX-1 and COX-2 enzymes.

COX-1 and COX-2 are critical components of the body’s inflammatory response. Prolonged inflammation can promote changes in cells that can cause them to become malignant. This appears to be particularly true in colorectal cancer, where inflammation can promote changes in the cells that line the lower gastrointestinal tract, leading to the formation of precancerous growths.

These studies have allowed researchers to home in on key players in this inflammatory cascade, changes which may be markers of cancer risk.

For example, a series of studies from researchers at Harvard and Dana-Farber Cancer Institute—using the same large cohorts as the June 2016 JAMA Oncology study—have pointed to specific biological factors that may influence its preventive potential.

One of their earlier studies, for example, showed that aspirin use appeared to only reduce the risk of colorectal cancers that produced large amounts of COX-2. More recent studies have zeroed in on other components of the COX-2 pathway, including one study that showed that aspirin reduced colorectal cancer risk only in people whose colonic mucosa—the cell layer that lines the colon—overexpressed the gene 15-PGDH, which encodes for an enzyme that disrupts COX-2 activity.

Although these potential biomarkers have not been validated, they start to show how, eventually, decisions about the use of aspirin to reduce cancer risk may potentially be tailored to individual patients, Dr. Brasky noted.

Clinical Trials: Identifying Side Effects, Hastening Translation

Researchers are continuing to investigate aspirin's potential role in cancer prevention. That research should help to better clarify who might benefit from aspirin, Dr. Bibbins-Domingo said.

"Especially in an environment where we know there can be real harms [of long-term aspirin use], we have to have the best possible information to make sure we know its benefits definitely outweigh its harms," she said.

Clinical trials will be crucial in this regard, explained Asad Umar, D.V.M., Ph.D., chief of the Gastrointestinal and Other Cancers Research Group in NCI’s Division of Cancer Prevention.

Randomized clinical trials can help validate what’s been seen in observational studies and provide "a more complete picture of what's going on" in people taking aspirin long term, he explained. That includes identifying potential safety concerns that aren’t always apparent in observational studies.

Dr. Umar cited the experience with celecoxib. Evidence of adverse cardiac effects from regular long-term treatment with this drug only emerged when it was tested in large trials with longer patient follow-up, including the NCI-funded Adenoma Prevention with Celecoxib trial.

The chief concern with aspirin is gastrointestinal bleeding. The available data from clinical trials on longer-term aspirin use, however, suggests that this risk may be modest.

In the eight trials included in an influential 2011 meta-analysis which found that regular aspirin use reduced the risk of dying from cancer, for example, there were more fatal bleeding events among participants who took a placebo than among those who took aspirin, although aspirin did increase the risk of nonfatal bleeding.

And in the CAPP2 trial, the number of cases of gastrointestinal bleeding in the aspirin group and placebo groups were very similar.

That doesn't mean that people using aspirin or their physicians shouldn’t be worried about bleeding.

"The population that primarily develops cancer, people over age 50, also have a greater risk of bleeding" by virtue of their age, Dr. Hawk said. "So we always have to be concerned about that."

To better answer questions about safety and who is most likely to benefit from aspirin, researchers are awaiting the results of several ongoing clinical trials that are testing aspirin either to reduce the risk of cancer or as an adjuvant therapy to reduce the risk of an already treated cancer from returning.

Included among them are: CAPP3, a follow-on study from CAPP2 that is testing three different aspirin doses in patients with Lynch syndrome; ASPREE, which is testing whether low-dose aspirin can reduce the risk of cancer, heart attack, stroke, or dementia in people aged 65 and older; and Add-Aspirin, which is examining two different doses of aspirin as an adjuvant treatment for people who have undergone surgery for early-stage breast, colorectal, prostate, or esophageal cancer.

These long-term studies, Dr. Umar stressed, "are needed to answer many important questions."