DOES ASPIRIN REDUCE RISK OF CANCER?

One of the most intriguing prospects in cancer prevention is a cheap and very familiar drug: aspirin. Later this year, in fact, the U.S. Preventive Services Task Force  is expected to release recommendations on the use of aspirin to reduce cancer risk.
Aspirin is already widely used. Tens of millions of people in the United States take it daily to reduce their risk of heart attack or stroke. And numerous studies over the last two decades have suggested that taking aspirin on a regular basis may substantially lower a person’s risk of developing or dying from cancer.
In 2011, for example, a meta-analysis of eight randomized clinical trials  that compared the risk of cancer death among participants who took daily aspirin for 4 years or more and those who took no aspirin found that, overall, aspirin use lowered the risk of dying from cancer by approximately 20 percent.
By looking at data from individual participants in these trials, the researchers, led by Peter Rothwell, MD, PhD, FRCP, of the University of Oxford, showed that this risk reduction was due mainly to fewer cancer deaths among participants who took aspirin for at least 5 years. The largest drop in risk was for gastrointestinal cancers, particularly colorectal cancer. The study also showed more modest risk reductions for several other common cancers, including lung and prostate.

The research findings on aspirin, however, are not clear cut. Not every study of aspirin and cancer has shown that it reduces the risk of developing or dying from cancer. And most of the research linking aspirin or other     nonsteroidal anti-inflammatory drugs (NSAIDs) and a lower risk of developing or dying from cancer have had limitations; most have been either observational studies, which cannot establish causal effect, or analyses of clinical trials testing aspirin’s effect on other health measures, most often vascular outcomes. None of the trials included in the 2011 meta-analysis, for example, was designed specifically to assess whether aspirin reduces the rate of cancer or cancer deaths.
But more definitive evidence may be on the horizon. In particular, researchers in search of answers are looking to several large clinical trials that have been launched to test whether aspirin reduces the risk of cancer incidence, death due to cancer, or both. (See the table.)

Trials of Aspirin for Cancer Prevention

Trial Name	Trial Design	Status
CAPP3	Enrolling 3,000 people with Lynch syndrome. Trial will test whether 100, 300, and 600 mg of aspirin per day for 2 years, followed by 100 mg per day, can reduce the risk of all Lynch syndrome-related cancers.	Will begin enrolling in 2014
ASCOLT	Enrolling patients recently treated for colorectal cancer to see if 200 mg of aspirin per day for 3 years can improve disease-free or overall survival	Currently enrolling participants
ASPREE	Enrolling 19,000 healthy U.S. participants aged 65 or older to see if the overall benefits (prevention of heart disease, stroke, certain cancers, and dementia) of taking daily low-dose aspirin for 5 years outweigh the risks, especially bleeding. Incidence of nonfatal and fatal cancers is a secondary endpoint.	Currently enrolling participants
AspECT	Enrolled 2,500 participants to test whether two different doses of an acid reflux drug with or without aspirin can reduce the risk of esophageal cancer in people with Barrett esophagus	Ongoing, enrollment complete

Consistent Findings, Mixed Opinions
The mounting evidence of aspirin’s strong anticancer effect for some malignancies is hard to ignore, said Dr. Rothwell, who led several more-recent studies that have strengthened the case for aspirin. The newer studies include a 2012 meta-analysis, which linked aspirin to a reduced risk of developing metastatic cancer.
"At a minimum, the data indicate that aspirin, in combination with the appropriate screening, would be highly effective in preventing esophageal and colon cancer," he said.
Dr. Rothwell is not alone in his opinion. "I do believe there is a role for using [NSAIDs] at a subtherapeutic level for various types of tumors," said Randall Harris, MD, PhD, of Ohio State University. A decade ago, Dr. Harris published findings from a prospective observational study of participants in the Women’s Health Initiative (WHI), which found that women who took aspirin or ibuprofen at least twice a week for 5 years or more had a reduced risk of breast cancer.
But that sentiment is not universal. John Baron, MD, MS, MSc, of the University of North Carolina Lineberger Cancer Center, agreed that there is strong evidence that aspirin reduces the risks of certain cancers. But, he noted, it’s still not enough. "More formal study is needed to nail down [aspirin’s] risks and benefits," he said.

How Does Aspirin Work against Cancer?
Researchers believe that aspirin may work, at least in part, by blocking the activity of COX-1 and COX-2 enzymes, lynchpins in the body’s inflammatory response. Inflammation is a normal response to tissue injury or infection that helps the injured tissue to heal or to clear the infection. In chronic inflammation, the inflammatory process does not end when it should. Over time, chronic inflammation can cause changes, such as the formation of new blood vessels and DNA mutations, which can promote tumor development and growth.

Reasons for Caution
Much of the hesitation expressed by Dr. Baron and others stems in part from the fact that few randomized clinical trials specifically designed to test the effect of aspirin on outcomes like cancer risk and mortality have been carried out. "Only when you do a randomized clinical trial do you get the complete picture of what’s going on," explained Asad Umar, DVM, PhD, of NCI’s Division of Cancer Prevention.
Progress is being made on this front. Take, for example, a large randomized placebo-controlled trial conducted in the United Kingdom called CAPP2. In that study, people with Lynch syndrome—an inherited disorder that substantially increases the risk of several cancers, including colorectal—who took high-dose aspirin (600 mg) for at least 2 years had a substantially lower incidence of colorectal cancer than participants who took a placebo.
Clinical trials can also highlight potential safety concerns that aren’t always apparent in observational studies or trials involving different patient populations. Dr. Umar cited the experience with a different NSAID, celecoxib (Celebrex®). Evidence of potential adverse cardiac effects from regular long-term treatment with celecoxib only emerged when it was tested in large trials with longer patient follow-up, including the NCI-funded Adenoma Prevention with Celecoxib trial.
The available data on aspirin’s safety are somewhat reassuring, Dr. Rothwell noted. In the trials included in the 2011 meta-analysis, for example, there were more fatal bleeding events among participants who took a placebo than among those who took aspirin (60 versus 40 events), even though aspirin increased 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 (11 versus 9 cases), according to the study’s lead author, Dr. John Burn of Newcastle University.

Filling in the Blanks
According to several researchers, several important questions need to be answered before aspirin can be considered for use as a cancer prevention measure, including: what dose provides the most protection against cancer and the lowest risk of serious side effects; who is most likely to benefit from aspirin use; which cancers does aspirin protect against; and how long after stopping aspirin does its anticancer protective effect last.
"Even for colorectal cancer, the data are incomplete or even conflicting regarding those details," Dr. Baron said. A recent case-control study, for example, found that use of low-dose aspirin after a colorectal cancer diagnosis did not improve cancer survival.
Dose is definitely a critical question, said Dr. Umar. "With an increased dose, the possibility of side effects increases," he said.
As for which cancers aspirin protects against, several studies have suggested that it may specifically prevent those that have certain molecular features. A study by researchers at the Dana-Farber Cancer Institute suggested that aspirin use prevents the development of cancers that have the normal version of a gene called BRAF, which has been implicated as a key driver of several cancers, but not cancers that have a mutated form of the gene. Another study by some of the same researchers found that aspirin use after a colorectal cancer diagnosis only reduced death from cancer if a patient’s tumor produced large amounts of  COX-2, an enzyme involved in inflammation. (See the sidebar.)
Although the results make biological sense, "these findings need to be replicated before we can be sure of them," Dr. Umar cautioned.
Meanwhile, ongoing studies should provide a better understanding of how aspirin (and other NSAIDs) protect against cancer and may aid the development of safer, more potent forms of these drugs.
Dipak Panigrahy, MD, and Charles N. Serhan, PhD, of Harvard Medical School are investigating how certain types of resolvins—anti-inflammatory molecules that are produced in the body when aspirin interacts with omega-3 fatty acids—block tumor growth and metastasis. His research is funded through NCI’s   Provocative Questions (PQ) program. Building on earlier NSAIDs research, another PQ-funded team, led by Laurie Hudson, PhD, and Angela Wandinger-Ness, PhD, of the University of New Mexico Cancer Center, are studying how NSAIDs that work differently than aspirin can affect the growth and spread of cancer cells.
And so, despite its promise, Dr. Umar cautioned that using aspirin to prevent cancer is still an active area of research and that “long-term trials are needed to answer several important questions.
"As with all drugs, there are potential risks and benefits with aspirin," he continued. And anybody considering taking aspirin on a regular basis "should talk to their primary care physician first.