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Regular Aspirin Use May Increase Older People’s Risk of Dying from Cancer

, by NCI Staff

In generally healthy people aged 70 and older, taking a daily low-dose aspirin increased their risk of being diagnosed with advanced cancer and dying from cancer, a large clinical trial found. 

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Numerous studies have suggested that people who regularly take low doses of aspirin may have reduced risks of being diagnosed with or dying from cancer. But new findings from a randomized clinical trial, called ASPREE, suggest that the same may not hold true for older adults.

The study included approximately 19,000 generally healthy people who were 70 years of age or older. Those who took 100 mg of aspirin daily were no more likely than those who took a placebo to be diagnosed with cancer. They did, however, have a greater likelihood of being diagnosed with an advanced cancer and of dying from cancer, the ASPREE research team reported August 11 in JNCI.

The finding of increased cancer death risk held true even for colorectal cancer. That may come as a surprise to many cancer prevention researchers, because most studies have linked aspirin use with a decreased risk for being diagnosed with or dying from colorectal cancer.

Data from those studies were considered strong enough that, in 2016, the US Preventive Services Task Force (USPSTF), an influential health panel of prevention experts, recommended the use of daily low-dose aspirin for certain people to reduce their risk of heart disease and colorectal cancer.

“These results are clearly unexpected,” said Andrew Chan, M.D., M.P.H., a professor of medicine at Massachusetts General Hospital and a senior researcher on the trial, which was funded primarily by the National Institute on Aging, and with support from NCI and others.

Participants in ASPREE have been followed for a median of approximately 5 years. Dr. Chan noted that they need to be followed for a longer period, to better understand the potential effect of aspirin on cancer diagnoses and deaths.  

This was a group of people starting to take aspirin when they were older. It’s unclear if the findings apply to people who begin taking aspirin regularly at an earlier age, he said. Dr. Chan also cautioned that people whose doctors have prescribed aspirin for specific medical issues (e.g., reduce heart attack risk) shouldn’t stop taking it.

“They shouldn’t discontinue [aspirin] based on these results,” he said. “But if they’re concerned, they should consult with their doctor.”

But from a broader perspective, the ASPREE results, combined with other recent research on aspirin, should cause clinicians to revisit “the clinical use of aspirin by the elderly,” argued Ernest Hawk, M.D., and Karen Colbert Maresso, M.P.H., of the Division of Cancer Prevention and Population Sciences at MD Anderson Cancer Center, in an editorial in JNCI that accompanied the trial results.

The impact of specific treatments on older people is often not clear, because so few studies focus on them, said Leslie Ford, M.D., associate director for clinical research in NCI’s Division of Cancer Prevention and part of the ASPREE team. That’s part of what makes this trial so important, Dr. Ford continued. 

“We … have to pay particular attention to studies done specifically in this age group,” she said.

Following the Trail of Earlier Research

The prospect that a cheap and relatively safe drug like aspirin could help reduce cancer risk has enticed researchers for decades. Low-dose, or baby, aspirin is already widely used to lower the chances of heart-related events (such as heart attacks) in people who have heart disease or who are otherwise at high risk of cardiac events.

This widespread use of aspirin allowed for the numerous observational studies that linked aspirin use with decreased chances of being diagnosed with cancer and dying from it. Those studies eventually led to clinical trials to confirm aspirin’s disease prevention potential, including for cancer.

Included among those trials were those in people with Lynch syndrome, a condition that greatly heightens the likelihood of developing some cancers, particularly colorectal cancer. In one such trial, people with Lynch syndrome who regularly took high-dose aspirin (600 mg) daily for at least 2 years cut their colorectal cancer risk by more than a third. Several trials have also shown that aspirin reduces the risk of developing precancerous colon polyps.

Other clinical trials have also indicated that taking aspirin could reduce cancer risk, with the largest reductions consistently seen for colorectal cancer. Most of these other trials, however, were not specifically designed to measure aspirin’s impact on cancer, so researchers tend to view those results with caution.

Largely conducted in Australia, but also with US participants, ASPREE is what is known as a primary prevention trial. It was launched to better understand the impact of low-dose aspirin on the risk of developing dementia or permanent physical disability among generally healthy older individuals. Whether aspirin affected cancer risk and cancer deaths was a planned, but secondary, goal of the study.

Initial results from ASPREE, published 2 years ago, showed that participants who had been randomly assigned to take daily low-dose aspirin had a modestly increased risk of dying from any cause compared with those who took a placebo. The increased risk was due almost entirely to a higher number of cancer-related deaths among those who took aspirin.

Increased Risk of Dying from Advanced Cancer

ASPREE began enrolling participants in 2010 and continued doing so until 2014. Participants were randomly assigned to take either aspirin or a placebo until the trial ended, and most had not taken aspirin regularly before entering the trial. The trial was stopped early in June 2017, when it was determined that there wouldn’t be an improvement in the study’s primary endpoint among those in the group taking aspirin. 

Approximately 1,900 ASPREE participants were diagnosed with cancer during the study. Overall, about two-thirds of those were localized cancers—that is, they had not spread, or metastasized, from their original location. 

About one-quarter of those diagnosed with cancer during the study ultimately died from it. 

The use of aspirin wasn’t associated with the diagnosis of any single type of cancer. However, participants in the aspirin group had a nearly 20% higher risk of being diagnosed with advanced cancer and about a 30% higher risk of dying from advanced cancer. 

The increased risk of being diagnosed with and dying from advanced cancer raise important questions, according to Dr. Hawk and Maresso. 

“The unexpected and unexplained results of ASPREE suggest that we may still be missing a critical piece of the puzzle in our understanding of aspirin’s biologic effects on cancer development and evolution within and across individuals of differing ages,” they wrote.

Chyke Doubeni, M.D., director of the Center for Health Equity and Community Engagement Research at the Mayo Clinic, agreed that the results were unanticipated, particularly given the findings from earlier studies. 

That participants in the aspirin group had a 77% higher risk of dying from colorectal cancer than those in the placebo group is particularly notable, continued Dr. Doubeni, who is a USPSTF member and was not involved in ASPREE. “I do think that what this is telling us is that we need more studies” on aspirin’s impact on colorectal cancer, he said. 

Is Age the Critical Factor?

The findings raise a critical question, Dr. Ford said: Why would aspirin use lead to even a small increase in the risk of advanced cancer in older people? Studies linking aspirin use to decreased risks of cancer and dying from cancer were, she noted, largely done in younger populations.

It could be because older people’s biology is different than that of younger people, the study team proposed. For example, older people often already have weaker immune systems. And aspirin, they wrote, may be disrupting the immune system response that is “critical to controlling later stage [tumor] growth and spread.” 

Dr. Ford agreed. “Maybe aspirin does have a different effect on people as they age,” she said. “And, similar to what we’ve seen with COVID-19, does it affect the immune system differently in an older population than it does in a younger, healthier one with a stronger immune system? It’s definitely a plausible explanation.”

Thanks in part to blood and tumor samples collected from participants as part of ASPREE, Dr. Chan said, the researchers are planning studies to look more carefully at immune-related or other potential molecular factors that aspirin may influence. They will also continue to follow participants to see if the risk of cancer and cancer death change over time.

Looking Ahead: Changes in Practice?

Dr. Doubeni said that the task force will consider the ASPREE results during its update of the 2016 recommendations, which is underway.

Results from other recent trials, Dr. Hawk and Maresso explained, have also raised concerns about the possible harms of aspirin. They noted, for example, that in the ASCEND trial, which tested low-dose aspirin in people with diabetes who were at increased risk of heart problems, participants who took aspirin had a substantially higher risk of gastrointestinal bleeding than those who took a placebo.

“Together, these findings alter the calculus of aspirin’s risks and benefits such that its use as a cancer [prevention] agent in the general population looks less likely,” they wrote.

Dr. Ford stressed that the ASPREE findings are relevant to older people and the use of aspirin as a means of primary prevention of cancer. They should not affect those with high cancer risk conditions like Lynch syndrome, she said, for which high-dose aspirin has been proven to have an important benefit.

In many other studies, Dr. Doubeni explained, the beneficial effects on cancer linked to aspirin use didn’t become apparent until long after people started using the drug, a decade or more in some cases. So the longer-term follow-up of trial participants will be critical, he said.

The results also support the notion that cancer prevention should be tailored to each person, Dr. Chan said.

“The old thinking was that one mode of prevention would work for everybody equally,” he said. “This clearly shows that we have to rethink that mindset. There’s a clear possibility that there’s something biologically different about the way cancers develop in older adults or how they respond to preventive agents.”

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