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With Canada’s population growing and aging, researchers predict that the number of new cancer cases in Canada will increase significantly in the next decade. About half of all cancers are preventable, though, so individuals have opportunities to reduce their risk of developing the disease by making healthy changes to their lifestyles and behaviours. Another potential strategy is chemoprevention – using medication to prevent cancer.
Chemoprevention usually repurposes an existing drug, one used for cancer treatment or a completely different condition, for use by people without cancer. For example, researchers have studied whether the breast cancer drugs tamoxifen and exemestane may prevent breast cancer in high-risk women. They have also studied the use of metformin, used to treat type II diabetes, in preventing a variety of cancers.
A cancer prevention drug would need to be taken by healthy people for a long period of time, so it must be extremely safe, inexpensive and easy to access and take, so that users are more likely to comply with the treatment.
A common pill found in many Canadian homes that can fit these criteria and may also prevent cancer is acetylsalicylic acid, also known as Aspirin. “Aspirin is an ideal drug – it is safe and affordable,” says Dr Stephanie Lheureux, a clinician investigator at the University Health Network in Toronto. “There is growing evidence and a lot of recent research that shows aspirin can potentially have an effect in preventing cancer.”
Here, we’ll describe how nonsteroidal anti-inflammatory drugs (NSAIDs) such as Aspirin might work to prevent cancer and review existing evidence of its effectiveness against the disease. Some research has suggested that NSAIDs other than Aspirin could be used for cancer prevention, but the evidence seems to be strongest for Aspirin, and as a result, it is the focus of this article.
Importantly, at this time the Canadian Cancer Society (CCS) does not recommend that Canadians take Aspirin to reduce their risk of cancer or cancer death. While the evidence so far is promising, we do not yet have a complete understanding of the full risks and benefits of Aspirin as a cancer prevention tool. Without this data, it is still too early for any official recommendations on taking Aspirin to reduce cancer risk. For more information, read the full CCS perspective on Aspirin and cancer.
How NSAIDs Work
Inflammation and NSAIDs
Inflammation is how the immune system responds to an infection by bacteria or viruses or an injury. White blood cells release chemicals and substances at the site of the problem that fight the infection and help with healing, but can also cause pain, redness and swelling.
Inflammation is an important part of the immune response, but if it happens when or where there is no infection, such as in auto-immune diseases like multiple sclerosis or rheumatoid arthritis, it can damage the body itself.
NSAIDs relieve inflammation. Some NSAIDs, such as Aspirin and ibuprofen, are frequently used to treat headaches, pain and fever, while others are used to treat conditions like arthritis and other inflammatory diseases.
A number of years ago, researchers found that Aspirin could help protect people from heart attacks, especially people at high risk. In addition to its pain-relieving and fever-reducing properties, Aspirin prevents the formation of platelets, the parts of blood that are responsible for clotting. With fewer platelets, the blood stays thin and the risks of a blood clot or heart attack go down.
As a result, doctors may recommend a daily low dose of Aspirin for older adults who are at high risk of heart attack. But large studies suggest that, on top of its heart-protective properties, Aspirin may also protect against cancer.
How might NSAIDs work in cancer?
Aspirin, even at low doses, interferes with many different biochemical chain reactions or pathways in the body. To prevent a complex disease like cancer, several different pathways are likely interacting and working together, rather than one single process being responsible.
One common hypothesis about how Aspirin may prevent cancer is through its anti-inflammation activity. Chronic inflammation is known to increase the risk of certain types of cancer, including colorectal and ovarian cancers, so it makes sense that an anti-inflammatory drug such as Aspirin could have a protective effect.
A protein called COX2 has an important role in promoting inflammation. This protein jumpstarts a biochemical pathway, helping to change one molecule called arachidonic acid into another type of molecule called a prostaglandin, which plays an important role in promoting inflammation. Prostaglandins also promote cell growth, increase blood vessel development and reduce cell death, all of which are important contributors to early tumour growth.
Aspirin shuts down the COX2 protein, essentially cutting off this inflammation pathway at the root. This is how it works to stop inflammation and may also be how it stops the early stages of cancer growth.
Another hypothesis is that the same mechanism that gives Aspirin its heart-protective properties may also help to prevent cancer. Platelets, the parts of blood responsible for clotting, may also be involved in cancer growth and spread. They can travel to a part of the body experiencing inflammation and actually make it worse by turning on pathways, like the COX2 pathway, that create even more inflammation and increase the risk of cancer development.
A protein called COX1 is an important part of the biochemical reaction that creates and activates platelets. As with COX2, Aspirin blocks COX1, stopping this pathway at the source and reducing the number of platelets in the blood to levels that help thin the blood and reduce inflammation. Evidence suggests that this indirect way to stop inflammation, with fewer platelets to trigger the COX2 inflammation pathway, may be the main mechanism at work in preventing cancer growth, particularly at low doses of Aspirin.
Other molecular pathways
A lot of different mechanisms work together to turn healthy cells into cancer cells, so it’s likely that many different molecular processes are also involved in preventing cancer.
On top of its anti-inflammation and anti-platelet activities, Aspirin may also block another molecular pathway called the Wnt pathway, which promotes normal tissue development and growth. As with inflammation, if this pathway is activated when or where it shouldn’t be, cells can grow out of control, leading to cancer. Some evidence suggests that Aspirin blocks the Wnt pathway possibly by decreasing the same prostaglandin molecules that are part of the COX2 inflammation pathway, ultimately reducing cell growth.
Exactly how Aspirin may be having an effect is still unclear, and researchers are still working to uncover the precise mechanisms involved. “Aspirin’s effects on cancer is still a relatively young area of research, despite the fact that it is an old drug,” says Dr Lheureux.
NSAIDs and Cancer
While researchers can use cell models to see how Aspirin works in the body, to actually find out whether it is effective in people, they need to do large clinical trials. Cancer prevention trials need to follow a large number of people for a long period of time, making them very expensive and difficult to coordinate. As a result, much of the research on Aspirin’s effectiveness come from analyzing data from many smaller studies together and from large population health studies that collected detailed health data from large groups of people over many years.
These studies are important and provide initial information, but they do have limitations. Since they weren’t set up to answer specific questions about Aspirin and cancer, participants may have used different doses or different schedules for different lengths of time. “Population data is important, and for Aspirin, large datasets are consistently showing that it has an impact, even with their limitations,” says Dr Lheureux. “But to change practice, we need objective data from rigorous clinical trials and selected populations.”
Still, a growing body of evidence shows that frequent Aspirin use can help reduce people’s risk of cancer, particularly colorectal cancer.
NSAIDs and colorectal cancer
The strongest evidence of Aspirin’s effects on cancer prevention is related to cancers of the digestive tract, especially colorectal cancer.
Some analyses of clinical trials and smaller studies have found that people who took Aspirin almost daily for at least 5 years had a nearly 40% lower risk of colorectal cancer than people who did not. Other studies haven’t shown quite that much of an effect, but still show an approximately 20% reduction in risk. These positive studies suggest that Aspirin needs to be taken for at least 5 years to be effective, and a reduction in risk isn’t seen until about a decade after the start of treatment.
However, other large population studies did not show any reduced risk of colorectal cancer with frequent Aspirin use, though this may be due to a different dosing schedule. Nevertheless, many studies have found that people who took Aspirin frequently were less likely to develop colorectal cancer, and the overall body of evidence is strong.
Aspirin also seems to help prevent other cancers of the digestive tract, such as esophageal and stomach cancers, though not to the same degree as colorectal cancer.
Researchers have some hypotheses about why Aspirin appears to be most effective at preventing colorectal cancer. Inflammation increases the risk of colorectal cancer, and the COX2 pathway is especially active in this disease. Researchers have found that Aspirin is better at preventing colorectal tumours with high levels of COX2 than tumours with low COX2. They have also found that the Wnt pathway, which promotes cell growth, is also highly active in colorectal cancer. Since Aspirin blocks both of these pathways, it could have a greater impact in colorectal cancer than in cancers where these pathways are not as important in development.
Could Aspirin prevent other cancers?
Colorectal cancer isn’t the only type of cancer where inflammation and COX2 proteins are involved, and Aspirin may be able to prevent these other cancers as well.
In various studies, researchers have seen that frequent low-dose Aspirin use reduces overall cancer risk, not all of which can be attributed to colorectal cancer. In one large analysis of 51 different studies, researchers found that people who frequently took Aspirin had a 12% lower risk of cancer diagnosis and a 21% lower risk of cancer death. But other studies have been inconsistent – some show an effect, others don’t.
Still, researchers are interested in a few different cancers, including breast, liver, ovarian and prostate cancers, that Aspirin has the potential to prevent.
In recent years, researchers have become more interested in ovarian cancer, with several studies published in the last few years suggesting that regular Aspirin use modestly reduces ovarian cancer risk. But more research needs to be done to understand and untangle these results.
Dr Lheureux is one of the leaders of a CCS-funded clinical trial testing whether Aspirin may prevent ovarian cancer in women with BRCA1 or BRCA2 gene mutations, which put them at a much higher risk of developing the disease. The women in the study will have already decided to have preventive surgery to remove their ovaries and fallopian tubes, and the researchers will test whether a low or standard dose of Aspirin before the surgery reduces the incidence of pre- or early cancerous tissue damage in the ovaries and fallopian tubes. If they find that Aspirin helps to prevent or reduce these lesions, they will be able to study how it might work.
“This trial is the first of its kind,” says Dr Lheureux. “We’re comparing Aspirin use with a placebo, so we’ll really be able to see whether any difference is attributable to Aspirin, and we’ll have access to the tissue to see the biological mechanisms involved.” Dr Lheureux adds that ovarian cancer presents a unique opportunity for this type of trial, since some women are known to be at high risk and develop pre-cancerous damage before a tumour develops. They hope that their results might be applied more broadly to different types of cancers where a similar trial might not be possible.
Need to identify people who will benefit
While Aspirin is safe, especially when used infrequently, it does have side effects that need to be considered, particularly bleeding in the digestive tract which can sometimes be severe and impact quality of life.
As a result, researchers are actively trying to find ways to identify people who would benefit the most from Aspirin by looking for genetic or molecular signals that would identify them. For example, a signal that indicates that someone has high levels of COX2 activity might suggest that they have a higher-than-average risk of colorectal cancer and may benefit from preventive Aspirin treatment.
Reliable ways to identify people who would benefit most from Aspirin use would allow its use to be targeted, and people unlikely to benefit could be spared from the side effects. It’s the same personalized medicine approach that researchers are taking for a variety of other medications and treatments in cancer.
Many Canadians have Aspirin at home, whether they use it every day for heart health or infrequently to treat a headache. It’s easy to find at every pharmacy, and it’s cheap. If there’s a role for Aspirin in preventing cancer, the potential impact could be substantial.
A lot of research remains to be done before Aspirin is commonly prescribed as a cancer prevention drug. Researchers aim to get a better understanding of how Aspirin works to prevent cancer in order to understand which cancers might be sensitive to Aspirin’s activity and how it can be used more effectively.
It’s also important to understand how much Aspirin is needed and how often and for how long to take it to prevent cancer. To avoid unnecessary side effects, we need to find ways to identify people who will benefit the most from Aspirin.
With more research, we’ll get closer to answering these questions.
“Aspirin is such an old drug, but there’s all this new data about its effects that we can’t ignore anymore,” says Dr Lheureux.
Eileen Hoftyzer, BSc