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High hopes for aspirin

For years, aspirin has been a go-to pain relief drug, but could it do more for our health than we originally thought?

Aspirin does more than alleviate aches and pains. Low-dose aspirin reduces the risk of heart attacks and strokes in high-risk patients, such as those who live with angina and those who have recently had a stroke, heart attack or heart surgery.

Additionally, during the 1980s, reports began to emerge that aspirin may show anti-cancer actions.1 National Institute for Health and Care Excellence (NICE) now suggests that people with Lynch syndrome, a rare genetic disease that increases the risk of many types of cancer, should take aspirin to reduce their risk of colorectal (bowel) cancer (CRC).2

As we entered the 21st century, evidence of aspirin’s anti-cancer actions continued to grow. Recently, American researchers combined results from 17 studies and found that frequent aspirin use reduced the likelihood of developing ovarian cancer by 13 per cent.3 “The protective association was observed among women with individual and multiple ovarian cancer risk factors,” says research lead, Dr Britton Trabert, assistant professor, Department of Obstetrics and Gynaecology and the Huntsman Cancer Institute at the Universityof Utah.

What are aspirin’s anti-cancer actions?

Aspirin blocks production of prostanoids – the family of chemical signals produced by the body that includes prostaglandins. The body makes prostanoids from a fat called arachidonic acid in the membrane that surrounds each cell.

Prostanoids have diverse actions. Prostaglandin D2 (PGD2), for example, regulates sleep and contributes to allergies.4 Many cancers use prostanoids to signal between cells.5 So, several malignancies, including breast, ovarian, colorectal, thyroid and lung cancer, produce high levels of a prostaglandin-creating enzyme, called cyclooxygenase (COX).6 “We know that aspirin inhibits COX, which synthesises pro-inflammatory prostaglandins,” says Dr Trabert. “We don’t yet know if aspirin may reduce ovarian cancer risk through this COX pathway, through targets of aspirin other than COX or through immune-related mechanisms.”

In addition to reducing the inflammation that often accompanies cancer, aspirin hinders the formation and proliferation of malignant cells and reduces production of the new blood vessels that tumours need to grow and spread. Aspirin inhibits platelets, the cells that cause blood clots and which also help spread cancer around the body. It may also increase a cell’s ability to repair damaged DNA or destroy abnormal cells.5 “In ongoing work, we are examining these pathways in ovarian cancer tissue from aspirin users and non-users to better understand how aspirin may influence ovarian cancer development,” adds Dr Trabert.

Aspirin’s anti-cancer effects go beyond direct attacks on the tumour. People with cancer are, for example, about four times more likely than healthy people to develop a clot in a blood vessel. Parts of the clot can break off, causing a stroke or pulmonary embolism. This is one reason why cancer patients are especially likely to develop heart disease.5 Aspirin’s ability to cut the risk of heart attacks and stroke may partly account for the benefit in people with cancer.

While aspirin is one of the world’s most popular drugs, users still need to balance the benefits and risks. Aspirin inhibits platelets, protecting against blood clots. But it also means that people using aspirin can experience serious bleeding in their gastrointestinal tract or brain. Aspirin increases the risk of a gastrointestinal bleed by between 50 per cent and 90 per cent, and an intra-cerebral bleed by about 50 per cent.5

These bleeds are potentially serious, but pharmacy staff can help patients understand the risks. One to two people in every 10,000 taking aspirin experience a cerebral bleed a year. About one to five people aged 50-84 in every 1,000 years taking low-dose aspirin experience a gastrointestinal bleed,5 meaning that, on average, a person of this age would need to take aspirin for at least 200 years before such an experience.

“Frequent aspirin use reduced the likelihood of developing ovarian cancer by 13 per cent”

What are the anti-cancer benefits?

Estimates of aspirin’s anti-cancer effects vary widely and depend on the malignancy.5,7 One analysis reported that regularly taking aspirin reduces the risk of pancreatic (22 per cent), CRC (27 per cent), oesophageal (33-39 per cent), stomach (36 per cent) and liver and bile duct (38 per cent) cancers. Aspirin did not seem to protect against head and neck cancer.7

Dr Trabert’s analysis included 17 studies involving 8,326 women with ovarian cancer. She says that the new study is the largest assessing aspirin’s effect on ovarian cancer. Overall, taking aspirin at least six days a week or at least 28 days a month for six months or more reduced the likelihood of developing ovarian cancer by 13 per cent and high-grade serous (non-endometrioid) ovarian cancer by 14 per cent.3

Frequent aspirin use reduced ovarian cancer risk to a similar amount in women with factors that increase risk (obesity and family history of breast or ovarian cancer) or decrease it (parity, oral contraceptive use and tubal ligation).3 Reduced risk was similar in women with and without a family history of breast or ovarian cancer – 14 per cent and 12 per cent respectively. Among women with two or more risk factors, frequent aspirin use was associated with a 19 per cent reduction in ovarian cancer risk.3

“Our study found that the association between frequent aspirin use and ovarian cancer risk does not appear to be modified by other risk factors. Aspirin reduced the risk of all histologic subtypes of ovarian cancer, including the more fatal high-grade serous cancers,” Dr Trabert says. “Further research is needed to determine the overall net benefits and harms of frequent aspirin use, including among women at elevated risk of ovarian cancer.

“We hope that with ongoing work in this area, combined with work to pinpoint biological mechanisms, we will continue to make progress towards the development of preventive interventions for ovarian cancer.”

For those with Lynch syndrome, gene mutations mean that this repair mechanism does not work properly.8 This increases the risk of developing several malignancies, including cancers of the stomach, ovaries, pancreas, kidney and brain.8 About one in every 35 people with CRC cancer and one in every 56 women with endometrial cancer have Lynch syndrome, for example.9

One study followed people with Lynch syndrome for an average of 10 years. It found that taking aspirin for at least two years reduced CRC cancer risk by 44 per cent and all Lynch syndrome cancers by 37 per cent.1 As a result, NICE recommends that people with Lynch syndrome should take aspirin daily for more than two years to prevent CRC cancer.2

“I hope that NICE’s recommendation of aspirin in the UK for CRC cancer prevention for people with Lynch syndrome will provide important benefits for this patient group,” says Kelly Lloyd, behavioural scientist and postgraduate researcher at the Institute of Health Sciences, University of Leeds. “The important outstanding question is whether using aspirin for CRC prevention would be suitable and acceptable outside of a Lynch syndrome population.”

aspirin VS other NSAIDs

Cells produce two types of cyclooxygenase (COX). Most human tissues produce COX-1, a ‘housekeeping’ enzyme. In other words, COX-1 keeps important pathways, such as those protecting the gut and maintaining kidney function and platelet aggregation, working normally.4 Blocking COX-1 can, therefore, cause gastrointestinal problems, from indigestion to bleeding, and damage the kidneys.4 COX-2 is usually undetectable. But levels rise dramatically in response to inflammation and injury.4 Many cancers produce high levels of COX-2.6

Aspirin’s clinical and commercial success prompted pharmaceutical companies to look for new drugs. Ibuprofen, launched in 1969, was the first non-steroidal anti-inflammatory drug (NSAID) to reach the market. NSAIDs block COX-1 and COX-2 to varying amounts.4

Aspirin binds strongly (technically called non-competitively and irreversibly) to COX so that COX can no longer transform arachidonic acid into prostanoids. This means, for example, that aspirin prevents aggregation for the rest of the platelet’s life.4 NSAIDs bind less strongly (competitively and reversibly) than aspirin to COX.

Thus, aspirin and NSAIDs have different actions. For example, NSAIDs do not markedly block platelet aggravation.4 It is for this reason that doctors prescribe aspirin and not NSAIDs to prevent heart attacks and strokes. Indeed, conventional NSAIDs seem to increase the risk of heart attacks and other cardiovascular side effects and complications.4

What patients and professionals say

Kelly is part of the Aspirin for Cancer Prevention (AsCaP) project, which is funded by Cancer Research UK. It aims to determine who is likely to benefit most, who is at greater risk of bleeding side-effects, and the best dose and treatment duration for cancer prevention.

As part of this on-going research programme, the Leeds team reviewed studies exploring public, patient and healthcare provider attitudes and behaviours towards using aspirin to prevent cancer.

They found that most patients took aspirin as recommended by their doctors (adherence was at least 80 per cent) and were willing to use aspirin to reduce their cancer risk (43.6-76 per cent). Three-quarters of healthcare providers (72-76 per cent) felt that aspirin was suitable for preventing cancer.10 “Most studies focused on patient and healthcare providers’ behaviour about using aspirin to reduce the risk of gastrointestinal cancers. Attitudes towards using aspirin for preventing non-gastrointestinal cancers are unknown and should be explored further,” Kelly adds.

The Leeds group also interviewed people with Lynch syndrome and healthcare professionals, including specialists, GPs and community pharmacists, about using aspirin to prevent CRC.11 “Healthcare professionals across the different professions agreed that GPs should be responsible for prescribing aspirin for cancer prevention,” Kelly says. “We are currently conducting a national survey of UK GPs to further identify the barriers to prescribing aspirin for a patient with Lynch syndrome.”

So, using aspirin to prevent cancer could become a community healthcare responsibility. And the publicity surrounding these exciting results could mean that people ask the pharmacy team about using aspirin to prevent cancer.

“I would recommend that anyone wanting to start any new, regular medication should speak to their GP,” Kelly says. “GPs can check the patient’s medical records to find out if aspirin would be suitable. While there are potential benefits of aspirin for CRC cancer reduction, patients can experience side-effects with regular use.”

Dr Trabert agrees, adding: “The community pharmacy team should recommend that individuals enquiring about aspirin for cancer chemoprevention should consult their healthcare providers before beginning any new medication to most appropriately balance any potential risks with the potential benefits”.

So, while increasing research suggests that aspirin protects against several cancers, we must not lose sight of the risks and the gaps in evidence. Further studies are needed to fully understand the side-effects, benefits, how best to deliver the anti-cancer promise and how aspirin protects against malignancy. We still have much to learn about this common drug.

References

1. Lancet 2020;395:1855-1863

2. Available at: nice.org.uk/guidance/ng151/resources/user-guide-and-data-sources-pdf-8834927870

3. Journal of Clinical Oncology 0:JCO.21.01900

4. Pharmaceuticals 2010;3:2146-2162

5. Open Biology 2022;12:220124

6. Hospital Pharmacy 2020;55:168-180

7. Annals of Oncology 2020;31:558-568

8. Nature Reviews Cancer 2015;15:181-194

9. Familial Cancer 2019;18:211-219

10. Preventive Medicine 2022;154:106872

11. Hereditary Cancer in Clinical Practice 2022;20:30

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