Preventive effect of aspirin on cancer development

Introduction

Despite their early stage of development, some important discoveries have been made for prevention of cancer. Of these, low-dose aspirin stands out as having the largest potential impact on the population at large. If aspirin has had earlier recommendations from professional bodies against using it in the general population based on some risks of gastrointestinal and cerebral bleeding, these recommendations now need to be updated in view of the much larger benefits seen for cancer prevention than for cardiovascular disease¹.

1. Why a specific focus on aspirin among the means to prevent some cancer incidence?

Among the factors that contribute to prevent cancer incidence, the World Cancer Report 2020 (WCR 2020) highlights specifically a series of observations that regular use of aspirin and other non-steroidal anti-inflammatory drugs has a major effect on the reduction of various tumour types².

There is indeed now, says the WRC 2020, overwhelming evidence that aspirin has a major effect in particular on three common gastrointestinal cancer types – colorectal, stomach and oesophageal cancer and potentially provides small reductions in three other major cancer types: lung, breast, and prostate cancer³ (see more details in Question 2 below).

Globally, long-term use of about 10 years of aspirin was estimated to reduce overall cancer incidence by about 9% in men and 7% in women, and overall cancer mortality by 13% in men and 9% in women.

Further, the additional preventive benefits of use of aspirin associated with high-dose proton-pump inhibitors, and with statins for other cancer types and for cardiovascular disease, makes that these drugs may be good candidates for chemoprevention in groups at high risk⁴.

However, questions still remain about aspirin’s optimal dose, duration, efficacy, safety, and impact on different sub-types of specific cancers, and more research is needed.

2. What are the main types of cancer prevented by a regular use of aspirin?

For colorectal cancer, regular long-term use of aspirin would contribute to reducing incidence and mortality by about one third⁵. In average-risk individuals, aspirin use (daily or alternating dose, ≥ 75 mg) does indeed appear to reduce the incidence of this cancer, with a small reduction in all-cause mortality within 10 years of initiating use.

For oesophageal cancer and stomach cancer, beneficial effects of a similar size have also been observed.

For pancreatic cancer, a review of epidemiological data performed by a working group in 2015 suggested that aspirin and statins may provide some protective effect, whereas non-aspirin non-steroidal anti-inflammatory drugs do not appear to have such an effect on pancreatic cancer risk .

For endometrial cancer, regular use of aspirin has also been associated with a reduced risk of among obese women; little effect was seen for normal-weight women. It is less clear whether any association is restricted to standard-dose aspirin or whether use of low-dose formulations may also confer a benefit.

For prostate cancer, widespread use of low-dose aspirin for 10 years between ages 50 and 65 years could have a major impact on cancer incidence and mortality.

For lung cancer and breast cancer, smaller and less convincing reductions of 5–15% have recently also been found.

For ovarian cancer, emerging evidence suggests that very frequent use of aspirin (≥ 6 days per week) would be associated with modest reductions in risk in both pooled case–control and prospective studies. However, the effects of long-term aspirin use (i.e.≥ 10 years) and use of other analgesics (e.g. acetaminophen) are required to weigh potential risks and benefits and to delineate target populations.

The effect is 30% for colorectal, stomach and oesophageal cancer and up to 50%, for oesophageal squamous cell carcinoma and oesophageal adenocarcinoma. This with smaller and less certain reductions for breast, prostate, and lung cancer (5–15%).

On other major cancer sites, there appears to be little or no effect⁷.

Globally, the relative impact of aspirin use appears to be similar between the sexes, but the overall effects are greater for men because these cancer types are relatively more common in men. The impact on cancer mortality appears to be larger than that for incidence, suggesting an anti-metastatic effect as well as a separate effect on incidence⁸.

The mechanisms that mediate these effects are currently not established, and trials are under way to examine aspirin as an adjuvant treatment for individuals with colorectal, stomach, oesophageal, breast, and prostate cancer.

3. What is the balance between the preventive effect and the harmful effects of aspirin?

Aspirin has had earlier recommendations from professional bodies against using it in the general population. However, those recommendations were based on comparing cardiovascular benefits with risks of bleeding, Gastrointestinal and cerebral bleeding are indeed the most important harms associated with aspirin use, and their risk and fatality rate increase with age.

As stated in the report, these recommendations now need to be updated in view of the much larger benefits seen for cancer prevention than for cardiovascular disease⁹. These benefits have only been reported more recently, largely because they were not apparent until after 3–5 years of aspirin use.

When the reduction in risk of cancer and cardiovascular disease and the risk of excess bleeding are all considered in the general population aged 50–65 years, use of prophylactic aspirin is likely to be beneficial with a benefit–risk ratio highly favourable for the general population, both men and women of at least 7:1 for deaths. The United States Preventive Services Task Force currently supports the use of aspirin for those at increased risk of cardiovascular disease or colorectal cancer.

4. After how long the use of aspirin is a preventive effect on cancer incidence observed?

The effects of daily use of aspirin on cancer incidence are not apparent until at least 3 years after the start of use, with a relative reduction in incidence after that time for all cancers of about 24%. Some benefits appear to be sustained for several years after treatment cessation in long-term users.

For sporadic colorectal cancer however, observational data show that aspirin use lowers risk of only after about a decade from onset of use¹⁰.

5. How aspirin would act to prevent some types of cancer?

As mentioned, the impact of aspirin use on cancer mortality appears to be larger than that for incidence, suggesting an anti-metastatic effect as well as a separate effect on incidence¹¹. Although the mechanisms that mediate these effects are currently not established, the role of inflammation as a crucial mediator of colorectal cancer is well established.

Gene variants that interact with environmental agents have been identified as associated with the use of aspirin and/or non-steroidal anti-inflammatory drugs (NSAIDs). The use of non-steroidal anti-inflammatory drugs such as aspirin but also ibuprofen has indeed been found to significantly reduce the risk of colorectal cancer in some patient populations. Prostaglandins are also particularly significant in view of the protective effect of aspirin on several human tumour types.

Relative reductions in cancer incidence appear to be similar in men and women although data are less extensive for women and men have a higher incidence of the cancer types for which the incidence is reduced by aspirin use, leading to greater absolute reductions.

Trials are under way to examine aspirin as an adjuvant treatment for individuals with colorectal, stomach, oesophageal, breast, and prostate cancer¹².

6. Are these cancer prevention effects of aspirin observed for other anti-inflammatory substances?

Data on other non-steroidal anti-inflammatory drugs, such as ibuprofen, sulindac, or celecoxib, are less extensive but there are no trials with long-term follow-up, except for studies of colorectal adenomas but observational studies have found similar overall effects on cancer incidence.

References
Reference document : The World Cancer Report 2020 : Cancer Research for Cancer Prevention  1 See WRC Report 2020, p. 528 2 See summary & Conclusions p. 527 3 See summary & table p. 523 4 See p. 330 5 See p. 27 6 See p. 372 7 See p. 415 & 418 8 See p. 523 9 See p. 528 10 See p. 94 11 See p. 523 12 See p. 523