Role of Aspirin in Cancer Prevention

Abstract Since its first synthesis in 1897, several medicinal roles and mechanisms of action of aspirin have become appar- ent; the latest among these being its role in cancer prevention and treatment. A large body of evidence supports aspirin’s effect in reducing cancer incidence and cancer mortality, but duration of use needs to be at least 5 years. The beneficial effects are particularly large for colorectal, oesophageal and gastric cancers, with apparently smaller reductions for breast, prostate and lung cancer. The major harm is gastrointestinal bleeding, but serious sequelae are minimal at ages <70 years. It is very likely that use of prophylactic aspirin in the general population aged 50–70+ years will result in net overall benefit. Outstanding issues are: whether standard dose (~300 mg/day) can lead to greater net benefits than low dose (75–100 mg/day), the optimum duration of use, and appropriate ages for use in average-risk individuals. Keywords : Aspirin . Prevention . Cancer . Cardiovascular disease . Myocardial infarction . Stroke . Peptic ulcer . Gastrointestinal bleeding . Benefit-harm . Helicobacter pylori Introduction Barks of willow tree were used for medicinal purposes for thousands of years before medicinal acetylsalicylic acid (ASA) was synthesised and labelled as Aspirin by Bayer AG in 1897 [1, 2]. While aspirin was extensively used for its analgesic, antipyretic and anti-inflammatory properties, the exact mechanism of action was elucidated more than 70 years later by John Vane [3, 4]. John Vane was jointly awarded the Nobel Prize in 1982 for his work on aspirin. Discovery of anti-platelet effects led to increasing use of aspirin as an anti-thrombotic agent in prevention of cardiovascular diseases from the 1980s [5]. Adding another dimension to its medicinal properties, cancer prevention and anti-cancer effects of aspirin have only recently become apparent, almost one hundred years after its launch [6]. We review the role of aspirin in cancer prevention in terms of mechanisms of action, general and site-specific effects on cancer incidence, potential harms of aspirin use and overall balance of benefits and harms. The role of aspirin in preventing deaths from cancer is also briefly discussed. In addition, we discuss methods for mitigation of harms of aspirin use and identify important research questions. Mechanisms of Action Aspirin has several different pharmacological effects. These range from anti-platelet action at low doses to anti-inflammatory action at high doses. Apart from these effects, several new mechanisms of action are still being discovered. Anti-Platelet Action Arachidonic acid is metabolised by Prostaglandin H Synthase (PGHS) or Cyclooxygenase (COX) to synthesise prostanoids.Prostanoids are tissue-specific lipid compounds involved in signalling, and these include Prostaglandin (PG) D2, E2, F2α, Thromboxane A2 (TXA2) and prostacyclin (PGI2). Two major isoforms of PGHS have been identified: COX-1 and COX-2. COX-1 is constitutively expressed in most tissues, while COX-2 is expressed in several tissues, such as vascular endo- thelium, brain and kidney. COX-1 is the only isoform present in mature platelets and is involved in synthesis of TXA2, which has a central role in platelet aggregation. COX-2 in the vascular endothelium, on the other hand, is involved in PGI2 synthesis [7]. Aspirin irreversibly inactivates both COX-1 and COX-2. The level of inhibition of activity by aspirin is dependent on drug availability in the target tissue and recovery of COX activity through de novo enzyme synthesis [8]. Mature platelets lack nuclei and therefore cannot synthesise COX-1 enzyme [8]. Platelets also pass through portal circulation where aspirin concentration is much higher than that in systemic circulation [9]. Therefore, cardio-protective anti-platelet effects of aspirin appear at doses as low as 30 mg/day, where it has very transient and minimal effects on non-platelet targets. Anti-Inflammatory Action Aspirin is metabolised rapidly during its first pass through liver and by plasma esterases, resulting in a very short half-life of 15–20 min [9]. Therefore, in order to maintain a sustained inhibition of COX-1 and COX-2 enzymes in nucleated cells, frequent dosing (3–4 times per day) of large doses (around 2, 000 mg/day) is needed. Anti-inflammatory action of aspirin is thought to be mediated through several mechanisms, includ- ing sustained inhibition of prostanoid synthesis, inhibition of protein kinase IkBkinase β (IKKβ) in the NF-kB pathway [10], and aspirin-triggered 15-epi-lipoxins [11]. Analgesic Action Analgesic effects of aspirin are thought to be mediated through numerous mechanisms [12]. There appears to be a dose–response relationship between aspirin dose and its anal- gesic effects [13]. Anti-Cancer Action Evidence from randomised controlled trials (RCTs) [14••, 15••, 16••] and observational studies [17–20] shows that as- pirin’s impact on mortality exceeds its effect on incidence (see below). This means that aspirin not only has chemopre- ventive action, but also prevents cancer progression and me- tastasis. The mechanisms of action at play in these anti-cancer effects are, however, not clear yet. Various hypotheses have been proposed; the most accepted among these proposes that anti-cancer action is mediated through COX-2 inhibition [21, 22]. Although supported by epidemiological data [23], this hypothesis cannot explain clear anti-cancer effects seen at low doses of aspirin [14••, 15••, 24••]. Several other mechanisms, like inhibition of NF-kB [23], induction of polyamine catabo- lism [25], inhibition of mTOR signalling [26] and activation of AMP-activated protein kinase [26, 27•], effects on PI3-kinase pathway [28•] or its crosstalk with COX-2 [29, 30], and induction of apoptosis through other pathways [31, 32], have been proposed. However, all these mechanisms require higher drug concentrations than those achieved by low-dose aspirin (≤ 100 mg/day) [33]. Anti-platelet action of aspirin may reduce direct interaction of platelets with cancer cells and thus prevent metastasis [34, 35]. Similarly, it may prevent platelet-mediated COX-2 induction and downstream signalling at the site of intestinal mucosal injury and thereby increase apoptosis, re- duce proliferation and angiogenesis, as proposed by Thun and colleagues [36]. These two mechanisms based on anti-platelet action of aspirin, the former resulting in prevention of cancer progression and the latter resulting in prevention of carcino- genesis, are compatible with the anti-cancer effects seen at low doses of aspirin. The relationship between aspirin dose and the magnitude of anti-cancer effect is unclear. While indirect com- parisons of RCTs show no clear indication of greater reduction in cancers [15••] or adenomas [37] with increasing dose, ob- servational studies [38, 39] have shown benefit above a 300 mg dose, and reductions in advanced adenomas were also greater with the higher dose [40]. RCT in high-risk individuals has also shown benefit of large magnitude with higher doses of 600 mg [41•]. It is plausible that mechanisms other than anti-platelet action are involved in aspirin’s anti-cancer effect when doses higher than 100 mg/ day are used. Overall Effects on Cancer The beneficial effect of aspirin in preventing colorectal cancer (CRC) and deaths due to CRC is now beyond question [14••, 15••, 24••, 38, 41•, 42••, 43••, 44••, 45, 46, 47•, 48, 49].Beneficial effects on two other gastrointestinal (GI) cancers, viz. oesophageal and gastric cancers [24••, 42••, 43••, 47•, 48, 49] and on lung [24••, 42••, 43••, 46], breast [24••, 42••, 43••, 46, 47•, 48, 49] and prostate cancers [24••, 42••, 43••, 47•, 50] have also emerged over the past several years [14••, 24••, 42••, 43••]. There appears to be little or no effect on other major cancer sites including pancreatic, endometrial, and haematopoietic tumours; even then, overall cancer incidence and mortality is reduced [14••, 24••, 44••, 47•]. Thus, aspirin reduces incidence of and/or mortality from several cancers and cardiovascular disease. Use of prophylactic aspirin in the general population for prevention of major diseases and relat- ed deaths is likely to be beneficial, when its benefits on both overall cancer and cardiovascular disease are considered to- gether, rather than just its effects on CRC [51] or cardiovas- cular disease [52] in isolation, as was done by the US Preventive Services Task Force (USPSTF) in the past [51, 52]. Cancer Incidence Analyses of data from RCTs showed that aspirin use at doses between 75 and 300 mg/day reduced overall cancer incidence by 12 % [14••]. The magnitude of benefit was larger (19 % reduction) when scheduled treatment duration was 5 years or more [14••]. The beneficial effects only became apparent after 3 years, with a 24 % reduction observed after 3 years of follow-up. Overall relative reductions in cancer incidence were similar in men and women [14••]. Cancer Mortality The beneficial effects of aspirin on overall cancer mortality are of a larger magnitude than effects on cancer incidence. Analyses of data from RCTs showed that reductions in cancer deaths became apparent after 5 years and the beneficial effects lasted for over 20 years in the trials with long follow-up [24••]. Overall, aspirin reduced cancer deaths by 20 %; the magnitude of benefit was larger at 34 % reduction seen after 5 years of follow-up. The magnitude of benefit was also larger with longer duration of aspirin use; there was a 31 % reduction in mortality with scheduled treatment duration of 7.5 years or more [24••]. Overall relative reductions were similar in men and women [24••]. Data from RCTs show that aspirin may have larger effect on adenocarcinomas than non-adenocarcinoma solid tumours [14••, 24••]. Evidence from epidemiological stud- ies shows a reduction in recurrence in both breast and colorectal cancers; trials are underway to examine aspirin as an adjuvant treatment (see below). Site-Specific Effects Aspirin use results in reduction in the incidence and mortality of range of cancers in the gastro-intestinal tract and cancers of breast, prostate and lung. The evidence is the strongest for reduction in CRC, followed by reductions in oesophageal and gastric cancers. The effects on breast, prostate and lung can- cers are smaller. Colorectal Cancer A very large body of evidence supports a reduction in colo- rectal cancer incidence and mortality as a result of regular aspirin use [14••, 15••, 24••, 38, 41•, 42••, 43••, 44••, 45, 46, 47•, 48, 49]. Long-term follow-up of three trials of low-dose aspirin (75–300 mg/day) use found a 25 % reduction in the incidence of colorectal cancer [15••]. The effects were not immediately apparent, and the reduction in incidence was 30 % when the scheduled treatment duration was 2.5 years or more, and 38 % when treatment duration was 5 years or more. Two trials, the Women’s Health Study (WHS) [44••] and the Physicians’ Health Study (PHS) [53] investigated alternate day use (WHS 100 mg alternate day, PHS 325 mg alternate day). Of these, WHS has now reported a 42 % post- treatment reduction (RR 0.58; 95 % CI 0.42–0.80) and an overall reduction of 20 % [44••]. PHS, however, has not shown any reduction in colorectal cancer [53, 54]. The ob- served benefit in WHS is noteworthy, because the majority of women enrolled in the trial were younger than 55 years. Observational studies, collectively based on a much larger number of cases, have similarly reported a 27 % reduction in CRC incidence; a 38 % reduction was seen in case-control studies and a 19 % reduction in cohort studies [42••, 43••].Larger benefits have been seen in individuals at high-risk of colorectal cancer [41•]. CAPP2, a randomised trial in Lynch syndrome carriers, reported a 63 % reduction in CRC incidence among those completing 2 years of 600 mg daily aspirin [41•]. The effects of aspirin have also been seen in prevention of adenoma, a pre-malignant lesion of CRC. A meta-analysis of four RCTs reported a 28 % reduction in advanced adenomas within a short 33-month follow-up [40]. The effect size of aspirin in preventing CRC mortality is greater than that for CRC incidence, with a 40 % overall reduction observed in meta-analyses of a large number of trials [15••, 24••]. The results of observational studies are also consistent with this observation [46, 48, 49]. Oesophageal Cancer Case-control studies have reported a 43 % reduction in the incidence of oesophageal cancer and cohort studies have reported a 27 % reduction [42••, 43••]. The observed reduc- tions in incidence are similar for squamous cell oesophageal cancers (39 %) and adenocarcinomas (36 %), including can- cers of gastric cardia [43••]. A larger effect on oesophageal cancer mortality reduction has been observed; a 44 % reduction in cohort studies [48, 49] and a 58 % reduction after 5 years of follow-up in randomised trials [24••]. RCTs, however, have suggested that the effect of aspirin is primarily on adenocarcinomas [16••, 24••]. Gastric Cancer Case-control studies have reported a 39 % reduction in gastric cancer incidence and cohort studies have reported a 25 % reduction in the incidence [42••, 43••]. While data on aspirin’s effect on gastric cancer incidence are not available from RCTs, an overall 31 % reduction (P =0.11) in deaths has been re- ported. The effect appeared mostly after 10 years of use, when a 58 % reduction (P =0.007) was observed [24••]. Cohort studies have also reported a 41 % reduction in gastric cancer mortality [48, 49]. Breast Cancer A much smaller effect is seen on breast cancer. Case-control studies reported an 18 % reduction in breast cancer incidence,while the reduction observed in cohort studies was 8 % [42••, 43••]. However, no effect on breast cancer incidence was seen in the WHS [55]; results remain unchanged after a longer 17.5-year follow-up [44••]. A meta-analysis of obser- vational studies and RCT found a 14 % reduction [56]. A similar small (5 % in case-control study [46] and 14 % in cohort studies), nonsignificant reduction in breast cancer mor- tality has also been observed [48, 49]. A nonsignificant in- crease in breast cancer mortality was seen in an overview of RCTs [42••]; however, this may be unreliable, as the number of events was very small (n =23). Prostate Cancer Similar to breast cancer, the effect on prostate cancer is also small. Case-control studies reported a 14 % reduction in prostate cancer incidence. While the reduction observed in cohort studies was 9 % [42••, 43••], the effect was predomi- nantly limited to high grade tumours. The effects on mortality are slightly larger; a nonsignificant 19 % reduction in mortal- ity was observed in the RCTs [24••], and a nonsignificant 16 % reduction in lethal prostate cancers (metastasis or death) was observed in the Health Professionals Follow-up Study (HPFS) [50]. Lung Cancer The evidence for aspirin’s effect on lung cancer is more variable, but generally favourable. Case-control studies re- ported a 19 % reduction in the incidence of lung cancer, but no reduction was observed in cohort studies [42••, 43••]. The reduction in lung cancer mortality in RCTs was 29 %, while it was 12 % (nonsignificant) in case-control studies. Two [47•, 49] of three cohort studies did not observe any reduction, while the third observed a 19 % reduction [48]. Other Cancers Among other cancers, there may be a small effect on pan- creatic cancer, but the evidence is variable and less clear. Cohort studies reported a nonsignificant 4 % reduction in incidence, while the reduction observed in case-control studies was 7 % (nonsignificant) [42••, 43••]. Although a nonsignificant 19 % reduction in mortality in the RCTs was seen [24••], the reduction in cohort studies was only 3 % (nonsignificant) [48, 57]. A study of patients with mismatch repair defects [41•] reported a large reduction in endometrial cancer, but the effect in average-risk women is unknown. A significant beneficial effect of aspirin has not been seen for any other cancer site. Aspirin as an Adjuvant Treatment Detailed discussion of potential role of aspirin in cancer treatment [58] is outside the scope of this paper; however, a brief note is necessary, as it has a role in prevention of cancer deaths and it may help us understand some of the multiple mechanisms of aspirin action. Observational studies in breast cancer [19], and colorectal cancer [17, 20, 23] have reported that taking or continuing aspirin after the diagnosis of cancer results in reduced metastasis and improved survival. Results of translational work from the Nurses’ Health Study (NHS) and the HPFS show that this benefit is pronounced and pos- sibly limited to cancers with PIK3CA mutation [28•]. Several trials are ongoing or have been planned to investigate adjuvant role of aspirin in treatment of cancers; notable examples are ASCOLT trial [59] in CRC, Big A trial [60] in non-small cell lung cancer, and ADD-Aspirin trial [58] in a range of cancers including colorectal, gastro-oesophageal, breast and prostate cancer. Harms The most important harms of aspirin are excess bleeding either intracranial (haemorrhagic stroke) or gastrointestinal and peptic ulcers. Any increase in the risk of haemorrhagic stroke is compensated by a larger reduction in ischaemic strokes. Hypertension is the major risk factor for haemorrhagic stroke and these tend to occur mainly in individuals with inadequately treated hypertension [61]. Ensuring adequate blood pressure control before starting aspirin and during aspirin use can minimise this harm. Several meta-analyses of RCTs and observational studies [62–65, 66••, 67] have estimated that both low-dose and standard dose aspirin result in a 1.5-fold to 1.7-fold increase in the risk of GI bleeding/complications. However, majority of these episodes are minor events and are considerably less severe as compared to the events prevented by aspirin, viz. cancer, myocardial infarction (MI) and strokes. Therefore, only major bleeding episodes should be considered in any analysis of benefit and harms; data from the Antithrombotic Trialists’ Collaboration (ATT) suggest that aspirin increases such major bleeding events by 0.3 per 1,000 per year [62]. Case-Fatality rates associated with GI bleeding or peptic ulcer perforations are around 5 % in those younger than 65 years [68–74]; fatality rises sharply beyond 70 years [7]. Pre-existing GI pathology or the presence of H. pylori infection are also major risk factors [75, 76]. A significant proportion of older individuals (50 years or more) are infected with H. pylori , even in the developed world [77, 78]. H. pylori eradication therapy is effective in preventing GI complications [79, 80]. Screening and eradication of H. pylori before starting aspirin may minimise its harms and also improve cost- effectiveness of such strategy to prevent gastric cancer [81, 82]. Diabetes, smoking, and raised cholesterol are other risk factors for GI bleeding [62]. It is also important to note that the excess risk of bleeding is high during the first few months of aspirin use, and then tends to approach normal risk [15••, 83]. Careful assessment of risk factors and monitoring for early bleeding episodes and their timely treatment [84] may considerably mitigate aspirin-related harms. Overall Balance of Benefits and Harms For every 1,000 men aged between 50 and 84 years in the UK, 14 are diagnosed with cancer and seven die due to cancer every year. The corresponding figures for women are 11 diagnoses and five deaths [85]. GI cancers alone account for 20 % of cancers (and cancer deaths) in men and 15 % of cancers (and cancer deaths) in women; whereas six cancers on which aspirin has a preventive effect account for 60 % of cancer diagnoses and 55 % of cancer deaths in men and women alike. Therefore, even if benefits of aspirin on cardio- vascular diseases are ignored, aspirin use can result in preven- tion of substantial number of cancers and cancer deaths. Aspirin-related major harms and fatalities, on the other hand, are relatively infrequent and can be minimised further. Therefore, aspirin appears to be a very effective cancer pre- vention agent that may also have a role in cancer treatment. Research Priorities It is clear that aspirin needs to be used for a minimum of 5 years for preventive benefits to accrue, which then appear to continue for several years after the drug is stopped. The most appropriate duration of drug use is, however, not clear. In order to minimise harms, it seems prudent to avoid using aspirin after 70 years of age. The results of ASPREE trial [86, 87] will shed light on the relative merits of aspirin use in elderly individuals age 65 years or more. While daily low- dose aspirin (≤ 100 mg/day) is an effective cancer-preventive agent, evidence from adenoma prevention studies [40] and studies in high-risk individuals [41•] points to a possibility of larger effect sizes with standard (300–325 mg/day) or higher doses (e.g. > 600 mg/day). Therefore, trials are needed to identify the dose of aspirin at which net benefits (benefits minus harms) are greatest and adherence to drug use is max- imum. The role of H. pylori screening and eradication before starting aspirin to minimise GI harms merits evaluation in a clinical trial; HEAT trial ( Identifier: NCT01506986) is addressing role of this strategy in current aspirin users. Further research is needed to identify markers of high bleeding risk; data and samples from participants of ongoing adjuvant aspirin trials may prove useful in this work.


Evidence from a very large number of studies points to a key role of aspirin in cancer prevention. Aspirin use results in a substantial reduction in cancer incidence and a larger reduction in cancer mortality. The beneficial effects of aspirin appear to be mainly through its effects on colorectal, oesophageal, and gastric can- cers, with small effects on breast, prostate and lung cancers. Although concerns regarding aspirin-related bleeding exist, the majority of such events are minor. The potential benefits of aspirin in terms of cancers and cancer deaths prevented are likely to be much larger than bleeding events of comparable severity. For a drug synthesised in the 19th century, aspirin may very well emerge as the cancer preventive agent of 21st century.

Compliance with Ethics Guidelines

Conflict of Interest Mangesh A. Thorat declares no conflict of interest.
Jack Cuzick is a member of Bayer advisory board.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as:
• Of importance
•• Of major importance

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