Mode of action and dosage of aspirin

A Chan

Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

Understanding of how aspirin reduces the risk of cancer is incomplete. Possible mechanisms include inhibition of nuclear factor-κB, induction of p38 kinase and catabolism of polyamines but most research has focused on the inhibition of COX-2 and this has the strongest evidence base. COX-2 is over-expressed by some cancers, including colorectal cancer (Figure 1) [1]. These mechanisms are not exclusive and may be synergistic.

Figure 1.
Expression of COX-2 by normal gastrointestinal cells, adenoma and colon cancer (adapted from Eberhart et al. [1]).

This hypothesis was tested by analysis of molecular markers in two large cohort studies providing long-term data on aspirin use: the Nurses’ Health Study (n = 121,700), which began in 1976, and the Health Professionals Follow-up Study (n = 51,539), which began in 1986. Both studies found that aspirin was associated with an ~30% reduced risk of colon cancer, which is consistent with the evidence of randomised trials.

Tumour specimens were collected from both cohorts from the late 1990s, representing 662 cases (58%) in the Nurses’ Health Study and 648 (76%) in the Health Professionals Follow-Up Study. Analysis was limited to 368 and 268 cases respectively for which samples of sufficient tumour tissue and adjacent normal tissue allowed comparison using positive and negative controls. Figure 2 illustrates how immunostaining identifies tumours that are negative (A and B) and positive (C and D) for COX-2.

Figure 2.
Immunostaining for COX-2 (dark brown areas) in colorectal tumours. Samples A and B are negative for COX-2; samples C and D are positive for COX-2.

Overall, these two studies showed that regular aspirin use was associated with a lower risk of colorectal cancer (relative risk, RR, 0.73; 95% CI 0.62–0.86). However, this benefit was largely confined to individuals whose tumour stained positive for COX-2 (RR 0.64, 95% CI 0.52–0.78) and not those with COX-2 negative tumours (RR 0.96, 95% CI 0.73–1.26) [2]. This finding suggests that COX-2 positive status may have potential as a marker of response to aspirin.

Patients diagnosed with colorectal cancer are a high-risk group for whom aspirin therapy may be useful. In these studies, 1,279 participants (mean age 65) were diagnosed with stage I, II or III colorectal cancer and underwent curative resection. After a median follow-up of 11.8 years there were 480 total deaths and 222 deaths due to colorectal cancer. Aspirin use before diagnosis was not associated with colorectal cancer-specific survival (HR 1.05, 95% CI 0.80–1.37) or overall survival (HR 0.93, 95% CI 0.77–1.11) [3]. This is not surprising because colon cancer was developing in these individuals despite their use of aspirin. By contrast, aspirin use after diagnosis was associated with a significant reduction in colorectal cancer-related death and overall mortality (Figure 3). This effect was more marked among participants who had not used aspirin before diagnosis (multivariate relative risk 0.53, 95% CI 0.33–0.86) compared with those who had (multivariate relative risk 0.89, 95% CI 0.59–1.35); and in those with COX-2 positive tumours (multivariate relative risk 0.39, 95% CI 0.20–0.76) compared with COX-2 negative tumours (multivariate relative risk 1.22, 95% CI 0.36–4.18). There was a strong dose-response relationship between aspirin (represented by number of 325 mg tablets taken per week) and the relative risk of adenoma (Figure 4) [4] and colorectal cancer in men and women (Figures 5 and 6) [5,6]. Secondary surveys demonstrated that people reporting consumption of 7–14 tablets per week were actually taking aspirin daily. These figures challenge the belief that low-dose aspirin provides sufficient protection against colorectal cancer and further studies are needed to clarify the minimum effective dose. This is supported by the Cancer Prevention Study II, which found greater risk reductions for colorectal, prostate and breast cancers with high versus low doses and longer use (<5 versus >5 years) of aspirin [7].

Figure 3.
Aspirin use after diagnosis and colorectal cancer-related and overall survival [3] (A) Colorectal cancer-related mortality (log rank P = 0.02). (B) Overall mortality (log rank P = 0.03).

Figure 4.
Dose of aspirin and risk of adenoma [4].

Figure 5.
Dose of aspirin and risk of colorectal cancer in women [6].

Figure 6.
Dose of aspirin and risk of colorectal cancer in men.

In these cohorts with ~20 years of follow-up, 11 deaths occurred due to gastrointestinal bleeding. The relative risk of major gastrointestinal bleeding (requiring a blood transfusion or hospitalisation for bleeding) was lower than has been reported in randomised trials of aspirin for secondary prevention of cardiovascular events (Figure 7). This may have been because these cohorts had lower morbidity than trial participants but the risk of major bleeding is attenuated with increasing duration of use and aspirin consumption by these cohorts was longer than in clinical trials, due either to adaptation of the gastrointestinal mucosa or treatment discontinuation when adverse events occur. These data also suggest that there is little difference in bleeding risk between low and higher doses of aspirin.

Figure 7.
Relative risk of major gastrointestinal bleeding and dose of aspirin in the Nurses’ Health Study and Health Professionals Follow-up Study cohorts.

References

1. Eberhart CE, Coffey RJ, Radhika A et al (1994) Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas Gastroenterology 107 1183–8 PMID: 7926468

2. Chan AT, Ogino S, Fuchs CS (2007) Aspirin and the risk of colorectal cancer in relation to the expression of COX-2 N Engl J Med 356 2131–42 PMID: 17522398 DOI: 10.1056/NEJMoa067208

3. Chan AT, Ogino S, Fuchs CS (2009) Aspirin use and survival after diagnosis of colorectal cancer JAMA 302 649–58 PMID: 19671906 DOI: 10.1001/jama.2009.1112

4. Chan AT, Giovannucci EL, Schernhammer ES et al (2004) A prospective study of aspirin use and the risk for colorectal adenoma Ann Intern Med 140 157–66 PMID: 14757613

5. Chan AT, Giovannucci EL, Meyerhardt JA et al (2005) Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer JAMA 294 914–23 PMID: 16118381 DOI: 10.1001/jama.294.8.914

6. Chan AT, Giovannucci EL, Meyerhardt JA et al (2008) Aspirin dose and duration of use and risk of colorectal cancer in men Gastroenterology 134 21–8 PMID: 18005960 DOI: 10.1053/j.gastro.2007.09.035

7. Jacobs EJ, Thun MJ, Bain EB et al (2007) A large cohort study of long-term daily use of adult-strength aspirin and cancer incidence J Natl Cancer Inst 99 608–15 PMID: 17440162 DOI: 10.1093/jnci/djk132

Aspirin, salicylates and cancer: Salicylate salts in plants

L Mur

Deputy Leader of Bio-renewables and Environmental Change Research Division, Aberystwyth University, Aberystwyth, UK

Plant sources of salicylates have been used for medicinal applications for thousands of years. The Egyptians used extracts of myrtle or willow leaves for joint pain and Hippocrates recommended chewing willow leaves to provide analgesia during childbirth. Edward Stone is credited with identifying salicylin as the active component of willow bark in the 18th century; willow bark is still used as a herbal medicine today. The concentration of salicylin is very high in willow, where it is presumed to act as an antifeedant [1]. It is present at lesser levels in every plant species and is readily metabolised to the more active forms salicylic acid and methyl salicylate; acetylated salicylate (aspirin) is not present in plants. Although plants do not have cyclo-oxygenases it is likely that the multiple roles played by salicylates may shed light on possible mechanisms of action that could be relevant to man.

Classically, salicylates have been associated with regulating defence against pathogens but they are now emerging as multifunctional hormones protecting plants against stress. They are involved in signalling and the plant’s response to stressors such as disease, cold and warming and in senescence. In disease, aalicylic acid plays a dual role: it facilitates the lethal effects of pathogens that kill the plant host in order to obtain nutrients (necrotrophs) but inhibits and confines the effects of pathogens that rely on plant survival (biotrophs) by promoting programmed cell death (PCD) as a means of confining the spread of disease. In plants PCD, is triggered by recognition of the pathogen which initiates a kinase-dependent signalling cascade leading to the generation of oxygen free radicals and nitric oxide. The synthesis of salicylic acid is increased within 4–5 hours of infection which promoting defence gene expression and PCD [2]. Salicylic acid is also distributed throughout the plant to promote systemic acquired resistance genes, conferring protection against a wide range of pathogens [3].

Additionally, a plant can evolve methyl salicylate into its environment and confer inter-plant resistance. Methyl salicylate is produced in response to an attack by predators such as greenfly; this attracts insects such as hover flies and ladybirds which feed on greenfly.

The generation of transgenic plants encoding the bacterial gene – salicylate hydroxylase (NahG) – which reduces salicylate levels has provided great insights have shown the importance of salicylate to other forms stress, for example, tolerance to heat and chilling is compromised in these plants. Salicylic acid increases production of heat shock proteins, which act as chaperone proteins to protect unfolded proteins from heat [4]. When a plant is chilled, salicylic acid suppresses growth by increasing cross-linkage in the cell wall, limiting expansion [5].

At a molecular level, NahG plants have indicated the salicylate regulates a plethora of plant genes but other features have direct relevance for salicylate action in humans. Specifically, salicylic acid (at microgram levels) acts to potentiate the activity of NADPH oxidase, which increase oxygen free radical generation and perturbs mitochondrial function [2]. This causes an oxidative burst that kills the pathogen There is some limited evidence that a similar potentiation of NADPH oxidase may occur in humans [6]. Unusually in plant biochemistry, salicylate promotes the release of cytochrome C from the mitochondrion which in man, C triggers the formation of apoptosomes, though there is no equivalent in plants and its role is uncertain [2]. This raises the possibility that salicylate could play an important role in triggering apoptosis in humans [6].

Salicylate levels are higher in plants that are exposed to stresses such as infection and temperature change than those cultivated in protected environments like greenhouses. This suggests that much of the food we grow may have low levels of salicylates. It is conceivable that humans benefitted from the protective effects of plant-derived salicylates when their diet comprised wild plants. Conversely, it is likely that a modern diet relying mass-produced plants lacks salicylate and, possibly, is less beneficial. However, salicylates also have industrial applications: they may be added artificially to improve a plant’s resistance to the effects of chilling and some fungicides act partly by increasing plant salicylate levels.

References

1. Wagner S, Ureña A, Reich E et al (2008) Validated HPTLC methods for the determination of salicin in Salix sp and of harpagoside in Harpagophytum [corrected] procumbens J Pharm Biomed Anal 48 587–91 PMID: 18602786 DOI: 10.1016/j.jpba.2008.05.030

2. Mur LA, Kenton P, Lloyd AJ et al (2008) The hypersensitive response; the centenary is upon us but how much do we know? J Exp Bot 59 501–20 PMID: 18079135 DOI: 10.1093/jxb/erm239

3. Ward ER, Uknes SJ, Williams SC et al (1991) Coordinate Gene Activity in Response to Agents That Induce Systemic Acquired Resistance Plant Cell 3 1085–94 PMID: 12324583 DOI: 10.1105/tpc.3.10.1085

4. Clarke SM, Mur LA, Wood JE et al (2004) Salicylic acid dependent signaling promotes basal thermotolerance but is not essential for acquired thermotolerance in Arabidopsis thaliana Plant J 38 432–47 PMID: 15086804 DOI: 10.1111/j.1365-313X.2004.02054.x

5. Scott IM, Clarke SM, Wood JE et al (2004) Salicylate accumulation inhibits growth at chilling temperature in Arabidopsis Plant Physiol 135 1040–9 PMID: 15173571 DOI: 10.1104/pp.104.041293

6. Chung YM, Bae YS, Lee SY (2003) Molecular ordering of ROS production, mitochondrial changes, and caspase activation during sodium salicylate-induced apoptosis Free Radic Biol Med 34 434–42 PMID: 12566069

Colon cancer screening programmes and the place for aspirin

D Morton

Professor of Colorectal Surgery, University of Birmingham, Birmingham, UK

Survival in patients with colorectal cancer has been increasing over the last 50 years (Figure 1), largely due to improvements in diagnosis and management. Whereas clinicians once sought primarily to diagnose disease in symptomatic patients they are now monitoring an at-risk population, some of whom will develop colorectal cancer.

Figure 1.
United Kingdom 1950–2003: males and females colorectal cancer mortality at ages 35–69.

Data from a faecal occult blood screening programme demonstrates the earlier detection of colorectal cancer (Table 1). The Dukes staging system grades colorectal cancer from A (essentially curable) to D (metastatic). The distribution of stages in an unscreened population is similar to that among people who do not respond to invitation for screening (column 4): almost a third of non-responders have metastatic disease and few have Stage A disease. With screening, over half of patients are diagnosed with Stage A disease and the proportion with metastatic disease is greatly reduced.

Table 1.
Faecal occult blood screening increases detection of early stage (Dukes’ A) colorectal cancer [1]

Increased screening has resulted in a huge shift in the stage of disease at diagnosis and in outcome: 2-yearly faecal occult blood screening reduces colorectal cancer mortality by 15% and increases the proportion of cancers diagnosed at an early stage [1,2].

We now have the opportunity to prevent colorectal cancer. The recent UK Flexible Sigmoidoscopy trial demonstrated the benefits of detection and removal of adenomas [3]. 170,000 people aged 55–64 were randomised to undergo once-only sigmoidoscopy or to be a silent control. Compliance was 70% and median follow-up was 11 years. Intent to treat analysis showed that the incidence of colorectal cancer was reduced by 22% and mortality was reduced by 31%. Per protocol analysis showed that, in adherent patients, incidence was reduced by 33% and mortality by 44%. The number needed to treat (i.e. screen) to prevent one cancer was 191. A pragmatic interpretation of this evidence suggests that, assuming a 50% compliance, faecal occult blood screening would identify 20,000 patients with adenomas annually, and flexible sigmoidoscopy would identify 50,000 new patients annually.

Screening can define four groups according to their risk of developing colorectal cancer. Individuals with colorectal cancer and high-risk adenomas are at greatest risk. It is important to reduce the risk of recurrent tumours in these groups, for which aspirin has a role to play. Those with low-risk adenomas or no adenomas are at least risk, though within these groups are an unknown number of individuals at high risk but who cannot be detected. It may be possible to identify these individuals by genetic screening. Genome-wide association studies have shown that the risk of colorectal cancer increases with the number of known risk alleles present [4–8], reaching a 2–4-fold increased risk with 14 or more alleles. Provided these individuals were also more likely to develop adenomas, surveillance by colonoscopy would avoid the development of cancer. An unpublished analysis of 900 patients in the APPROVE trial [9] identified 7 single nucleotide polymorphisms (SNPs) strongly associated with adenoma risk; this suggests that people carrying high-risk alleles are also at increased risk of developing adenomas. Further, these individuals are likely to benefit from the therapeutic interventions currently provided for colorectal cancer.

This evidence makes a strong case for introducing chemoprevention of adenoma and colorectal cancer in high-risk individuals. There are now four randomised trials of aspirin as chemoprevention, involving a total of almost 5,000 patients; all have demonstrated a reduction in adenoma of 20–35%. This is overwhelming evidence that aspirin will prevent the formation of adenomas. The fact that aspirin reduces the risk of colorectal cancer with a latency of 10 years [10] indicates that adenoma prevention, rather than down-staging cancer or preventing progression, is probably the mechanism involved. Based on our knowledge of its safety profile, aspirin is therefore the chemoprevention agent of choice. It may be possible to increase the effectiveness of aspirin with adjunctive agents such as calcium (for which there is evidence from a randomised controlled trial [11]), vitamin D [12], selenium [13] and difluoromethylornithine [14].

It is feasible to conduct a trial to identify genetic and environmental interactions for colorectal risk assessment and prevention. A suitable design would be a cross-sectional cohort study involving 20,000 people embedded within the screening programme. This could define the effect of known and novel genomic factors associated with increased colorectal neoplasia risk through their influence on adenoma occurrence. Within this, a nested randomised controlled trial of 6,000 people could determine the combined impact of aspirin and nutritional supplements in reducing adenoma recurrence. A biosample collection programme would facilitate genomic studies.

An algorithm for this design is illustrated in Figure 2. In such a trial, 20,000 participants would be identified within the screening programme by faecal occult blood testing or colonoscopy and then undergo risk stratification. All would be entered into the genomic study but individuals with no or low-risk adenomas would not undergo randomisation. Those with high-risk adenoma who accepted aspirin treatment and consented to a trial would be randomised to adjunctive treatment, each compared with placebo. Individuals with cancer could also undergo randomisation though this may complicate interpretation of the trial.

Figure 2.
Study design for evaluating the efficacy of aspirin plus adjunctive therapy in adenoma prevention and targeting therapy.

References

1. Hardcastle JD, Chamberlain JO, Robinson MH et al (1996) Randomised controlled trial of faecal-occult-blood screening for colorectal cancer Lancet 348 1472–7 PMID: 8942775 DOI: 10.1016/S0140-6736(96)03386-7

2. Kronborg O, Fenger C, Olsen J et al (1996) Randomised study of screening for colorectal cancer with faecal-occult-blood test Lancet 348 1467–71 PMID: 8942774 DOI: 10.1016/S0140-6736(96)03430-7

3. Atkin WS, Edwards R, Kralj-Hans I et al (2010) Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial Lancet 375 1624–33 PMID: 20430429 DOI: 10.1016/S0140-6736(10)60551-X

4. Broderick P, Carvajal-Carmona L, Pittman AM et al (2007) A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk Nat Genet 39 1315–17 PMID: 17934461 DOI: 10.1038/ng.2007.18

5. Tomlinson I, Webb E, Carvajal-Carmona L et al (2007) A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q2421 Nat Genet 39 984–88 PMID: 17618284 DOI: 10.1038/ng2085

6. Zanke BW, Greenwood CM, Rangrej J et al (2007) Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24 Nat Genet 39 989–94 PMID: 17618283 DOI: 10.1038/ng2089

7. Tomlinson IP, Webb E, Carvajal-Carmona L et al (2008) A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q233 Nat Genet 40 623–30 PMID: 18372905 DOI: 10.1038/ng.111

8. Houlston RS, Webb E, Broderick P et al (2008) Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer Nat Genet 40 1426–35 PMID: 19011631 DOI: 10.1038/ng.262

9. Baron JA, Sandler RS, Bresalier RS et al (2006) A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas Gastroenterology 131 1674–82 PMID: 17499602 DOI: 10.1016/S0140-6736(07)60747-8

10. Flossmann E, Rothwell PM; British Doctors Aspirin Trial and the UK-TIA Aspirin Trial (2007) Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies Lancet 369 1603–13 PMID: 17499602 DOI: 10.1016/S0140-6736(07)60747-8

11. Shaukat A, Scouras N, Schünemann HJ (2005) Role of supplemental calcium in the recurrence of colorectal adenomas: a metaanalysis of randomized controlled trials Am J Gastroenterol 100 390–4 PMID: 15667497 DOI: 10.1111/j.1572-0241.2005.41220.x

12. Grau MV, Baron JA, Sandler RS et al (2003) Vitamin D, calcium supplementation, and colorectal adenomas: results of a randomized trial J Natl Cancer Inst 95 1765–71 PMID: 14652238

13. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C (2008) Antioxidant supplements for preventing gastrointestinal cancers Cochrane Database Syst Rev CD004183 PMID: 18677777 DOI: 10.1002/14651858.CD004183.pub3

14. Meyskens FL Jr, McLaren CE, Pelot D et al (2008) Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial Cancer Prev Res (Phila) 1 32–8 PMID: 18841250 DOI: 10.1158/1940-6207.CAPR-08-0042

Aspirin and other NSAIDs for cancer prevention

J Cuzick

Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, London, UK

It has been almost 30 years since a reduction in adenoma formation after administration of the non-steroidal anti-inflammatory drug (NSAID) sulindac was first reported [1] and 20 years since it was confirmed in a randomised trial [2]. There is now consistent evidence from observational studies and randomised trials that aspirin and other NSAIDs reduces the risk of developing colorectal cancer and adenomas. Evidence from clinical trials also demonstrates a striking effect of combining an NSAID (sulindac) with difluoromethylornithine, which has been shown to reduce the incidence of adenomas by up to 70% compared with placebo [3]. Combinations of NSAIDs with other agents therefore offers the best approach to minimising risk, especially for high risk individuals, where toxicity is a lesser concern.

Observational studies also show that aspirin and NSAIDs are associated with reduced mortality in patients with colorectal adenoma [4,5]. This is inconsistent with the 10-year latency in reducing colorectal cancer risk that has been identified in observational and interventional studies and that has been attributed to an effect on adenomas, and suggests the possibility of two distinct mechanisms of action.

There is increasing evidence from case–control studies, though less strongly from cohort studies, that use of aspirin or NSAIDs over about 20 years is associated with a reduced risk of oesophageal cancer (Figure 1), with less conclusive evidence of a lower risk of stomach cancer(Figure 2) [6]. NSAIDs do not appear to reduce the risk of lung cancer, with case control studies suggesting a marginal effect and no reduction detected in cohort studies (Figure 3). There is accumulating evidence of a benefit in hormone-dependent cancers such as breast (Figure 4); the effect size appears to be smaller in more recent studies, suggesting the possibility of early publication bias. A recent multivariate analysis of the Nurses’ Health Study found a 40–60% reduction in the risk of recurrence among women who, after being diagnosed with breast cancer, took aspirin for 2–7 days per week [7]. Although it is not possible to determine the possible of bias in this study, this represents a greater benefit from a less expensive drug compared with current treatments. Trials are now being planned to determine whether these effects can be replicated in prospective randomised studies. Evidence of a benefit against ovarian cancer is less clear (Figure 5).

Figure 1.
NSAIDs – oesophageal cancer [6]

Figure 2.
NSAIDs – stomach cancer [6].

Figure 3.
NSAIDs – lung cancer [6].

Figure 4.
NSAIDs – breast cancer [6].

Figure 5.
NSAIDs – ovarian cancer [6].

The traditional approach to phase I, II and III trials for evaluating new treatments is expensive (trials cost $10–100 million each) and may not be appropriate for evaluating preventative therapies. Instead, phase I (discovery) could rely on cohort studies and the identification of biomarkers and precursor lesions. Case–control studies are less reliable than cohort studies due to their retrospective nature and they should be carried out in carefully selected groups of patients.

Phase II studies for early validation should be improved. It is important that these studies are randomised because of the biases inherent in cohort studies. Their cost can be minimised by using biomarkers and precursor lesions as endpoints, and recruiting patients with cancer. The value of this approach is illustrated by studies of the prevention of contralateral breast tumours in women taking tamoxifen after diagnosis of breast cancer, which demonstrated a similar effect 15–20 years before it was shown in randomised trials. In the case of aromatase inhibitors, the effects on contralateral tumours suggest a 75% reduction in recurrence risk. If this strategy is shown to provide a reliable estimate of the outcomes of randomised trials, it may become the standard in the future.

Phase III studies (late definitive validation) take 10–20 years to complete and cost hundreds of millions of dollars. They are unlikely to be funded for inexpensive drugs such as aspirin, so any that are carried out must be carefully designed and use cancer mortality or incidence as an endpoint.

References

1. Waddell WR, Loughry RW (1983) Sulindac for polyposis of the colon J Surg Oncol 24 83–7 PMID: 6887943

2. Nugent KP, Farmer KC, Spigelman AD et al (1993) Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis Br J Surg 80 1618–9 PMID: 8298943

3. Meyskens FL Jr, McLaren CE, Pelot D et al (2008) Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial Cancer Prev Res (Phila) 1 32–8 PMID: 19827153 DOI: 10.1002/cncr.24705

4. Zell JA, Ziogas A, Bernstein L et al (2009) Nonsteroidal anti-inflammatory drugs: effects on mortality after colorectal cancer diagnosis Cancer 115 5662–71 PMID: 19827153 DOI: 10.1002/cncr.24705

5. Chan AT, Ogino S, Fuchs CS (2009) Aspirin use and survival after diagnosis of colorectal cancer JAMA 302 649–58

6. Bosetti C, Gallus S, La Vecchia C (2009) Aspirin and cancer risk: a summary review to 2007 Recent Results Cancer Res 181 231–51 PMID: 19213573

7. Holmes MD, Chen WY, Li L et al (2010) Aspirin intake and survival after breast cancer J Clin Oncol 28 1467–72 PMID: 20159825 DOI: 10.1200/JCO.2009.22.7918

Commentary

G McVie

Senior Consultant, Insituto Europeo di Oncologia, Italy

It is important to consider aspirin’s mechanism of action in the context of what we know about carcinogenesis. The idea that aspirin has at least two mechanisms of action is not new but the hypothesis that its effects on cancer risk are due to inhibition of COX-2 is less plausible than an effect on inflammation. It is therefore surprising that longitudinal studies have not been conducted in patients with inflammatory bowel disease. Studies on breast cancer stem cells show that DNA repair is important in carcinogenesis but this has not been discussed with respect to the effects of aspirin. The study proposed by Professor Dion could include a combination of aspirin with a poly (ADP-ribose) polymerase 1 (PARP1) inhibitor (PARP1 is involved in cell proliferation and differentiation and DNA repair). While the use of such a compound is not appropriate in healthy individuals, the balance of risk and benefit may be acceptable in individuals at high risk.

Another cohort that is potentially interesting is patients who have developed autoimmune colitis after treatment with ipilimumab, a T-cell suppressor. Combinations of aspirin with other treatments are another avenue that is well worth exploring in clinical trials. Vitamin D was recently shown to reduce all-cause death [1]. This would be a suitable endpoint in randomised trials of aspirin, given its effects on cardiovascular disease and cancer, though it should be acknowledged that trials are unlikely to attract large funding. In the future, trials should be randomised, smaller in scale and carried out in better-defined populations.

We need to identify early markers of outcome and it is important that we improve the collection of samples by biobanks. At the moment we do not know what tissue will be informative but the librarianship of potentially relevant tissues is essential for future research. Nor do we know the initial COX status of people who develop cancers subsequently found to be COX-2 positive or negative. Activity should focus on people who are participating in studies, whether observational or interventional, so that early markers of risk can be identified.

Several issues remain unresolved. What is the dose–response relationship in the prevention of colorectal cancer? From what we know of plant biochemistry, the effects of salicylate depend on its concentration. Little has been said about the effect of enteric-coating: bearing in mind its different effects on the left and right colon cancer, though there is evidence from the literature that COX2 levels are higher in tumours of the distal colon and rectum than proximal colon. It would be interesting to measure how much aspirin from an enteric-coated preparation reaches the sigmoid junction.

The aetiology of adenomas and colorectal cancer is uncertain and new therapeutic targets should be considered. The effects of aspirin on mitochondrial crypts are interesting: many treatments for parasitic diseases target parasite mitochondria but this mechanism has not been explored on clinical oncology. Molecular targets are also being identified: trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2, has recently been shown to be effective in the treatment of stomach and oesophageal cancers.

Reference

1. Autier P, Gandini S (2007) Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials Arch Intern Med 167 1730–7 PMID: 17846391 DOI: 10.1001/archinte.167.16.1730