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Aspirin as a Cancer Prevention AgentPhilip J. Moos IntroductionPrevention of prevalent diseases, such as cancer, through the daily ingestion of low cost drugs or vitamins has not general y met with great success based on evidence from large-scale clinical trials.[1,2] However, recent clinical data indicate that aspirin (acetylsalicylic acid, ASA) and its precursor, salicylate, which have been used as analgesics and to reduce inflammation since antiquity,[3] may have potential for use Clinical Evidence for Aspirin’s Efficacy as a ChemopreventiveAgentPerhaps the most compel ing evidence for the cancer prevention effects of aspirin comes from the examination of the national medical records of individuals enrol ed in nine non-cancer clinical trials.[4] Taken together, these studies represent data from >23,000 patients who regularly took aspirin (at least ≥ 75 mg/day). While none of these studies intended cancer outcomes to be primary endpoints, the meta-analysis of these studies demonstrated nearly 20% decreased risk in overal cancer mortality after a 20-year fol ow-up period, with most of the benefit occurring after five years of aspirin use (hazard ratio 0.66, p = 0.003). The reduction of cancers was most significant for esophageal and colorectal cancers, but an overal gastrointestinal (GI) cancer reduction was observed for patients with >10 years of fol ow-up (representing a larger pool of patients). Particular attention was paid to GI cancers as studies have long suggested that aspirin and even other NSAIDs may decrease colorectal cancers.[4-6] Moreover, in this meta-analysis, significant reductions in cancer deaths were also observed for lung cancer and for a variety of other solid cancers; no survival benefit was observed for hematological cancers.
In another recent meta-analysis,[7] 51 trials (representing ~77,500 patients) of daily aspirin versus no aspirin were evaluated for cancer death and adverse effects.
Aspirin reduced the risk of cancer death and colorectal cancer (odds ratio = 0.58), and lymphoma (odds ratio = 0.61). The aspirin benefit occurred after 5 years of fol ow-up. In this meta-analysis, 10% of low dose aspirin users had GI ulcers but the risk for cancer and major extracranial bleeds decreased with prolonged use of aspirin. In addition, aspirin appeared to reduce the metastatic spread of adenocarcinoma to distant sites.[8] Thus, aspirin may decrease incidence as wel as spread of adenocarcinoma, and serve as an adjuvant therapy in treatment of GI Possible Mechanisms for Aspirin’s Chemopreventative Effects Insights into possible mechanisms of aspirin’s anti-cancer activity come from recent pharmacogenetic studies using aspirin as an adjuvant therapy. The Nurses’ Health Study and the Health Professionals Fol ow-up Study set out to determine if there was a pharmacogenetic contribution to the sensitivity of colorectal cancers to aspirin.[9] Subjects (al health professionals) were queried regarding their aspirin use and characterized as either users of aspirin most weeks or not regular users of aspirin.
From the ~170,000 participants, there were 964 colorectal cancer samples that were tested for mutations in PIK3CA (exons 9 and 20), KRAS (codons 12 and 13), BRAF (codon 600), and methylation analysis of LINE-1 elements of eight CpG island methylator phenotype-specific loci. PIK3CA mutational status demonstrated the strongest genetic influence on survival with aspirin use. Mutations of PIK3CA, primarily activating mutations for PI3 kinase, correlated with reduced probability of death with aspirin use (hazard ratio 0.18). Patients with wild-type PIK3CA demonstrated no reduction of death probability with or without aspirin use. While these data are compel ing, the number of patients in this study was relatively smal and additional research is clearly warranted to evaluate the mechanistic relationship between cancer-related mutations and aspirin use. The correlation of activating mutations of PIK3CA and the mechanism of action of aspirin in colon cancer could be related to the regulation of PTGS2 expression, which is mediated by the PI3 kinase pathway.[10] PTGS2 codes for COX-2, one of the primary targets of aspirin. However, the mechanistic relationship of PTGS2 and PIK3CA to cancer prevention requires additional study.[11] It is noteworthy that no significant correlation was observed between NSAID use and PIK3CA mutational status, indicating that the correlation between PIK3CA and aspirin is likely distinct from a general anti-inflammatory effect of NSAIDs. Thus, aspirin, or perhaps salicylate, may have another important pharmacological activity that is separate from the cyclooxygenase inhibitory activity that is common to aspirin and other NSAIDs. A model system that would al ow genetic manipulation of PTGS2 and PIK3CA might clarify the relation between aspirin, PTGS2, PIK3CA, and colorectal cancer.
SummaryAlthough the results of a number of clinical studies indicate that aspirin may function as a broad spectrum cancer prevention agent, the results have been mixed, due to different study designs, uneven use of aspirin, as wel as the long time periods and large patient numbers required to col ect statistical y significant results. Even among the studies presented herein, there is a potential contradiction in the outcomes from aspirin use and hematological malignancies among the long-term use and the short- term studies. However, clinical data are accumulating that support the use of aspirin, an inexpensive and widely available drug, to prevent two of the top mortal diseases, adenocarcinoma and myocardial infarction. Prospective cancer prevention trials would provide definitive evidence of aspirin’s cancer prevention efficacy and determine if the risk of potential adverse effects, like bleeding, is genuinely mitigated 1. Gaziano JM, Glynn RJ, Christen WG, et al. Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study I randomized control ed trial. JAMA 2009;301(1):52-62. [PMID: 19066368] 2. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2009;301(1):39-51. [PMID: 19066370] 3. Yeomans, ND. Aspirin: old drug, new uses and chal enges. J Gastroenterol Hepatol 2010;26(3):426-31. [PMID: 21062358] 4. Rothwel PM, Fowkes FG, Belch JF, et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011;377(9759):31-41. [PMID: 21144578] 5. Rothwel PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year fol ow-up of five randomised trials.
Lancet 2010;376(9754):1741-50. [PMID: 20970847] 6. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA 2009;302(6):649-58. [PMID: 19671906] 7. Rothwel PM, Price JF, Fowkes FG, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised control ed trials. Lancet 8. Rothwel PM Wilson M, Price JF, et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised control ed trials.
Lancet 2012;379(9826):1591-601. [PMID: 22440947] 9. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 2012;367(17):1596-606. [PMID: 10. Kaur J, Sanyal SN. PI3-kinase/Wnt association mediates COX-2/PGE(2) pathway to inhibit apoptosis in early stages of colon carcinogenesis: chemoprevention by diclofenac. Tumour Biol 2010;31(6):623-31. [PMID: 11. Chan AT. COX-2 expression in adenoma: an imperfect marker for chemoprevention. Gut 2010;59(5):568-9. [PMID: 20427388] AccessMedicine from McGraw-Hil 2013 The McGraw-Hil Companies


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