Commentary ASPREE: Aspirin and Cancer Prevention in the Elderly: Where do we go from here?

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References 1. Rothwell PM, Algra A, Chen Z, Diener HC, Norrving B, Mehta Z. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials. Lancet 2016; 18th May online.
Recently published science of interest about aspirin: aspirin mechanism In an Opinion article in press at Nature Reviews Cancer, we review the weight of the evidence supporting aspirin’s chemo preventive potential and highlight advances in our understanding of aspirin’s mechanisms of action. We challenge the notion that aspirin prevents cancer through a single, dominant pathway and propose an integrative multi-pathway model for its mode of action. We highlight how these pathways can be leveraged to develop mechanistic biomarkers for personalised risk stratification. Such biomarkers may then be translated clinically in a precision medicine approach critical to the future of aspirin chemoprevention.

1.           Gaciong Z. The real dimension of analgesic activity of aspirin. Thromb Res. 2003;110(5-6):361-4.

2.           Seymour RA, Hawkesford JE, Sykes J, Stillings M, Hill CM. An investigation into the comparative efficacy of soluble aspirin and solid paracetamol in postoperative pain after third molar surgery. Br Dent J. 2003;194(3):153- 7; discussion 49.

3.           Lampl C, Voelker M, Steiner TJ. Aspirin is first-line treatment for migraine and episodic tension-type headache regardless of headache intensity. Headache. 2012;52(1):48-56.

4.           Lecchi M, D’Alonzo L, Negro A, Martelletti P. Pharmacokinetics and safety of a new aspirin formulation for the acute treatment of primary headaches. Expert Opin Drug Metab Toxicol. 2014;10(10):1381-95.

5.           Eccles R, Loose I, Jawad M, Nyman L. Effects of acetylsalicylic acid on sore throat pain and other pain symptoms associated with acute upper respiratory tract infection. Pain Med. 2003;4(2):118-24.

6.           Bachert C, Chuchalin AG, Eisebitt R, Netayzhenko VZ, Voelker M. Aspirin compared with acetaminophen in the treatment of fever and other symptoms of upper respiratory tract infection in adults: a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, single-dose, 6-hour dose-ranging study. Clin Ther. 2005;27(7):993-1003.

7.           Leonards JR. The influence of solubility on the rate of gastrointestinal absorption of aspirin. Clin Pharmacol Ther. 1963;4:476-9.

8.           Davison C. Salicylate metabolism in man. Ann N Y Acad Sci. 1971;179:249-68.

9.           Fonseca MD, Cunha FQ, Kashfi K, Cunha TM. NOSH-aspirin (NBS-1120), a dual nitric oxide and hydrogen sulfide-releasing hybrid, reduces inflammatory pain. Pharmacol Res Perspect. 2015;3(3):e00133.

1.       Final Recommendation Statement: Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Preventive Medication. U.S. Preventive Services Task Force. April 2016.

2.       Bibbins-Domingo K; U.S. Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164:836-45. doi:10.7326 /M16-0577

3.       U.S. Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: recommendation statement. Ann Intern Med 2009;150:396-404.

4.       Dehmer SP, Maciosek MV, Flottemesch TJ, LaFrance AB, Whitlock EP. Aspirin for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: A Decision Analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2016 Jun 21;164(12):777-86.

5.       EA, Whitlock EP. Aspirin for the Primary Prevention of Cardiovascular Events: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 131. AHRQ Publication No.13-05195-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015. [PMID: 26491760]

6.       Chubak J, Kamineni A, Buist DSM, Anderson ML, Whitlock EP. Aspirin Use for the Prevention of Colorectal Cancer: An Updated Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 133. AHRQ Publication No. 15-05228-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015. [PMID: 26491758]

7.       Whitlock EP, Williams SB, Burda BU, Feightner A, Beil T. Aspirin Use in Adults: Cancer, All-Cause Mortality and Harms. A Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 132. AHRQ Publication No. 13-05193-EF-1.Rockville, MD: Agency for Healthcare Research and Quality; 2015.[PMID: 26491756]

8.       Guirguis-Blake JM, Evans CV, Senger CA, O’Connor EA, Whitlock EP. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164:804-13. doi:10.7326/M15-2113

9.       Chubak J, Whitlock EP, Williams SB, Kamineni A, Burda BU, Buist DSM, et al. Aspirin for the prevention of cancer incidence and mortality: systematic evidence reviews for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164:814-25. doi:10.7326 /M15-2117

10.    Whitlock EP, Burda BU, Williams SB, Guirguis-Blake JM, Evans CV. Bleeding risks with aspirin use for primary prevention in adults: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164:826-35. doi:10.7326/M15-2112

Table 1 Studies examining PIK3CA mutation, aspirin use and colorectal cancer outcomes.

Study

%

PIK3CA Mutant

End­point

PIK3CA Mutant

PIK3CA Wild-Type

No aspirin

Aspirin

HR (p value)

No aspirin

Aspirin

HR (p value)

Nurses' Health Study ft Health Professionals Follow-up Study (Liao 2012)

16.7%

OS

95

66

0.54 (0.01)

466

337

0.94 (0.96)

CSS

-

-

0.18 (<0.001)

-

-

0.96 (0.76)

VICTOR trial
(Domingo 2013)

11.6%

OS

90

14

0.29 (0.19)

681

111

0.95 (0.26)

RFS

-

-

0.11 (0.027)

-

-

0.94 (0.79)

Moffitt Cancer Centre & Royal Melbourne Hospital (Kothari 201S)

12.4%

OS

136

49

0.96 (0.86)

-

-

-

CSS

-

-

0.60 (0.14)

-

-

-

Eindhoven Cancer Registry (Reimen 2014)

15.8%

OS

73

27

0.73* (0.4)

348

147

0.55 (<0.001)

Characteristic

No. of Patients

No. of Deaths

Univariate RR (95% CI)

P Value"

Adjusted RR (95% Ci)c

P Value"

HLA class I antigen

 

 

 

 

 

 

Loss

 

 

 

 

 

 

No aspirin use

263

123

1 (Reference)

.74

1 (Reference)

.91

Aspirin use

57

26

1.08 (0.70-1.64)

1.03 (0.66-1.61)

Expression

 

 

 

 

 

 

No aspirin use

521

257

1 (Reference)

.003

1 (Reference)

<.001

Aspirin use

122

42

0.61 (0.44-0.85)

0.53 (0.38-0.74)

 

1.     Langley RE, Burdett S, Tierney JF, Cafferty F, Parmar MK, Venning G. Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy? Br J Cancer. 2011; 105(8): 1107-13.

2.     Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010; 376(9754): 1741-50.

3.     Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. 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.

4.     Rothwell PM, Price JF, Fowkes FG, Zanchetti A, Roncaglioni MC, Tognoni G, 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 controlled trials. Lancet. 2012; 379(9826): 1602-12.

5.     Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012.

6.     Coyle C, Cafferty FH and Langley RE. Aspirin and Colorectal Cancer Prevention – Is it for everyone? Curr Colorectal Cancer Rep (2016) 12:27–34

7.     Reimers MS, Bastiaannet E, Langley RE, van Eijk R, van Vlierberghe RL, Lemmens VE, et al. Expression of HLA Class-I Antigen, Aspirin Use, and Survival After a Diagnosis of Colon Cancer. JAMA Intern Med, 2014 174(5) 732-739.

Current clinical trials of aspirin in Italy include ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes), a primary prevention trial coordinated by Dr. Nicolucci at the Mario Negri Institute in Milan, and ASAMET, a randomized, 2x2 biomarker prevention trial of low-dose aspirin and metformin in colon cancer patients coordinated by Dr. De Censi at the E.O. Ospedali Galliera in Genova. Moreover, investigators in Rome, Chieti, Verona, Siena and Bari, coordinated by Prof. Paola Patrignani, are collaborating in investigating the role of platelet activation in intestinal tumorigenesis. They will test the hypothesis that inhibition of platelet activation may explain the efficacy of low-dose aspirin as a chemopreventive agent.
Besides the references quoted in the text, the following may be of interest: Patrono C (2015) The multifaceted clinical readouts of platelet inhibition by low-dose aspirin. J Am Coll Cardiol 66:74-85. Scavone M, Femia EA, Caroppo V, Cattaneo M. Inhibition of the platelet P2Y12 receptor for adenosine diphosphate does not impair the capacity of platelet to synthesize thromboxane A2.Eur Heart J. 2015 Oct 29. pii: ehv551. [Epub ahead of print] Chan AT, Ladabaum U. Where do we stand with aspirin for the prevention of colorectal cancer? The USPTF recommendations. Gastroenterology. 2015 Nov 18. pii: S0016-5085(15)01665-0. doi: 10.1053 / j.gastro.2015.11.018. [Epub ahead of print]
ever for any consequences arising from any reliance placed on such information, views, opinions and other materials in lieu of professional medical advice.
For further information please contact International Aspirin Foundation Bower House 34 Bower Mount Road Maidstone Kent ME16 8AU Tel: +44(0) 1622 320118 Fax: +44(0) 1436 840194 Email: aspirin@aspirin-foundation.com www.aspirin-foundation.com

Professors Andrew Chan and John McNeil provide an insightful commentary, currently in press with Gastroenterology, in which they discuss the results of the recently reported ASPREE trial in the context of pre-existing evidence and support for the effectiveness of aspirin as a primary prevention agent for cardiovascular disease (CVD) and cancer.

Within the commentary they explore 5 possible hypotheses which include variation in the effect of aspirin depending on the timing of exposure, the age of the individual taking it or other risk factors they may have for cancer and where ASPREE sits within the body of existing evidence.

They conclude:

“The contrary results of ASPREE compared with prior RCTs are humbling. It was perhaps naïve to assume that a preventative agent would offer a uniform effect across a broad population.”

To read the article please visit the link to the Gastroenterology, published by Elsevier (2018), below: https://doi.org/10.1053/j.gastro.2018.11.063

N.B This is the uncorrected proof of the paper the full and final corrected proof will appear in the journal issue in due course.