JNCI J Natl Cancer Inst (2021) 113(3): djaa114
doi: 10.1093/jnci/djaa114
First published online August 11, 2020
ArticleEffect of Aspirin on Cancer Incidence and Mortality in Older Adults, MBBS, MSc, PhD,1, *Peter Gibbs, MBBS, MD2 Suzanne G. Orchard

John J. McNeil, MBBS,1 Wendy B. Bernstein, MD,3 Yin Cao

Jessica E. Lockery

1, BSc(Hons), PhD,1, ScD, MPH,4 Leslie Ford, MD,5

6

Andrew Haydon, MBBS, PhD, Brenda Kirpach, CCRA, Finlay Macrae, MBBS, MD,7
Catriona McLean, MBBS, MD,8 Jeremy Millar
Mark R. Nelson, MBBS(Hons), MFM, PhD,
Christopher M. Reid
12

Raj C. Shah, MD,

1,10, MBChB, BMedSc,1 Anne M. Murray
Galina Polekhina

1,11, BA, MSc, PhD, MPH,

Jeanne Tie

Ellen Richmond, MBioStat, PhD,

, MD, MSc,6,9

1, MS, GNP-BC,5 Luz Maria Rodrıguez, MD,3,5

2, MBChB, MD, Asad Umar, PhD, DVM,5 G. J. van Londen, MD, MS,13

Kathlyn Ronaldson, MPH, DPhil,1 Rory Wolfe, BSc, PhD,1 Robyn L. Woods
1

John Zalcberg, MBBS, PhD, Andrew T. Chan, MD, MPH

14, BSc(Hons), PhD,1

on behalf of the ASPREE Investigator Group1
Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Victoria, Australia; 2The Walter & Eliza Hall Institute of Medical Research,
Melbourne, Victoria, Australia; and Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; 3Walter Reed National Military
Medical Center, Bethesda, MD, USA; 4Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA;
5
Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA; 6Berman Center for Outcomes and Clinical Research, Hennepin Health ResearchInstitute, Hennepin, HealthCare, Minneapolis, MN, USA; 7Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia; and Department ofColorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Victoria, Australia; 8Department of Anatomical Pathology, Alfred Hospital, Melbourne,
Victoria, Australia; 9Division of Geriatrics, Department of Medicine, Hennepin County Medical Center and University of Minnesota, Minneapolis, MN, USA; 10Menzies
Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia; 11School of Public Health, Curtin University, Perth, WA, Australia; 12Department of
Family Medicine and Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA; 13Department of Medicine, University of Pittsburgh,
Pittsburgh, PA, USA and 14Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA*Correspondence to: John J. McNeil, MBBS, MSc, PhD, School of Public Health and Preventive Medicine, Monash University, Alfred Centre, 99 Commercial Rd,
Melbourne, Victoria 3004, Australia (e-mail: john.mcneil@monash.edu).
**ASPREE Investigator Group listed on www.aspree.org.

ARTICLE

Abstract
Background: ASPirin in Reducing Events in the Elderly, a randomized, double-blind, placebo-controlled trial of daily low-dose
aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast, prior randomized controlled trials, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality. Methods: 19 114 Australian and US community-dwelling participants aged 70 years and older (US minorities 65 years and older) without cardiovascular disease, dementia, or physicaldisability were randomly assigned and followed for a median of 4.7 years. Fatal and nonfatal cancer events, a prespecified
secondary endpoint, were adjudicated based on clinical records. Results: 981 cancer events occurred in the aspirin and 952 in
the placebo groups. There was no statistically significant difference between groups for all incident cancers (hazard ratio [HR]
¼ 1.04, 95% confidence interval [CI] ¼ 0.95 to 1.14), hematological cancer (HR ¼ 0.98, 95% CI ¼ 0.73 to 1.30), or all solid cancers(HR ¼ 1.05, 95% CI ¼ 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk ofincident cancer that had metastasized (HR ¼ 1.19, 95% CI ¼ 1.00 to 1.43) or was stage 4 at diagnosis (HR ¼ 1.22, 95% CI ¼ 1.02 to1.45), and with higher risk of death for cancers that presented at stages 3 (HR ¼ 2.11, 95% CI ¼ 1.03 to 4.33) or 4 (HR ¼ 1.31, 95%
CI ¼ 1.04 to 1.64). Conclusions: In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution.
These findings suggest that in older persons, aspirin may accelerate the progression of cancer and, thus, suggest caution with
its use in this age group.

Received: March 9, 2020; Revised: June 22, 2020; Accepted: July 30, 2020
© The Author(s) 2020. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work
is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com258

J. J. McNeil et al. | 259

Methods
Trial Design
Details of the ASPREE trial have been described elsewhere (Trial
Registration No.: ASPREE ClinicalTrials.gov No. NCT01038583)(1,2). From March 2010 through December 2014, a total of 19 114
participants across Australia (n ¼ 16 703) and the United States(n ¼ 2411) gave written informed consent and were randomly
assigned to receive daily 100 mg of enteric-coated aspirin(n ¼ 9525) or matching placebo (n ¼ 9589). A previous history ofcancer was not an exclusion criterion and was present in 19% of
those randomly assigned. However, all participants were required to be in good health and free of major diseases andexpected to survive for at least 5 years (details of follow-up andcompliance in Supplementary Methods, available online) (10).

Ascertainment of Cancer Outcomes
Fatal and nonfatal cancers occurring during the randomized
treatment phase were a prespecified secondary endpoint.
Detailed clinical records, including histopathology reports, weresought from treating practitioners and health-care institutions
when evidence of a new or recurrent cancer was recorded, or after a participant had died. If available, TNM staging and histological grading were also collected. When death certificateswere the only source of information, cases where cancer was included as the underlying cause of death were included within
the dataset (details of blinded adjudication and definitions in
Supplementary Methods, Supplementary Box 1 andSupplementary Figure 1, available online).
Analyses were conducted by “person” and by “incident cancer,” the former analysis accounting for the number ofindividuals developing 1 or more “cancer events” (either a newincident cancer that could be localized or distant, or a metastatic recurrence of a cancer diagnosed prior to study entry) during the period of the trial. The incident cancer analysis included
each new cancer subtype diagnosis reported and confirmed after random assignment and included the possibility for participants to contribute 2 or more distinct cancer endpoints if thesubtype differed. For example, a participant diagnosed withprostate cancer after being randomly assigned, who subsequently developed pancreatic cancer, would contribute 2 incident cancers. If a subsequent death was considered the result ofcancer, the cancer considered most likely to have led to thedeath was determined. Among those who entered the trial witha history of cancer, any new cancer type was included amongincident cancers, whereas a local recurrence of the same type
was not (see Supplementary Figure 2, available online). Distantrecurrence of a primary tumor present at baseline was included
as a new metastatic cancer (details in Supplementary Methods,
available online).

Statistical Analysis
Cox proportional-hazards models were used in intention-totreat analyses to compare aspirin and placebo groups on timeto-event cancer outcomes during the intervention phase of thetrial (on or prior to June 12, 2017, median of 4.7 years follow-up
for both groups). An analysis was performed for the event of“first diagnosis” of cancer of any type (ie, incident cancers) that
occurred during the trial, and a separate set of analyses, 1 foreach anatomical cancer type, was also conducted. These analyses were all time to first event, and if participants experienced
multiple anatomical cancer types, then only their first occurrence contributed to the analysis of “cancer of any type,” andtheir first occurrence of each specific anatomical type contributed to that anatomical type’s analysis. Cause-specific hazard
ratios (HR) were determined for total cancer, nonmetastatic
cancer, metastatic cancer, and specific cancer types with censoring at the time of the competing risk of death. The proportional hazards assumption was checked for all models by using
a test based on Schoenfeld residuals. A competing risk model
was used to develop the cumulative incidence plots.
Subgroups that were prespecified in the trial protocol included country of residence, age, sex, ethnicity, smoking status,
body mass index category, prior regular use of aspirin, baseline
history of diabetes, hypertension, dyslipidemia, and prior cancer history (1,2,11). Effect heterogeneity between subgroups wasassessed with omnibus tests of whether coefficients for interaction terms in Cox proportional-hazards models were different
from zero. All P values are 2-sided, with cut point for statisticalsignificance P less than .05, and all analyses were restricted toevents that occurred on, or prior to, the end of the treatment
phase.

Compliance With Ethical Standards
The ASPREE trial was conducted in accordance with the
Declaration of Helsinki 1964 as revised in 2008, the National
Health and Medical Research Council Guidelines on Human
Experimentation, the federal patient privacy (Health Insurance
Portability and Accountability Act) law, and the International
Conference of Harmonization guidelines for Good Clinical
Practice. ASPREE also follows the Code of Federal Regulations as
it relates to areas of clinical research.

ARTICLEThe ASPirin in Reducing Events in the Elderly (ASPREE) was arandomized controlled trial (RCT) comparing daily low-dose aspirin (100 mg) vs placebo in 19 114 Australian and US adults
aged 70 years or older (or aged 65 years or older among US
African Americans and Hispanics) who were free of known
cardiovascular disease, dementia, or physical disability at trial
entry (1,2). We recently reported that ASPREE participants
randomized to aspirin experienced higher all-cause mortality(3). This became evident at 3 years postrandomization and waslargely attributable to death from cancer.
This finding was unexpected in the context of results fromprior RCTs and meta-analyses (4–6). Generally, these studies,
conducted in a younger average age group, reported that aspirin
did not affect the short-term risk of cancer although Rothwell
et al. (7) recently reported an increase in cancer incidence during the early years of follow-up among older trial participants.
With more prolonged follow-up, participants randomized todaily aspirin had a reduced risk of incident cancer and deathfrom cancer, particularly colorectal cancer (7,8). This led the US
Preventive Services Task Force in 2016 to recommend low-dose
aspirin for primary prevention of cardiovascular events and colorectal cancer among US adults aged 50-59 years with a greaterthan 10% 10-year risk of a cardiovascular event (9). However,this advice did not extend to adults aged 70 years and older
where the evidence was considered insufficient (9).
The present report now provides a more detailed analysis of
the effect of aspirin on cancer incidence and mortality occurringin the ASPREE participants with the aim of better understanding
the findings and implications of the study.

260 | JNCI J Natl Cancer Inst, 2021, Vol. 113, No. 3

Results

Table 1. Baseline characteristics of the ASPREE population by treatment group

Participants
Baseline characteristics of the participants are presented inTable 1 showing treatment groups well balanced in terms ofestablished or putative risk factors for cancer (2). Prior aspirin
use was low (11.0%) and balanced across groups (aspirin
n ¼ 1053, placebo n ¼ 1041). At the end of the trial, the total number of years during which participants were at risk of cancer
mortality was 44 007 person-years in the aspirin group and
44 382 person-years in the placebo group. At trial entry, 3660
(19.1%) had a prior diagnosis of cancer (excluding nonmelanoma
skin cancer), 15 375 (80.4%) were not known to have cancer prior
to random assignment, and the cancer history status was unknown for 79 (0.4%) (see Table 1). The compliance to study medication, expressed as a proportion of the time in study that anindividual spent taking randomized medication, was on average
72.7% for the aspirin group and 74.5% for the placebo group.

Incidence

ARTICLE

Table 2 indicates that 981 individuals in the aspirin group and 952
in the placebo group had a first incident cancer after random assignment, regardless of whether they had a past cancer history atbaseline. Corresponding numbers of deaths adjudicated as caused
by cancer are also shown. During the in-trial follow-up, 1933
(10.1%) were diagnosed with a new incident cancer. Among these,
1270 (65.7%) presented with localized cancer (ie, nonmetastatic
cancer), 363 (18.8%) presented with new metastatic disease (ie, incident metastatic disease), 113 (5.8%) presented with metastatic disease of a cancer type already present before study entry (ie,metastatic recurrence), and 187 (9.7%) with a hematological or lymphatic cancer (subgroup analyses Supplementary Tables 1 and 2,
available online). A total of 495 (25.6%) participants died as a resultof their malignancy; of these, 52 died from progression of a cancer
initially diagnosed prior to trial entry (Table 2; CONSORT diagram,
Supplementary Figure 3, available online).
Aspirin was not associated with risk of diagnosis of a first incident cancer event (HR ¼ 1.04, 95% CI ¼ 0.95 to 1.14), an incident localized cancer (HR¼ 0.99, 95% CI ¼ 089 to 1.11), or an
incident hematological or lymphatic cancer (HR ¼ 0.98, 95% CI ¼
0.73 to 1.30). However, the number of participants with metastatic cancer at diagnosis (HR¼ 1.19, 95% CI ¼ 1.00 to 1.43) was
increased among those randomly assigned to aspirin.
Table 3 compares the impact of aspirin and placebo on theincidence of, and mortality from, solid tumors (ie, excluding hematological and lymphatic cancers) according to stage and anatomical origin, and Figure 1 shows the cumulative incidence ofsolid tumor cancers according to stage at diagnosis. There wasno association of aspirin with the overall incidence of solid
tumors (HR ¼ 1.05, 95% CI ¼ 0.95 to 1.15) or with the incidence ofcancers that were diagnosed at stages 1, 2, or 3. By contrast, aspirin was associated with an increase in the incidence of cancers presenting at stage 4 (HR ¼ 1.22, 95% CI ¼ 1.02 to 1.45).

Characteristic
Age, y
65-69
70-74
75-79
80-84
85
Male sex
BMI 25, kg/m2
Smoking
Current
FormerNever
Alcohol use
Current
FormerNever
Previous regular
aspirin usea
Personal cancer history
Family cancer historyb
Previous cancer
screening, % of askedc

Aspirin (n ¼ 9525)
No. (%)

Placebo (n ¼ 9589)
No. (%)

284 (3.0)5243 (55.0)2533 (26.6)
1085 (11.4)
380 (4.0)4152 (43.6)
6981 (73.6)

280 (2.9)5356 (55.9)
2490 (26.0)1111 (11.6)
352 (3.7)4180 (43.6)
7080 (74.2)

352 (3.7)
3909 (41.0)5264 (55.3)

383 (4.0)
3890 (40.6)
5316 (55.4)

7309 (76.7)
566 (5.9)1650 (17.3)
1053 (11.1)

7333 (76.5)
570 (5.9)
1686 (17.6)
1041 (10.9)

1827 (19.2)

1833 (19.1)

5554 (58.5)
2924 (96.6)

5605 (58.3)
2934 (96.7)

aPrevious regular aspirin use was defined according to participant-reported reg-ular use of aspirin immediately before entering the study. ASPREE ¼ ASPirin in
Reducing Events in the Elderly; BMI ¼ body mass index.
b

Family cancer history includes a history of cancer in the participant’s mother,father, siblings, and children, as reported by each participant at baseline.

cPrevious cancer screening questions asked of 3022 participants in the aspiringroup and 3035 participants in the placebo group.

the aspirin group presenting with stage 3 (HR ¼ 2.11, 95% CI ¼
1.03 to 4.33) or stage 4 disease (HR ¼ 1.31, 95% CI ¼ 1.04 to 1.64).
Prostate, colorectal, breast, melanoma, and lung were the mostcommon incident cancers, accounting for 80% of all solid tumor
cancers. There was no association of aspirin with the incidence ofcancer in any anatomic subtype. However, the aspirin-treatedgroup was observed to have more deaths from solid tumors irrespective of anatomical site, including colorectal cancer deaths (35vs 20, HR ¼ 1.77, 95% CI ¼ 1.02 to 3.06). In absolute terms, the rateof solid tumor cancers with subsequent death was increased from
4.4 cases per 1000 person-years of observation among those randomly assigned to placebo to 5.9 cases per 1000 person-years
among those receiving aspirin (HR ¼ 1.33, 95% CI ¼ 1.11 to 1.61).

Subgroup Analyses
The effect of aspirin on solid tumor incidence (Figure 3,A), solid tumor mortality (Figure 3,B), and all incident cancers (Supplementary
Figure 4, available online) appeared similar across a series of prespecified and nonprespecified subgroups. Notably, an aspirinassociated non-statistically significant trend toward increasing
cancer mortality, but not cancer incidence, was observed with age.

DeathsAn increased progression to death was observed among thoserandomly assigned to aspirin, regardless of whether the initialcancer presentation had been localized or metastatic (Table 2
and Figure 2). Table 3 demonstrates a higher death rate among

Compliance-Adjusted Treatment Effects
Adjusting for compliance (Supplementary Tables 3 and 4, available online) did not diminish the intention-to-treat aspirin
effects presented in Tables 2 and 3.

J. J. McNeil et al. | 261

Table 2. Number of individuals with incident cancer (n ¼ 1933) and deaths from cancer (n ¼ 495), by presentation of first cancer event, in the aspirin or placebo study arms (summarized as rates per 1000 person-years of follow-up)
Cancer incidencea

Cancer mortalityb,cNo. individuals withcancer diagnosis(rate per 1000 person-years)

Aspirin vsplacebo

No. individuals
dying from cancer(rate per 1000 person-years)

Aspirin vsplaceboCancer endpoint

AspirinPlaceboHR (95% CI)

AspirinPlaceboHR (95% CI)

First incident cancer
Incident localized cancer
Metastatic cancer
Incident metastatic cancer
Metastatic spread fromcancer reported prior
to random assignmentd
Hematological or
lymphatic cancer

981 (23.9)
631 (15.2)
258 (6.1)
196 (4.6)
62 (1.5)952 (23.0)
639 (15.3)
218 (5.1)
167 (3.9)51 (1.2)

1.04 (0.95 to 1.14)
0.99 (0.89 to 1.11)
1.19 (1.00 to 1.43)
1.18 (0.96 to 1.46)
1.23 (0.85 to 1.77)

283 (6.4)
93 (2.1)
171 (3.9)
143 (3.2)
28 (0.6)

212 (4.8)
64 (1.4)
133 (3.0)
109 (2.5)
24 (0.5)

1.35 (1.13 to 1.61)
1.47 (1.07 to 2.02)
1.30 (1.03 to 1.63)
1.32 (1.03 to 1.70)
1.18 (0.68 to 2.03)

92 (2.2)

95 (2.2)

0.98 (0.73 to 1.30)

19 (0.4)

15 (0.3)

1.28 (0.65 to 2.51)

aBased on time from random assignment to first incident cancer. CI ¼ confidence interval; HR ¼ hazard ratio.

b

Based on time from random assignment to cancer-related death in those who developed cancer.

cMortality definitions: Adjudicated cancer deaths only are included in this table. Note: 522 cancer-related deaths are reported in the recent publication by the same firstauthor (McNeil et al., N Eng J Med, 2018, “Effect of aspirin on all-cause mortality in the healthy elderly”; ref. 2), whereas only 495 deaths are reported here. Deaths that
could not be adjudicated but were attributed to cancer using death certificate codes are not included (n ¼ 7). Cancer deaths in participants who did not present withcancer prior to death are not included (n ¼ 20).

dDiscussion
We previously reported that among older adults taking lowdose aspirin for primary prevention in the ASPREE RCT, there
was an increased mortality rate, largely attributed to a higher
death rate from cancer (3). More deaths were observed amongaspirin-treated participants from cancers originating from a variety of anatomical sites, and these deaths were not attributable
to a specific “proximal” cause of death such as bleeding (3).
In this paper, we provide a more detailed assessment of thecancer incidence and mortality from cancer among the major
cancer subtypes according to stage of disease at presentation to
help provide a better understanding of the mortality findings.
Essentially, whereas the incidence of new localized cancer was
similar in those randomly assigned to aspirin or placebo, thenumber of individuals diagnosed with malignancy at an advanced stage (including those with metastatic cancer at diagnosis) was higher in the aspirin group.
Additionally, a higher death rate from cancer among thoserandomly assigned to low-dose aspirin was observed for all
solid tumors, regardless of whether the cancer was localized ormetastatic at presentation. This was most evident for cancers
that were stage 3 or 4 at diagnosis and for colorectal cancer. No
similar effect was seen with blood and lymphatic cancers.
There was no evidence of effect modification on mortality byage, sex, or risk factors for malignancy. The impact on mortality
from colorectal cancer was at least equal in magnitude to thatat other sites, and the findings were similar among subgroups
from both Australia and the United States.
The observed increase in risk of cancers presenting at an advanced stage and the increased death rate among those diagnosed with a later stage cancer, consistently observed acrossmultiple primary sites, suggest that aspirin may promote theprogression of advanced malignancies in this age group.
Possible explanations for this finding include aspirin suppressing (or blunting) antitumor inflammatory or immune responses

critical to controlling later stage growth and spread (12–14).
Such an effect may be particularly evident among an older population for which underlying antitumor immunity may alreadybe compromised (15).
Differences in the biology and behavior of tumors in older
adults are also well described. For example, among older adults,
colorectal cancer occurs more commonly in the right side of thecolon (16) and has a higher prevalence of specific molecularchanges, including deficiencies in mismatch repair and BRAF
mutations (17). In a previous study, we observed that regular aspirin use was associated with a lower risk of BRAF–wild-type colorectal cancer but not BRAF-mutated colorectal cancer (18).
Additionally, age has been shown to impact the types of mutations found within specific genes of tumors, such as the greater
incidence of the G12 mutation of KRAS in those younger than 40
years compared with the more common Q61 KRAS mutation inolder patients (19), along with a difference in the mutated geneitself (20). Other molecular changes have also been shown to be
more prominent in cancers of older people, such as the methylation state of certain genes (20, 21).
These reports make it plausible that aspirin might also act
differently, at the cellular or molecular level, in older individuals. Our results contrast with other data from previous RCTs,
summarized in earlier systematic reviews by Rothwell et al. (4),the US Preventive Services Task Force (22), and Haykal et al. (23).
Pooled analysis of trials, which included populations with amean age of approximately 10 years younger than in ASPREE,
found that aspirin neither increased nor decreased cancer incidence or mortality during the period of aspirin intervention,
typically 5 years (23). The recent ASCEND primary prevention
trial, conducted in somewhat younger individuals with diabetes
mellitus, also found no evidence of increased cancer mortality
after 7.4 years of follow-up (24). However, the most recently
published meta-analysis by Rothwell et al. (7) reported an increase in risk of cancer diagnosis with low-dose aspirin amongindividuals aged 70 years and older, when follow-up was limited

ARTICLE

Metastatic cancer of the same type as preexisting (prior to random assignment) cancer.

262 | JNCI J Natl Cancer Inst, 2021, Vol. 113, No. 3

Table 3. Cancer incidence and cancer mortality by stage, anatomical site, and treatment arm, as rates per 1000 person-years of observation
Cancer incidencea

AspirinCancer stage
at diagnosis
or anatomical site
All solid tumorsb
Stage 1
Stage 2
Stage 3
Stage 4c
Uncertain stage
Anatomic site of origind
Prostatee
Colorectal
Breastf
MelanomaLung
Bladder
Brain
Cervicalf
Gallbladder orbile duct
KidneyLiver
Mesothelioma
Esophageal
Ovary orendometriumf
Pancreatic
StomachThyroid
Other
Unknown

Cancer mortalitya
Aspirin vsplacebo

Placebo

No. cancer events No. cancer events(rate per(rate per1000 person-years) 1000 person-years)

HR (95% CI)

AspirinPlacebo

No. cancer events No. cancer events(rate per(rate per1000 person-years) 1000 person-years)

Aspirin vsplaceboHR (95% CI)

893 (21.7)
210 (5.0)
219 (5.2)
98 (2.3)
275 (6.5)
91 (2.1)

859 (20.7)
225 (5.3)
236 (5.5)
99 (2.3)
228 (5.3)
71 (1.7)

1.05 (0.95 to 1.15)
0.94 (0.78 to 1.13)
0.94 (0.78 to 1.12)
1.00 (0.75 to 1.32)
1.22 (1.02 to 1.45)
1.29 (0.95 to 1.76)

259 (5.9)
5 (0.1)
16 (0.4)
23 (0.5)
172 (3.9)30 (0.7)

196 (4.4)
9 (0.2)9 (0.2)11 (0.2)
133 (3.00)
16 (0.4)

1.33 (1.11 to 1.61)
0.56 (0.19 to 1.67)
1.80 (0.79 to 4.06)
2.11 (1.03 to 4.33)
1.31 (1.04 to 1.64)
1.89 (1.03 to 3.47)

199 (11.1)
139 (3.3)
127 (5.3)
87 (2.0)86 (2.0)37 (0.9)
18 (0.4)
2 (0.1)
11 (0.3)

202 (11.1)
137 (3.2)
124 (5.1)
106 (2.5)
84 (2.0)38 (0.9)9 (0.2)1 (0.04)
12 (0.3)

1.00 (0.82 to 1.21)
1.02 (0.81 to 1.30)
1.03 (0.80 to 1.32)
0.83 (0.62 to 1.10)
1.03 (0.76 to 1.40)
0.98 (0.62 to 1.54)
2.02 (0.91 to 4.49)
2.01 (0.18 to 22.13)
0.93 (0.41 to 2.10)

17 (0.9)35 (0.8)
15 (0.6)
12 (0.3)
55 (1.2)
8 (0.2)14 (0.3)
0 (0.0)8 (0.2)17 (0.9)20 (0.5)
7 (0.3)8 (0.2)51 (1.1)
9 (0.2)9 (0.2)0 (0.0)8 (0.2)

1.02 (0.52 to 2.01)
1.77 (1.02 to 3.06)
2.15 (0.88 to 5.27)
1.51 (0.62 to 3.69)
1.09 (0.74 to 1.59)
0.90 (0.35 to 2.33)
1.57 (0.68 to 3.62)
n/a1.01 (0.38 to 2.69)

25 (0.6)
7 (0.2)9 (0.2)11 (0.3)
40 (1.6)

18 (0.4)
1 (0.02)
6 (0.1)18 (0.4)
37 (1.5)

1.40 (0.76 to 2.57)
n/a1.52 (0.54 to 4.26)
0.62 (0.29 to 1.30)
1.09 (0.69 to 1.70)

9 (0.2)4 (0.1)5 (0.1)7 (0.2)15 (0.6)

4 (0.1)0 (0.0)2 (0.05)
13 (0.3)
13 (0.5)

2.28 (0.70 to 7.39)
n/a2.53 (0.49 to 13.03)
0.54 (0.22 to 1.36)
1.16 (0.55 to 2.43)

37 (0.9)
18 (0.4)
6 (0.1)66 (1.5)
20 (0.5)

29 (0.7)
11 (0.3)
5 (0.1)55 (1.3)
13 (0.3)

1.29 (0.79 to 2.09)
1.65 (0.78 to 3.49)
1.21 (0.37 to 3.97)
1.21 (0.85 to 1.73)
1.55 (0.77 to 3.12)

29 (0.7)
9 (0.2)0 (0.0)15 (0.3)
12 (0.3)

21 (0.5)
4 (0.1)0 (0.0)8 (0.2)9 (0.2)

1.39 (0.80 to 2.45)
2.27 (0.70 to 7.38)
n/a1.89 (0.80 to 4.46)
1.35 (0.57 to 3.19)

ARTICLEa

Cancer incidence is the first cancer event of anatomical type, noting that participants with more than 1 cancer type will be counted for each type. Cancer mortality

reports deaths from the same individuals included in the same row under incidence. CI ¼ confidence interval; HR ¼ hazard ratio.
b

Excludes hematological cancer and hematological cancer death. Stage 1 cancer incidence includes the first presentation with a cancer that was stage 1 at presenta-

tion. Cancer mortality is death from a cancer that was stage 1 at presentation. This format is repeated for stages 2-4 and uncertain stage.
c
Some cancer types (eg, prostate and bladder) can have nonmetastatic disease staged as stage 4.
dCancer type is ordered with the top 5 most prevalent cancers by incident listed first, then listed alphabetically.

efMales only.

Females only.

to 3 years. The authors noted this effect was observed only inthose with low body weight. Statistically significant effects fromaspirin were not seen in cancer deaths.
Given the multiple analyses undertaken without statisticalcontrol for multiple testing, the possibility that findings havearisen by chance, or from a bias in the ascertainment of relevant
outcomes, must also be considered. However, the objective endpoint of all-cause mortality was statistically significantly higher
among those randomly assigned to aspirin and is less likely to
be a chance finding. The difference in cancer mortality
explained virtually all of this difference. The process for allocating cause of death required blinded adjudicators to confirm allcancer diagnoses and determine the underlying reason for the
trajectory to death, which reduced the likelihood of biased ascertainment of cancer endpoints. In an older age group, wheremultimorbidity is common and clinical investigations may belimited, the illness ultimately leading to death frequently
requires a review of clinical documentation to determine themost likely pathology. This process was undertaken to review

all deaths occurring during ASPREE, in contrast with earlier aspirin trials.
The results might also be explained if there was a bias in theascertainment of the outcome, most obviously, if aspirin led toa systematic delay in the recognition of cancer, so that among
those taking aspirin, cancer was diagnosed at a more advanced
stage. However, this is unlikely because we did not observe atime-dependent compensatory decrease in incidence of stages
1-3 cancers that would offset the observed increase in the incidence of stage 4 cancer. As reported previously, the difference
also did not appear to be explained by differences in the modeof death, for example, if aspirin increased the likelihood of a patient with cancer dying prematurely from hemorrhage or infection (3).
During more prolonged follow-up of participants in earlier
primary and secondary prevention trials, a delayed protective
effect of aspirin on cancer incidence and mortality has been observed, particularly for colorectal cancers (8,22). In 2010,
Rothwell and colleagues (8) reported a long-term follow-up of

J. J. McNeil et al. | 263

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Figure 1. Cumulative incidence of first incidence of solid tumor cancer, by stage and treatment group.

Figure 2. Cumulative incidence of cancer-related death following a first presentation of localized or metastatic cancer. Panel (A) shows localized cancer, and panel (B)shows metastatic cancer. Time is from random assignment to the occurrence of death following the cancer event.

participants from 4 large random assignment trials of aspirin(75-300 mg/d), which found that allocation to aspirin reduced
the 20-year risk of cancer mortality (HR ¼ 0.65, 95% CI ¼ 0.48 to0.88), and the benefit increased with treatment duration. In the
Women’s Health Study (alternate-day 100 mg aspirin), aspirin
was associated with reduced colorectal cancer incidence that
became apparent during subsequent posttrial follow-up
10 years after random assignment (25). These results aresuggestive of a delayed benefit of aspirin and emphasize the importance of ongoing follow-up of the ASPREE cohort.
Strengths of ASPREE include the use of blinded expert
reviewers to categorize both tumor stage and causes of death,thus minimizing bias or misclassification. However, limited statistical power was available to examine the effect of aspirin
within subgroups or on specific cancer subtypes, and consideration about the multiplicity of statistical analyses also

264 | JNCI J Natl Cancer Inst, 2021, Vol. 113, No. 3

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Figure 3. Forest plots of solid tumor cancer incidence and mortality by subgroup. Solid tumor cancer incidence is shown (A) and mortality is shown (B). Subgroups areclassed from baseline (enrollment) and include age in years, BMI (in kg/m2), prior cancer history, and family cancer history. For ’Other’, within the ethnicity/race subgroup, all events occurred in the aspirin arm (ie, no events in the placebo arm), and thus, HR cannot be estimated. Not all participants were asked about cancer-related
medical screening (questionnaire introduced late in recruitment, 2013). AUS ¼ Australian; BMI ¼ body mass index; CI ¼ confidence interval; HR ¼ hazard ratio; pts ¼
participant; NA ¼ not applicable.

constrains some of our conclusions. Finally, although we did
not observe a differential effect of aspirin on cancer mortality
according to a history of prior aspirin use, our overall results do
not specifically address whether aspirin use initiated at a younger age should be discontinued after ages 65 to 70 years.
If confirmed, the clinical implications of these findings could
be important for the use of aspirin in an older population. If
low-dose aspirin were to hasten the progression of cancers, itsrole as a primary prevention agent would be further diminished.
However, the increased risk in ASPREE was small (an extra 1.5
deaths from cancer per 1000 person-years) in comparison withthe risk of mortality from other causes. Several RCTs are currently underway to address the use of aspirin after diagnosis
and treatment of cancer with curative intent, and these results
may be of particular value in supporting or refuting these findings, provided they include sufficient numbers of older subjects(26–30).
In summary, among generally healthy adults predominantly
70 years of age or older at enrollment and followed for a medianof 4.7 years, daily low-dose aspirin was associated with anincreased risk of incident solid cancers presenting at an advanced stage. Mortality from both localized and advanced cancers was higher in those taking aspirin, suggesting a possible
adverse effect of aspirin on cancer evolution in older adults.
Cancer molecular and genetic data give reason to suggest thatthe potential adverse impact of aspirin identified in ASPREE
might be specific to this age group. The cohort continues to befollowed to explore the possibility of a delayed reduction in cancer incidence and/or mortality that may emerge with longerterm observation.

Funding
This work was supported by grants from the National
Institute on Aging (U01AG029824, U19AG062682), from the
National Cancer Institute (R01CA137178 and R35CA253185
to ATC), from the National Health and Medical ResearchCouncil of Australia (334047 and 1127060), and from Monash

University and the Victorian Cancer Agency. Dr Chan is a
Stuart and Suzanne Steele MGH Research Scholar.

Notes
Role of the funders: No sponsor had any role in the study design, data collection, analysis, interpretation, the writing, anddecision to submit the manuscript.
Disclosure: Drs Chan, Murray, and Nelson received travel compensation and a consulting fee for presentation of results of the
ASPREE primary papers at a Bayer PharmaAG–sponsored conference in October 2018. Drs Chan and Zalcberg have received
research funding for unrelated studies from Bayer Pharma AG.
All other authors certify that there is no actual or potential conflict of interest in relation to this article. Dr McNeil had full access to the data in the study and takes final responsibility forthe decision to publish. He was not paid to write this article.
Author contributions: JMcN: conceptualization, methodology,
supervision, resources funding acquisition, writing—originaldraft. PG: methodology, validation, investigation. SO: methodology, project administration, data collection, writing, supervision, investigation. JL: methodology, investigation, software,data curation, supervision, validation. WB: investigation, validation. YC: investigation, validation. AH: investigation, validation. FM: investigation, validation. CM: investigation, validation.
JM: investigation, validation. LMR: investigation, validation. JT:investigation, validation. AU: methodolgy. JvL: investigation,
validation. JZ: investigation, validation. LF: methodology. ER:
methodology. methodology. BK: methodology, investigation,
project administration. AM: investigation, project administration. MN: investigation, project administration. CR: investigation, project administration. RS: investigation, project
administration. KR: writing (review and editing). GP: data analysis, data interpretation, visualization. RW: data analysis, datainterpretation, visualization. RLW: methodology, investigation,
supervision, resources funding acquisition, project administration. ATC: conceptualization, methodology, supervision, writing. All authors were involved in writing (review and editing).
Acknowledgments: The authors would like to thank the participants, the collaborating general practitioners and other clinicalstaff, the data monitoring committee, Catherine Smith who
conducted the compliance-adjusted analyses, and all the administrative and other staff who helped conduct the trial. A fulllisting of the ASPREE collaborators is listed at www.aspree.org.

Data availability
The data underlying this article will be shared on reasonable request addressed to ASPREE.AMS@monash.edu.

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