- Although aspirin use has been studied for decades, there are still many gaps in our understanding its role in cancer prevention.
- Risk-benefit analyses should be conducted to ensure that the right patients are receiving aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) to reduce cancer incidence and cancer-related mortalities.
The National Cancer Institute (NCI) Division of Cancer Prevention (DCP) hosted a two-day virtual meeting to discuss aspirin and NSAIDs in cancer prevention and treatment.
The workshop was catalyzed by the ASPirin in Reducing Events in the Elderly (ASPREE) trial. In 2018, study investigators reported that relatively healthy older adults who received daily aspirin had higher all-cause mortality than a placebo group. A long-term follow-up of the cohort is ongoing to understand if aspirin effect is modulated after a long-term follow-up as seen with other randomized clinical trials.
The goals for the workshop were to stimulate ideas on research gaps, determine future directions, and discuss possible opportunities.
Past studies and meta-analyses have indicated that aspirin reduces overall cancer incidence and mortality in the general population, both in the short and long term. But recent prevention trials have had differing results. These trials include ASPREE, A Study of Cardiovascular Events iN Diabetes (ASCEND), and Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE).
|Trial||Participants||Intervention||Mean age or age range (years)||On-treatment duration (years)|
|ASPREE||19,114||100 mg aspirin daily vs. placebo||70+||4.7|
|ASCEND||15,481||100 mg aspirin daily vs. placebo||63||7.4|
|ARRIVE||12,546||100 mg aspirin daily vs. placebo||64||5|
ASPREE recruited an older population than previous trials. Some workshop attendees voiced concern that the reported analyses were undertaken without statistical control for multiple testing.
ASCEND recruited adults with diabetes and no known cardiovascular disease. The trial found that daily aspirin did not significantly alter the incidence of gastrointestinal tract cancer or all cancers.
ARRIVE recruited participants with moderate risk of cardiovascular disease. The trial did not find that aspirin altered cancer incidence, but the study duration may not have been sufficient to investigate long-term outcomes. Additional results about cancer incidence will be reported after a longer follow-up in the study participants in the future.
Longer-term follow-up will also be available from ASPREE and ASCEND in the coming years.
Research Gap: Mechanism
The molecular mechanisms by which aspirin and NSAIDs exert a cancer preventive effect are not fully understood. Several lines of evidence, however, suggest aspirin’s anti-inflammatory activity may play a key role in this effect. The role of aspirin relevant to inflammation and immune response were discussed in the meeting and outlined here.
Aspirin blocks the activity of the enzymes prostaglandin G/H synthase 1 (PTGS1) and PTGS2, also known as cyclooxygenase-1 (COX-1) and COX-2. These enzymes produce prostaglandins and other compounds involved in the inflammatory response.
Aspirin’s anti-cancer effect appears to rely on the prostaglandin pathways. Tumor specimens from the Nurses’ Health Study and the Health Professionals Follow-up Study showed that regular use of aspirin reduced the risk of colorectal cancers with high levels of PTGS2 protein, but not the risk of colorectal cancers with low levels or no expression or PTGS2.
PGE-M, a molecule produced by prostaglandin pathways, is associated with increased risk for colorectal cancer. The ASPirin Intervention for the REDuction of Colorectal Cancer Risk (ASPIRED) trial found that aspirin use reduced urinary PGE-M levels in individuals with a history of colorectal adenoma, to levels consistent with a lower risk for colorectal cancer. Potentially, PGE-M could be used as a biomarker to identify who would benefit most by taking aspirin.
Another area of investigation is how inflammation and inflammatory mediators affect the type and density of immune cells in the tumor microenvironment. New targets are being investigated, such as E-prostanoid (EP) receptors EP2 to EP4 and C-X-C motif chemokine receptor 2 (CXCR2). Drugs directed to these pathways may potentially have fewer side effects than aspirin.
Given the findings of ASPREE, there is a need to explore biological mechanisms in older adults. Aspirin may be suppressing the inflammatory response and allowing cancer to progress in the context of less robust immune response in older individuals. Older populations could also experience different drug interactions, have altered tumor microenvironments, and face different types of cancer. More mechanistic research is needed to understand age as a modifier of aspirin’s cancer preventive efficacy.
Research Gap: Population
A theme throughout the workshop was identifying populations for whom the benefits of aspirin for cancer prevention outweigh harms, like gastrointestinal bleeding and intracranial bleeding.
One approach could be recommending aspirin for people with the highest risk of developing cancer, due to genetics, exposures, or behavior. A risk calculator could provide a score by factoring predictors like smoking, body mass index (BMI), and age. Another consideration is to evaluate individuals’ risk for complications from aspirin use.
Discussions during the meeting highlighted specific sub-populations that are being evaluated in randomized control trials or could be studied in the future.
Lynch syndrome is an inherited condition that causes increased risk of colorectal, endometrial, and other cancers. One in 279 individuals are estimated to have a gene mutation associated with Lynch syndrome, but most people with Lynch syndrome are not being identified.
The UK CaPP2 trial found that two standard aspirins per day for 2 years reduced colorectal cancer incidence in people with Lynch syndrome. This effect was only seen after long-term follow-up (over a decade) but was not apparent until about 5 years after the study began.
Meta-analyses of cerebrovascular endpoint trials suggest that aspirin reduces the risk of developing cancer or risk of death from cancer. Large population-based studies also indicate that post-diagnosis use of aspirin reduces cancer mortality.
The Add-Aspirin trial is examining whether daily aspirin prevents cancer recurrence and prolongs survival in people who have had early-stage breast, colorectal, esophageal, or prostate tumors removed. One aim is to explore platelet activation as a potential mechanism of action for aspirin’s benefit.
A 2018 meta-analysis of 10 primary prevention studies found aspirin-mediated reductions in long-term risk of colorectal cancer dependent on body weight. While aspirin had no effect on the overall number of cancer-related deaths, it reduced cancer-related deaths after 5 years of follow-up in participants weighing less than 70 kilograms.
Some meeting attendees were concerned that this meta-analysis did not properly account for multiple comparisons. Additionally, a post hoc analysis of the ASPREE trial found that neither body weight nor BMI altered aspirin’s effect on the risk of cardiovascular disease or major hemorrhage.
Earlier studies did not examine racial/ethnic differences in the use of aspirin for cancer prevention. This is something that needs to be considered in future trials.
Research Gap: Dosage Regimen
It is not clear what dose, route and frequency of aspirin would be most beneficial for high-risk groups or a younger general population.
Several trials are currently evaluating multiple doses of aspirin, with the goal of minimizing harms, while still reducing the risk of cancer.
- CaPP3 is testing three doses of aspirin in people with Lynch syndrome: 600 milligrams, 300 milligrams, or 100 milligrams per day.
- Add-Aspirin is comparing two doses of aspirin to a placebo as an adjuvant treatment: 300 milligrams or 100 milligrams per day.
The 2018 meta-analysis of 10 primary prevention trials mentioned above found that low doses of aspirin (75-100 milligrams) reduced the 20-year risk of colorectal cancer only in participants weighing less than 70 kilograms. Higher doses of aspirin (325 or more milligrams), however, benefited participants weighing up to 80 kilograms.
Future trials evaluating aspirin may need to consider body weight and body-mass index (BMI) of trial participants to determine the optimal drug dosage. Some workshop attendees cautioned, however, that these conclusions were a result of multiple comparisons of the data.
Some workshop attendees suggested that biomarkers from prostaglandin pathways, like PGE-M, could provide a readout that would allow the aspirin dose to be lowered while still reducing cancer risk.
Other formulations of aspirin may have fewer side effects. Vazalore is a liquid-filled targeted-release aspirin capsule and Innovate Pharmaceuticals has developed a liquid aspirin (licensed by Innovate Anti-Infectives).
There was discussion about administering aspirin once per week, instead of daily, to reduce toxicity. Meeting attendees did not recall previous trials that had tested such a frequency, though the Women’s Health Study investigated low-dose aspirin given every other day. More studies are needed to evaluate intermittent dosing.
Research Gap: Other NSAIDs
Other agents may achieve the same anti-tumorigenic effects as aspirin.
Celecoxib selectively blocks cyclooxygenase-2 (COX-2, also known as PTGS2). A 2000 study reported that in patients with familial adenomatous polyposis (FAP), treatment with daily celecoxib for 6 months reduced the number of colorectal polyps. A longer study, the Adenoma Prevention with Celecoxib (APC) trial, followed participants who had adenomas removed before study entry and received celecoxib daily. Colonoscopies at year 1 and year 3 showed that celecoxib effectively prevented colorectal adenomas. But trial participants also had an increased risk of cardiovascular events.
In 2011, marketing authorization of celecoxib for reducing colorectal polyps in FAP was withdrawn in the United States and Europe because a postmarketing study intended to verify clinical benefit and required as a condition of approval was not completed. However, more recent comparison of celecoxib with other major NSAIDs showed that at moderate doses, celecoxib was non-inferior to ibuprofen or naproxen with regard to cardiovascular safety.
There are unanswered questions about who can take celecoxib safely for cancer risk reduction. There is a subset of individuals who appear not to suffer the same cardiovascular side effects but have not been prospectively tested. Additional areas for investigation include the optimal dosing regimen and whether celecoxib has other anti-cancer mechanisms.
Sulindac blocks both human cyclooxygenase enzymes. A phase III trial found that a low dose of sulindac in combination with DFMO (eflornithine) daily for 36 months reduced colon polyp recurrence. A recent study in patients with FAP did not show that disease progression was lower with a combination of these drugs than with either drug alone.
Naproxen blocks both human cyclooxygenase enzymes. A phase Ib randomized clinical trial in patients with Lynch syndrome found that naproxen is a safe intervention for cancer prevention when administered daily for 6 months. The authors found that naproxen activated immune cells in the colorectal mucosa.
Next Steps: Trial
The final session of the think tank discussed a clinical trial that could begin to address these research gaps. A large population-based trial of participants 50 to 65 years of age was presented, randomized to low-dose and standard-dose aspirin, as well as to a 5- and 10-year treatment duration. A focus would be identifying those at high risk of bleeding. Smaller trials could be done in select high-risk populations, such as individuals with early age onset colorectal cancer, building on the work done with Lynch syndrome.
There was additional discussion without a clear consensus:
- Is a placebo arm needed? And is it sufficient to just evaluate a standard dose of aspirin.
- Will it be necessary to consider dosing relative to body size?
There was also a call to action to include primary providers in discussions, to learn their concerns about prescribing aspirin and to ensure that primary care providers can deliver simple and effective messaging to patients.
The final remarks of the meeting were to keep the momentum going and to establish a small group to begin designing a draft protocol.
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