At the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology 2026, held in Paris, Pierre Michel, MD , professor and hospital practitioner at Rouen University Hospital, Rouen, France, presented data on aspirin in the prevention of colorectal cancer (CRC).

Practical Lessons

• Current evidence does not support routine long-term aspirin use for the primary prevention of CRC in the general population.
• Aspirin shows benefits in Lynch syndrome, although the optimal dose has not yet been defined.
• After CRC surgery, aspirin may be considered for patients whose tumors show alterations in the PI3K PTEN pathway.
• Aspirin is well known, inexpensive, and generally has low toxicity compared with cancer treatments.

Mechanistic Basis

Aspirin has long been used for its analgesic, antipyretic, and antiplatelet properties. Interest in its role in oncology, particularly in CRC, has expanded over time.

Its primary mechanism involves the inhibition of cyclooxygenase enzymes, which are key mediators of prostaglandin synthesis. Three biologic compartments are implicated in colorectal carcinogenesis: platelets, inflammatory and immune cells, and colonocytes.

At the platelet level, aspirin reduces aggregation through inhibition of thromboxane A2 and may limit tumor cell adhesion to the endothelium.

Within the inflammatory and immune pathways, aspirin reduces prostaglandin E2 (PGE2), a mediator associated with tumor immune tolerance.

Direct effects on colonocytes also involve reduced PGE2 production, which influences signaling pathways associated with cellular proliferation, including APC, RAS, RAF, MAPK, PI3K, and PTEN. This reduction may slow the progression of CRC.

Additional PGE2-independent mechanisms include inhibition of the NF-κB pathway and induction of cytochrome C release from the mitochondria, which promotes apoptosis. These combined effects contribute to the suppression of carcinogenic pathways.

Observational Evidence

The hypothesis that aspirin reduces CRC incidence dates back to the 1950s. Multiple meta-analyses, including those published in The Lancet (2010), The Lancet Oncology (2012), and Annals of Oncology (2020), have reported beneficial effects of aspirin on the incidence of CRC.

These benefits extend beyond CRC to other gastrointestinal cancers, including esophageal, gastric, and biliary cancers.

Key findings from these meta-analyses include the following:

• A probable dose effect: although early studies used relatively high doses, more recent data suggest benefits at lower doses, in the range of 75-300 mg/d.
• An effect related to the duration of intake or intervention > 5 years is associated with benefits.
• Timing of treatment initiation: starting aspirin after the age of 70 years does not change the incidence of CRC.
• A particularly marked effect on metastatic forms: a greater reduction in cancers diagnosed at a metastatic stage.

Recent population-based studies from the US, Spain, and Norway revealed that long-term, low-dose aspirin use significantly reduced CRC incidence, particularly in patients with cardiovascular (CV) risk factors. No reduction was observed among individuals without CV risk factors. In higher-risk populations, aspirin use was associated with a CRC incidence closer to that of the broader population.

In these studies, aspirin use was not controlled, and the indication for prescribing aspirin was not specified, although it may have been linked to the underlying CV risk factors.

These findings support the consideration of aspirin for the primary prevention of CRC in populations with CV risk but not in the general population.

Genetic Risk

To date, no proven benefit of aspirin has been reported for familial adenomatous polyposis.

Evidence supports a preventive effect in Lynch syndrome. Aspirin at 600 mg/d for ≥ 2 years reduced the risk for CRC by 37% (hazard ratio [HR], 0.63; P = .018). These findings support its use in this high-risk group, although the minimum effective dose remains under evaluation, with ongoing studies assessing doses of 300-600 mg/d.

Postoperative Use

Another area of interest for aspirin is the postoperative period after CRC resection. A study published in 2012 reported a substantial benefit in patients with tumors harboring PI3K mutations, with an HR of 0.18 (P < .001). This observation prompted prospective randomized trials.

A Swiss study evaluated aspirin 100 mg daily for 3 years in 112 patients with PI3K mutations after surgery. Disease-free survival over 4 years improved but did not reach statistical significance (HR, 0.57).

Another Swedish study conducted in nearly 3000 patients with PI3K alterations showed improved 3-year disease-free survival among 515 patients treated with aspirin 160 mg/day for 3 years, although the result did not reach statistical significance (HR, 0.61; 95% CI, 0.34-1.08).

Further analysis of the second study strengthened the findings when extended to mutations in the PTEN pathway. In 588 patients with abnormalities in both the PI3K and PTEN pathways, aspirin was associated with a significant survival benefit (HR, 0.51; 95% CI, 0.29-0.88).

In the same group, postoperative aspirin reduced the risk for recurrence by approximately 40% (HR, 0.42; 95% CI, 0.21-0.83).

A third study expected in 2026 could help confirm these findings, and current evidence suggests that low-dose aspirin (100-160 mg/d) may have a role as adjuvant therapy in patients with PI3K and PTEN mutations, which account for approximately 37% of CRC.

This story was translated from Univadis France, part of the Medscape Professional Network.