Aspirin in Colorectal Cancer Care: Who to Treat, When, and Why

Purpose of Review: Aspirin is ubiquitous, inexpensive, and mechanistically compelling in colorectal cancer (CRC), yet its clinical role has become more ambiguous with—notwithstanding—new data. Neutral phase III results in unselected disease, biomarker-restricted signals of benefit, and guideline shifts driven by bleeding risk have left clinicians without a consistent, setting-specific approach. This review fills that gap by translating the post-precision aspirin literature into a selection-first framework that specifies who may benefit, when off-trial use is reasonable versus discouraged, and why trial enrolment remains the preferred option in key areas of uncertainty. Recent Findings: In prevention, aspirin produces modest reductions in adenoma recurrence in selected high-risk surveillance cohorts and shows delayed cancer-endpoint benefit in Lynch syndrome, highlighting that baseline CRC risk and time horizon are decisive. In older adults and lower-risk settings, the time-to-benefit often does not align with a higher, earlier bleeding liability. After curative-intent treatment, randomised trials now define clear boundaries: routine adjuvant aspirin in unselected resected CRC is not supported, whereas recurrence reduction appears confined to PI3K-pathway /PIK3CA-altered localised disease, supporting biomarker-restricted consideration and rigorous prospective validation. In metastatic CRC, existing signals are largely non-randomised and confounded, precluding anticancer-motivated prescribing outside prospective studies. Summary: Aspirin in CRC should be targeted rather than routine. The proposed clinical algorithm integrates setting, absolute risk, PI3K/PIK3CA status, bleeding/antithrombotic context, and expected time horizon to maximise net benefit while reducing avoidable harm, and to prioritise trial enrolment where equipoise persists.