Although aspirin has been considered a promising agent for prevention of colorectal cancer (CRC), recent data suggest a lack of benefit among older individuals. Whether some individuals with higher risk of CRC may benefit from aspirin remains unknown. We used a 95-variant CRC polygenic risk score (PRS) to explore the association between genetic susceptibility to CRC and aspirin use in a prospective study of 12,609 individuals of European descent aged {greater than or equal to} 70 years, enrolled in the ASPREE (ASPirin in Reducing Events in the Elderly) double-blinded, placebo-controlled randomized trial (RCT). Cox proportional hazards models were used to assess the association of aspirin use on CRC, as well as the interaction between the PRS and aspirin treatment on CRC. Over a median of 4.7 years follow-up, 143 participants were diagnosed with incident CRC. Aspirin assignment was not associated with incidence of CRC overall (hazard ratio [HR]=0.94, 95% confidence interval (CI) 0.68-1.30) or within strata of PRS (p for interaction=0.97). However, the PRS was associated with an increased risk of CRC (HR=1.28 per standard deviation [SD], 95% CI 1.09-1.51). Individuals in the top quintile of the PRS distribution had an 85% higher risk compared with individuals in the bottom quintile (HR=1.85, 95% CI 1.08-3.15). In a prospective RCT of older individuals, a PRS is associated with incident CRC risk, but aspirin use was not associated with a reduction of incident CRC, regardless of baseline genetic risk.

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