Clin Cancer Res. 2013 Dec 10. [Epub ahead of print]

Aspirin and colorectal cancer: Back to the Future.

Tougeron D, Sha D, Manthravadi S, Sinicrope FA.

Author information

• Gastroenterology Research Unit, Mayo Clinic.

Abstract

Abundant epidemiological evidence indicates that regular and long term use of aspirin is associated with a significant reduction in the incidence of colorectal cancer (CRC). The long duration of aspirin needed to prevent CRC is believed to be due to inhibition of precursor lesions known as adenomas, whose recurrence is inhibited by aspirin in randomized trials. Aspirin intake has also been associated with a statistically significant improvement in patient survival after curative resection of CRC in large observational studies. In these cohorts, the survival benefit of aspirin was shown to depend upon the level of cyclooxygenase-2 (COX-2) expression in the primary CRC. More recent analysis of patient tumors from these observational cohorts suggests that the benefit of aspirin may be limited to specific molecular subtypes. Aspirin intake following CRC resection was associated with a significant improvement of survival in patients whose tumors carried mutant, but not wild-type, copies of the phosphatidylinositol 3-kinase (PI3KCA) gene, especially tumors that overexpressed COX-2. A mechanistic explanation is suggested by the finding that inhibition of COX-mediated prostaglandin E2 synthesis by aspirin attenuates PI3K signaling activity that is known to regulate cancer cell proliferation and survival. Aspirin has also been shown to reduce the incidence of CRCs bearing wild-type, but not mutant alleles of the BRAFV600E oncogene. While provocative, the potential utility of these molecular markers for predicting aspirin efficacy awaits prospective evaluation in clinical trials. If validated, these finding may support a personalized approach to using aspirin for the therapy of CRC.