Aspirin use reduced BRAF wild-type colorectal cancer risk

David H. Ilson, MD, PhD

Regular therapy with aspirin has been shown to have a significant impact on the development and natural history of colorectal cancer. Use of aspirin and similar agents that inhibit prostaglandin synthetic pathways reduces polyp formation in individuals with familial adenomatous polyposis. Several decades of regular aspirin use results in up to a 30%-50% reduction in the risk of colorectal cancer mortality as reported in two large patient population observational studies, the Nurses’ Health Study and the Health Professional Follow-Up Study. In addition, after curative colorectal cancer treatment, use of aspirin improves survival and reduces the risk of colorectal cancer recurrence.

Study of tumor tissue derived from patients in the Nurses’ and Health Professionals studies is now revealing potential mechanisms of aspirin as a preventive therapy, and whether specific molecular subtypes of colorectal cancer might be affected differently depending on tumor genomic profile.

The authors of the current study have pursued several hypothesis-driven analyses of colorectal cancer tissue from participants on these large studies. Because cyclooxygenases — and in particular, cyclooxygenase-2 — are targets of inhibition of aspirin, the investigators initially investigated expression of COX-2 as a potential predictive marker for a preventive effect of aspirin in colorectal cancer.

Overexpression in tumors of COX-2 by immunohistochemistry correlated with a preventive benefit for aspirin usage, with no benefit seen for normal COX-2 expression, supporting COX-2 as the potential chemoprevention target. A subsequent study, and the current study, explore potential genomic mutations in these tumors, with the hypothesis that mutations that potentially upregulate or enhance COX pathways might enhance the effect of aspirin as a preventive therapy, and conversely some activating genomic mutations might abrogate an aspirin effect. Activating mutations in PI3kinase, which are present in up to 10% of colorectal cancers and potentially impact downstream on COX-2, identified patients who had a reduced risk of colorectal cancer with aspirin, compared with no benefit seen in PI3 kinase wild-type tumors.

The current study evaluates BRAF mutation status in these tumors.  Activating BRAF mutations, present in 5%-10% of colorectal cancers, may be important in downstream upregulation of COX-2 activity. The authors make a number of intriguing observations in this study. The relative reduction of colorectal cancer development is limited to the BRAF wild-type cancers, and the benefit shows an aspirin dose response and dose duration effect that lead to increasing risk reduction. Neither usage, dose nor duration of aspirin had any impact on development of BRAF-mutant cancers. Whereas COX-2 expression by immunohistochemistry correlated with a reduced risk of colorectal cancer in BRAF wild-type tumors, no impact was seen in BRAF-mutant tumors. No impact was seen for PI3 kinase mutation status and BRAF wild-type tumor risk and aspirin usage.

How will such studies be applied to clinical practice? We now have a better understanding how aspirin mediates cancer prevention. The results are hypothesis generating and suggest that aspirin therapy may exert risk reduction only in certain tumor molecular subtypes. Such a greater understanding may lead to more targeted use of chemopreventive strategies after colorectal cancer therapy. The problem however, is given that multiple potential biomarkers have been identified in these studies, which should be studied and validated in further analysis? Which, if any, of these biomarkers could potentially be used to select appropriate patients likely to benefit from aspirin therapy — or other preventive therapies — after curative treatment of incident colorectal cancer? Current practice is to recommend aspirin prophylaxis in patients with documented Lynch syndrome, and aspirin therapy is also recommended after curative treatment of colorectal cancer.