Differential Effects of Aspirin Before and After Diagnosis of Colorectal Cancer

Abstract

ALTHOUGH MORBIDITY AND MORTALITY FROM COLOrectal cancer have steadily decreased over the past 3 decades, colorectal cancer remains the third most common form of cancer and the third most common cause of cancer death in the United States. Early disease detection through increases in screening that can identify and allow removal of precancerous polyps is thought to be the major reason for the decrease in colorectal cancer incidence. Additionally, new chemotherapy regimens and targeted therapies have improved the outcome of patients with locally advanced and metastatic colorectal cancer. Several risk factors for colorectal cancer have been identified in epidemiologic studies. These include obesity, 50 years or older, personal and family history of polyps or colorectal cancer, diabetes, and black race/ethnicity. Similarly, several factors are associated with decreased colorectal cancer risk. For example, observational data suggest that physical activity and increased dietary calcium intake are associated with decreased risk of colorectal cancer. There are no generally accepted chemopreventive recommendations for individuals at average risk of colorectal cancer but several medications have been shown to have a cancer preventive effect in averageand high-risk populations. The most compelling evidence comes from observational and interventional trials showing that aspirin is protective against the development of colorectal cancer, colorectal cancer metastases, and disease recurrence after diagnosis of the disease. In addition, the protective effect of aspirin also has been demonstrated in patients with hereditary colorectal cancer. The mechanism of action of the colorectal cancer chemopreventive and anticancer effects of aspirin is not fully understood, but it has been attributed to the antiinflammatory effects of the drug, specifically inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2, formerly named cyclooxygenase 2 or COX-2). PTGS2 is the ratelimiting step for the conversion of arachidonic acid to prostaglandins, and it is overexpressed in the majority of colorectal cancers. In the past few years, several studies have attempted to dissect aspirin’s mechanism of action with respect to colorectal cancer development and progression to identify which subtypes of colorectal cancer aspirin most effectively prevents both before and after diagnosis. In 2009, Chan et al demonstrated that regular aspirin intake after diagnosis of colorectal cancer in patients whose primary tumors overexpressed PTGS2 as assessed by immunohistochemistry was associated with a 60% decreased risk of colorectal cancer– specific mortality. In contrast, there was no association between aspirin use and lower mortality risk among patients whose primary tumors had weak or absent PTGS2 expression. In 2012, Liao et al tested the hypothesis that mutations in the PIK3CA gene, one of the most commonly mutated genes in colorectal cancer, might influence the effect of aspirin in patients with a diagnosis of colorectal cancer. This study showed that the decreased risk of colorectal cancer recurrence associated with the use of aspirin was restricted to patients with tumors harboring a mutated PIK3CA gene. PIK3CA belongs to the PI3K-AKT signaling pathway, which is inappropriately activated in many cancers, including colorectal cancer. The BRAF gene belongs to the RAS-RAF-MEK-ERK signaling pathway and is mutated in approximately 14% of colorectal cancers leading to uncontrolled activation of the pathway. Furthermore, there is evidence that somatically acquired mutations of the BRAF gene portend a poor prognosis. Whether the BRAF gene acts as a mediator of the effect of aspirin prior to and after diagnosis of colorectal cancer is unknown. Importantly, both pathways are directly activated by the epidermal growth factor receptor (EGFR), an established therapeutic target in advanced colorectal cancer. In this issue of JAMA, Nishihara et al analyzed tumors from 1226 patients with a diagnosis of colorectal cancer for mutations within the BRAF gene. When compared to nonusers, aspirin users had a 27% lower risk of having tumors with an intact BRAF gene. In contrast, aspirin use was not associated with any change in risk for BRAF-mutated tumors. Use of aspirin after diagnosis of colorectal cancer did not modify the outcome for patients with either BRAFmutated or BRAF–wild-type tumors.