BRAF-Mutated Colon Cancer May Be Less Responsive to Aspirin's Positive Effects

Compiling results of two large studies, researchers have identified biomarkers of response to aspirin among those taking the oral drug either as a way to treat or prevent colorectal cancer. The analysis shows that the effect of aspirin on colorectal cancer depends on whether or not the cancer harbors a BRAF mutation: those cancers that were BRAF mutated were less sensitive to aspirin. The study is published in JAMA.

Compelling evidence of aspirin as a preventive measure against colorectal cancer has been accumulating in the last several years. Aspirin has been shown to stave off initial colorectal cancer (including in those with a genetic predisposition to colorectal cancer) and metastasis after a diagnosis of localized prostate cancer, as well as to lower the rate of recurrence of the disease. The way aspirin dampens the cancer is not well understood. The best hypothesis thus far is that aspirin decreases inflammation by inhibiting prostaglandin-endoperoxide synthase 2 (PTGS2, also known as COX-2), which is overexpressed in many colorectal cancers.

Reiko Nishihara, PhD, of the Dana-Farber Cancer Institute in Boston, and colleagues analyzed whether aspirin use influenced the risk of either BRAF wild type or BRAF-mutated colorectal cancer. The data came from two questionnaire data-the Nurses’ Health Study (from 1980) and the Health Professionals Follow-Up Study (from 1986). Of the 127,865 participants in the studies, the authors analyzed tumors from 1,226 patients who were diagnosed with colorectal cancer for BRAF mutation status. The participants were followed from 2006 until 2012.

Those patients who took aspirin had a 27% lower risk of being diagnosed with a BRAF wild type colorectal cancer but no change in risk was seen for the emergence of BRAF-mutated tumors. This association was regardless of whether the tumor showed overexpression of PTGS2. Those who took an increasing number of aspirin tablets weekly (more than 14 tablets per week) had an even lower risk of BRAF wild type cancer compared to those who did not take aspirin, but this trend was not statistically significant. Longer aspirin use correlated with a significant decrease in the BRAF wild type form of the cancer.

The potential protective effect of aspirin was only seen early in the disease, and not after colorectal cancer had already developed. Aspirin use did not appear to influence clinical outcomes in patients diagnosed with colorectal cancer, regardless of BRAF mutation status.

As Boris Pasche, MD, PhD, of the University of Alabama in Birmingham, notes in his editorial on the study, risk factors that both increase and decrease the risk of colon cancer have been identified. Physical activity and a diet high in calcium have both been identified, in observational studies, to lower risk of the disease. Risk factors for colorectal cancer, identified through epidemiological studies, include age older than 50, personal and family history of polyps or colorectal cancer, diabetes, obesity, and black race/ethnicity.

According to Pasche, further studies need to address the effect of aspirin on the black population, since these are the individuals who have the highest incidence of colorectal cancer in the United States. A limitation of the current study is that the population of the study participants is predominantly Caucasian-98% of the women in the Nurses’ Health Study and 95% of the Health Professionals cohort.

Other limitations of the study include potential confounding factors that could also account for the observations. Large, prospective studies are needed to better tease out the link between BRAF signaling and the potential positive effects of aspirin on colorectal cancer development.

BRAF is a part of the RAS-MEK signaling pathway and is found mutated in approximately 14% of colorectal cancers. Another important pathway in colorectal cancer is the PI3 kinase pathway-the PI3KCA gene is commonly mutated in colorectal cancer. Both of these pathways are influenced by epidermal growth factor receptor (EGFR) signaling and PI3K may also be an important biomarker for response to aspirin.

In this study, the association of regular aspirin use and lower risk of BRAF wild type colorectal cancer was regardless of PI3KCA and KRAS mutation status.

Continuing studies to identify subsets of colorectal cancer patients who are likely to respond to aspirin, or cancer subtypes that are prevented by aspirin, will also help researchers understand how aspirin influences the underlying biology of the tumor.