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BRAF Mutation Status May Have Effect on Benefit of Aspirin Use for Patients with Colorectal Cancer

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Key Points

  • Researchers examined the association of aspirin use with the risk of colorectal cancer according to BRAF mutation status among individuals from two large studies, the Nurses’ Health Study and the Health Professionals Follow-up Study.
  • Regular aspirin use was associated with a significantly lower risk (27%) of BRAF wild-type cancer, but was not associated with a lower risk of BRAF-mutated cancer.
  • A lower risk of BRAF wild-type cancer was seen with increasing aspirin tablets per week and longer duration of aspirin use. These factors were not significantly associated with BRAF-mutated cancer risk.

In two large studies, the association between aspirin use and risk of colorectal cancer was affected by BRAF mutation status, with regular aspirin use associated with a lower risk of BRAF wild-type colorectal cancer but not with risk of BRAF-mutated cancer. The findings, published today in JAMA, suggest that BRAF-mutant colon tumor cells may be less sensitive to the effect of aspirin.

Previous randomized controlled trials have demonstrated that aspirin use reduces the risk of colorectal cancer, and the authors had previously shown that the use of aspirin is also associated with a lower risk of colorectal cancer with prostaglandin-endoperoxide synthase 2 overexpression. Experimental evidence has suggested that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin than BRAF-wild-type neoplastic cells.

Study Details

Reiko Nishihara, PhD, of the Dana-Farber Cancer Institute, Boston, and colleagues examined the association of aspirin use with the risk of colorectal cancer according to BRAF mutation status.

The researchers collected biennial questionnaire data on aspirin use and followed up participants in the Nurses’ Health Study (1980) and the Health Professionals Follow-up Study (1986) until July 2006 for cancer incidence and until January 2012 for cancer mortality.

Risk Reduction Differed by BRAF Mutation Status

Among 127,865 individuals, 1,226 incident rectal and colon cancers were identified with available molecular data. The researchers found that regular aspirin use was associated with a significantly lower risk (27%) of BRAF wild-type cancer. Regular aspirin use was not associated with a lower risk of BRAF-mutated cancer.

The authors also observed a lower risk of BRAF wild-type cancer with increasing aspirin tablets per week; however, there was not a significant trend in risk reduction for BRAF-mutated cancer. “The association of aspirin tablets per week with cancer risk differed significantly by BRAF mutation status,” they wrote. “Compared with individuals who reported no aspirin use, a significantly lower risk of BRAF-wild-type cancer was observed among individuals who used six to 14 tablets of aspirin per week and among those who used more than 14 tablets of aspirin per week.”

In addition, longer duration of aspirin use was associated with significant risk reduction for BRAF wild-type cancer, whereas duration of aspirin use was not significantly associated with BRAF-mutated cancer risk.

“There was no statistically significant interaction between postdiagnosis aspirin use and BRAF mutation status in colorectal cancer–specific or overall survival analysis. This suggests that the potential protective effect of aspirin may differ by BRAF status in the early phase of tumor evolution before clinical detection but not during later phases of tumor progression,” the authors wrote.

Findings May Lead to Tailored Screening Strategies

According to the authors, there are several reasons that identifying specific cancer subtypes preventable by aspirin is important. “First, it enhances our understanding of the molecular pathogenesis of colorectal neoplasia and the mechanisms through which aspirin may exert its antineoplastic effects,” they wrote. “Second, development of clinical, genetic, or molecular predictors of specific subtypes of colorectal cancer might lead to the development of more tailored screening or chemo-preventive strategies. Nevertheless, given the modest absolute risk difference, further investigations are necessary to evaluate clinical implications of our findings. Lastly, our data provide additional support for a causal association between aspirin use and risk reduction for a specific subtype of colorectal cancers. Accumulating evidence supports preventive effect of aspirin against colorectal cancer.”

Commenting on the study in an accompanying editorial, Boris Pasche, MD, PhD, of the University of Alabama at Birmingham, wrote, “These results identify biomarkers of response to aspirin administered either preventively or therapeutically and are likely to help tailor the use of aspirin in the prevention and treatment of colorectal cancer.”

The study was conducted with support from the National Institutes of Health, the Bennett Family Fund for Targeted Therapies Research, and the National Colorectal Cancer Research Alliance. Dr. Lochhead is a Scottish Government Clinical Academic Fellow and was supported by a Harvard University Frank Knox Memorial Fellowship. Dr. Chan is a Damon Runyon Clinical Investigator and reported that he has previously served as a consultant for Bayer Healthcare, Millennium Pharmaceuticals, Pfizer Inc, and Pozen Inc.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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