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Original Contribution
June 26, 2013

Aspirin Use and Risk of Colorectal Cancer According to BRAF Mutation Status

Author Affiliations

Author Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute (Drs Nishihara, Lochhead, Kuchiba, Yamauchi, Liao, Imamura, Qian, Morikawa, Fuchs, and Ogino), Channing Division of Network Medicine, Department of Medicine (Drs Jung, Wang, Spiegelman, Cho, Giovannucci, Fuchs, and Chan) and Department of Pathology (Dr Ogino), Brigham and Women's Hospital and Harvard Medical School, and Departments of Nutrition (Drs Nishihara, Kuchiba, and Giovannucci), Epidemiology (Drs Wang, Spiegelman, Giovannucci, and Ogino), and Biostatistics (Drs Wang and Spiegelman), Harvard School of Public Health, Boston, Massachusetts; Gastrointestinal Research Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland (Dr Lochhead); Department of Pathology, University of Tokyo Hospital, Tokyo, Japan (Dr Morikawa); and Division of Gastroenterology, Massachusetts General Hospital, Boston (Dr Chan).

JAMA. 2013;309(24):2563-2571. doi:10.1001/jama.2013.6599

Importance Aspirin use reduces the risk of colorectal carcinoma. Experimental evidence implicates a role of RAF kinases in up-regulation of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2), suggesting that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin than BRAF–wild-type neoplastic cells.

Objective To examine whether the association of aspirin intake with colorectal cancer risk differs according to status of tumor BRAF oncogene mutation.

Design and Setting We collected biennial questionnaire data on aspirin use and followed up participants in the Nurses' Health Study (from 1980) and the Health Professionals Follow-up Study (from 1986) until July 1, 2006, for cancer incidence and until January 1, 2012, for cancer mortality. Duplication-method Cox proportional cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for colorectal carcinoma incidence according to BRAF mutation status.

Main Outcomes and Measures Incidence of colorectal cancer cases according to tumor BRAF mutation status.

Results Among 127 865 individuals, with 3 165 985 person-years of follow-up, we identified 1226 incident rectal and colon cancers with available molecular data. Compared with nonuse, regular aspirin use was associated with lower BRAF–wild-type cancer risk (multivariable HR, 0.73; 95% CI, 0.64 to 0.83; age-adjusted incidence rate difference [RD], −9.7; 95% CI, −12.6 to −6.7 per 100 000 person-years). This association was observed irrespective of status of tumor PTGS2 expression or PIK3CA or KRAS mutation. In contrast, regular aspirin use was not associated with a lower risk of BRAF-mutated cancer (multivariable HR, 1.03; 95% CI, 0.76 to 1.38; age-adjusted, incidence RD, 0.7; 95% CI, −0.3 to 1.7 per 100 000 person-years: P for heterogeneity = .037, between BRAF–wild-type vs BRAF-mutated cancer risks). Compared with no aspirin use, aspirin use of more than 14 tablets per week was associated with a lower risk of BRAF–wild-type cancer (multivariable HR, 0.43; 95% CI, 0.25 to 0.75; age-adjusted incidence RD, −19.8; 95% CI, −26.3 to −13.3 per 100 000 person-years). The relationship between the number of aspirin tablets per week and colorectal cancer risk differed significantly by BRAF mutation status (P for heterogeneity = .005).

Conclusions and Relevance Regular aspirin use was associated with lower risk of BRAF–wild-type colorectal cancer but not with BRAF-mutated cancer risk. These findings suggest that BRAF-mutant colon tumor cells may be less sensitive to the effect of aspirin. Given the modest absolute risk difference, further investigations are necessary to determine clinical implications of our findings.