Aspirin use and risk of colorectal cancer according to BRAF mutation status

Reiko Nishihara, Paul Lochhead, Aya Kuchiba, Seungyoun Jung, Mai Yamauchi, Xiaoyun Liao, Yu Imamura, Zhi Rong Qian, Teppei Morikawa, Molin Wang, Donna Spiegelman, Eunyoung Cho, Edward Giovannucci, Charles S Fuchs, Andrew T Chan, Shuji Ogino

Research output: Contribution to journalArticlepeer-review

152 Citations (Scopus)


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.

Colorectal cancer is a leading cause of cancer-related mortality worldwide. Randomized controlled trials have demonstrated that aspirin use reduces the risk of colorectal neoplasia,1- 2 including the risk of colorectal cancer in individuals with Lynch syndrome.3 Aspirin is an inhibitor of prostaglandin-endoperoxide synthase 2 (PTGS2, alias cyclooxygenase 2), a key mediator of inflammatory responses.4 We have previously shown that aspirin use is associated with a lower risk of colorectal cancer with PTGS2 overexpression.5 However, since colorectal cancer represents a complex disease that cannot be explained by a single biomarker,6 the association of aspirin with various tumorigenic processes requires further investigation, which may help develop effective preventive strategies.7

Colorectal cancers develop through accumulation of genetic and epigenetic alterations and through tumor-host interactions (including immune and inflammatory reactions) in the tumor microenvironment.8- 9BRAF is a member of the RAF kinase family, and an important regulator of the mitogen-activated protein kinase (MAPK) pathway.8- 10 Activating mutations in the BRAF oncogene are observed in approximately 10% to 15% of colorectal cancers.8- 9 Experimental evidence suggests that RAF-MAPK signaling plays an important role in up-regulation of PTGS2 activity and prostaglandin E2 synthesis.11- 12 Considering that oncogenic BRAFmutation causes constitutive activation of RAF-MAPK signaling, we hypothesized that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin, whereas BRAF–wild-type neoplastic cells might be more susceptible to its antitumor effects.

To test this hypothesis, we examined the association of aspirin use with the risk of colorectal cancer according to BRAF mutation status within 2, large, US nationwide prospective cohort studies that provided detailed and updated information on aspirin use. Because of the close relationship among RAF, RAS, and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), we additionally examined the association between regular aspirin use and incident colorectal cancer according to BRAF mutation status in strata of PTGS2 expression, PIK3CA mutation, and KRAS mutation status. As an exploratory analysis, we examined patient survival according to postdiagnosis aspirin use and BRAF mutation status.
Original languageEnglish
Pages (from-to)2563-2571
Number of pages9
Issue number24
Publication statusPublished - 26 Jun 2013


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