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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 100000 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 100000 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 100000 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. [ABSTRACT FROM AUTHOR]

Context: Alterations of the WNT signaling pathway and cadherin-associated protein β 1 (CTNNB1 or β-catenin) have been implicated in colorectal carcinogenesis and metabolic diseases.Objective: To test the hypothesis that CTNNB1 activation in colorectal cancer modifies prognostic associations of body mass index (BMI) and level of postdiagnosis physical activity.Design, Setting, and Patients: Two US prospective cohort studies (Nurses' Health Study and the Health Professionals Follow-up Study) were used to evaluate CTNNB1 localization by immunohistochemistry in 955 patients with stage I, II, III, or IV colon and rectal cancer from 1980 through 2004. A Cox proportional hazards model was used to compute the hazard ratio (HR) for mortality, adjusting for clinical and tumor features, including microsatellite instability, CpG island methylator phenotype, level of long interspersed nucleotide element 1 methylation, mutations in KRAS, BRAF, or PIK3CA, and tumor protein p53.Main Outcome Measures: Colorectal cancer-specific mortality and overall mortality through June 30, 2009.Results: In obese patients (BMI ≥30), positive status for nuclear CTNNB1 was associated with significantly better colorectal cancer-specific survival (adjusted HR, 0.24 [95% confidence interval {CI}, 0.12-0.49], P <.001 for interaction; 5-year survival: 0.85 for patients with positive nuclear CTNNB1 status vs 0.78 for those with negative status) and overall survival (adjusted HR, 0.56 [95% CI, 0.35-0.90], P = .03 for interaction; 5-year survival: 0.77 for patients with positive nuclear CTNNB1 status vs 0.74 for those with negative status), while CTNNB1 status was not associated with prognosis among nonobese patients (BMI <30). Among patients with negative status for nuclear CTNNB1 and cancer in stages I, II, or III, postdiagnosis physical activity was associated with better colorectal cancer-specific survival (adjusted HR, 0.33 [95% CI, 0.13-0.81], P = .05 for interaction; 5-year survival: 0.97 for ≥18 vs 0.89 for <18 metabolic equivalent task hours/week), while postdiagnosis physical activity was not associated with colorectal cancer-specific survival among patients with positive status for nuclear CTNNB1 (adjusted HR, 1.07 [95% CI, 0.50-2.30]).Conclusions: Among obese patients only, activation of CTNNB1 was associated with better colorectal cancer-specific survival and overall survival. Postdiagnosis physical activity was associated with better colorectal cancer-specific survival only among patients with negative status for nuclear CTNNB1. These molecular pathological epidemiology findings suggest that the effects of alterations in the WNT-CTNNB1 pathway on outcome are modified by BMI and physical activity. [ABSTRACT FROM AUTHOR]

The article focuses on a study on the association of wingless type (WNT)-cadherin-associated protein β1 (CTNNB1 or βcatenin) activation in colorectal cancer with changes in the prognostic associations of body mass index (BMI) and level of postdiagnosis physical activity. The study has involved data from the Nurses' Health Study and the Health Professionals Follow-up Study in which cohort participants received follow-up questionnaires on dietary and lifestyle factors and new cancer diagnosis. Results of the study are given, one is the association between the positive status for nuclear CTNNB1 and better cancer-specific and overall mortality in obese patients. It concludes that tumor cell behavior is influenced by CTNNB1 changes and energy balance status.

The article discusses a study which investigated the association between aspirin use after colorectal cancer diagnosis on colorectal cancer-specific and overall survival. The study involved 1,279 men and women diagnosed with stage I, stage II, or III colorectal cancer, who were enrolled in two nationwide health professional cohorts in the U.S. in 1980 and 1986. The researchers found that there has been an association between regular aspirin use after the diagnosis of colorectal cancer and lower risk of colorectal cancer-specific and overall mortality.

The article focuses on the significance of subtyping obesity. An estimated 70 percent of adults and 33 percent of children and adolescents are considered overweight or obese in the U.S. Due to standard grouping of all types of overweight and obesity, there is a lack of stronger associations with risk factors or treatments. Example of possible subtypes that may be used for obesity include high insulin secretion and learned patterns and preference for foods high in calories, fat, sugar and salt.

A response by A. T. Chan and colleagues to a letter to the editor about their article "Aspirin Use and Survival After Diagnosis of Colorectal Cancer" in the 2009 issue is presented.