Aspirin and Colorectal Cancer Incidence and Mortality by CTNNB1 Expression: A Molecular Pathological Epidemiology (MPE) Study

Abstract

Abstract Purpose: Experimental studies showed that aspirin down-regulates the WNT/CTNNB1 (β-catenin) signaling pathway in colon cancer cells. We investigated whether aspirin use was associated with lower incidence and superior survival in nuclear CTNNB1-positive colorectal cancer. Methods: In two large prospective studies (the Nurses' Health Study and the Health Professionals Follow-up Study), we collected the information on aspirin use every 2 years from 1980 through 2008. We used Cox proportional hazards regression to compute the multivariate hazard ratio for incidence and mortality according to tumor CTNNB1 expression patterns. Results: During 28 years and 3,166,091 person-years of follow-up, we documented 931 incident cases of colorectal cancer with available CTNNB1 expression data. Regular aspirin use was associated with a significantly lower risk of CTNNB1-positive cancer (multivariate HR = 0.65; 95% CI, 0.53–0.80), but not with the risk of CTNNB1-negative cancer (multivariate HR = 0.84; 95% CI, 0.70–1.01). A formal test of heterogeneity of the association according to CTNNB1 expression status did not reach statistical significance (P = 0.07). Regular aspirin use after diagnosis of colorectal cancer was associated with better colorectal cancer-specific survival among CTNNB1-positive tumor patients (multivariate HR = 0.53; 95% CI, 0.30–0.95). In contrast, among CTNNB1-negative tumor patients, post-diagnosis regular aspirin use was not associated with colorectal cancer-specific survival (multivariate HR = 1.06; 95% CI, 0.62–1.83) (P = 0.04 for interaction test between aspirin use and CTNNB1 status). Conclusions: Regular aspirin use was associated with lower incidence of nuclear CTNNB1-positive cancer, and better survival among patients with nuclear CTNNB1-positive cancer. Our molecular pathological epidemiology (MPE) study revealed the anti-tumor mechanism of aspirin, which might prevent cancer incidence and mortality by inhibiting tumor initiation and/or progression in the WNT/CTNNB1-related carcinogenesis pathway.