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Regular Aspirin Use Associates With Lower Risk of Colorectal Cancers With Low Numbers of Tumor-Infiltrating Lymphocytes.
Cao, Y, Nishihara, R, Qian, ZR, Song, M, Mima, K, Inamura, K, Nowak, JA, Drew, DA, Lochhead, P, Nosho, K, et al
Gastroenterology. 2016;(5):879-892.e4
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Abstract
BACKGROUND & AIMS Aspirin use reduces colorectal cancer risk. Aspirin, a nonsteroidal anti-inflammatory drug, inhibits prostaglandin-endoperoxide synthase 2 (PTGS2 or cyclooxygenase-2); PTGS2 promotes inflammation and suppresses T-cell-mediated adaptive immunity. We investigated whether the inverse association of aspirin use with colorectal carcinoma risk was stronger for tumors with lower degrees of lymphocytic infiltrates than for tumors with higher degrees of lymphocytic infiltrates. METHODS We collected aspirin use data biennially from participants in the Nurses' Health Study and Health Professionals Follow-up Study. Participants were asked whether they took aspirin in most weeks, the number of tablets taken per week, and years of aspirin use. We collected available tumor specimens (n = 1458) from pathology laboratories in the United States. A pathologist confirmed the diagnosis of colorectal adenocarcinoma (excluding anal squamous cell carcinoma), and evaluated histopathology features, including patterns and degrees of lymphocytic infiltrates within and around tumor areas. Person-years of follow-up evaluation were accrued from the date of return of questionnaires until dates of colorectal cancer diagnosis, death, or the end of follow-up evaluation (June 2010). Duplication-method Cox proportional hazards regression was used to assess the association of aspirin with the incidence of colorectal carcinoma subgroups according to the degree of tumor-infiltrating lymphocytes (TILs), intratumoral periglandular reaction, peritumoral reaction, or Crohn's-like reaction. RESULTS We documented 1458 rectal and colon cancers. The inverse association between regular aspirin use and colorectal cancer risk significantly differed by concentrations of TILs (Pheterogeneity = .007). Compared with nonregular use, regular aspirin use was associated with a lower risk of tumors that had low levels of TILs (relative risk, 0.72; 95% confidence interval, 0.63-0.81), and strength of the association depended on aspirin dose and duration (both Ptrend < .001). In contrast, aspirin use was not associated with a risk of tumors having intermediate or high levels of TILs. This differential association was consistent regardless of the status of tumor microsatellite instability, mutations in BRAF, or expression of PTGS2. Regular aspirin use was associated with a lower risk of tumors that contained low levels of CD3+ T cells, CD8+ T cells, or CD45RO (PTPRC)+ T cells (measured by immunohistochemistry and computer-assisted image analysis). CONCLUSIONS Based on data from the prospective cohort studies, regular use of aspirin is associated with a lower risk of colorectal carcinomas with low concentrations of TILs. These findings indicate that the immune response in the tumor microenvironment could be involved in the chemopreventive effects of aspirin.
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Aspirin and COX-2 inhibitor use in patients with stage III colon cancer.
Ng, K, Meyerhardt, JA, Chan, AT, Sato, K, Chan, JA, Niedzwiecki, D, Saltz, LB, Mayer, RJ, Benson, AB, Schaefer, PL, et al
Journal of the National Cancer Institute. 2015;(1):345
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Abstract
We conducted a prospective, observational study of aspirin and COX-2 inhibitor use and survival in stage III colon cancer patients enrolled in an adjuvant chemotherapy trial. Among 799 eligible patients, aspirin use was associated with improved recurrence-free survival (RFS) (multivariable hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.28 to 0.95), disease-free survival (DFS) (HR = 0.68, 95% CI = 0.42 to 1.11), and overall survival (OS) (HR = 0.63, 95% CI = 0.35 to 1.12). Adjusted HRs for DFS and OS censored at five years (in an attempt to minimize misclassification from noncancer death) were 0.61 (95% CI = 0.36 to 1.04) and 0.48 (95% CI = 0.23 to 0.99). Among 843 eligible patients, those who used COX-2 inhibitors had multivariable HRs for RFS, DFS, and OS of 0.53 (95% CI = 0.27 to 1.04), 0.60 (95% CI = 0.33 to 1.08), and 0.50 (95% CI = 0.23 to 1.07), and HRs of 0.47 (95% CI = 0.24 to 0.91) and 0.26 (95% CI = 0.08 to 0.81) for DFS and OS censored at five years. Aspirin and COX-2 inhibitor use may be associated with improved outcomes in stage III colon cancer patients.