Regular Aspirin Use Associates With Lower Risk of Colorectal Cancers With Low Numbers of Tumor-Infiltrating Lymphocytes

  • Author Footnotes
    ∗ Authors share co-first authorship.
    Yin Cao
    Footnotes
    ∗ Authors share co-first authorship.
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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  • Author Footnotes
    ∗ Authors share co-first authorship.
    Reiko Nishihara
    Footnotes
    ∗ Authors share co-first authorship.
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts

    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Author Footnotes
    ∗ Authors share co-first authorship.
    Zhi Rong Qian
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    ∗ Authors share co-first authorship.
    Affiliations
    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
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  • Author Footnotes
    ∗ Authors share co-first authorship.
    Mingyang Song
    Footnotes
    ∗ Authors share co-first authorship.
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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  • Kosuke Mima
    Affiliations
    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
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  • Kentaro Inamura
    Affiliations
    Division of Pathology, Cancer Institute, Japan Foundation for Cancer Research, Tokyo, Japan
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  • Jonathan A. Nowak
    Affiliations
    Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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  • David A. Drew
    Affiliations
    Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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  • Paul Lochhead
    Affiliations
    Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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  • Katsuhiko Nosho
    Affiliations
    Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan
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  • Teppei Morikawa
    Affiliations
    Department of Pathology, University of Tokyo Hospital, Tokyo, Japan
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  • Xuehong Zhang
    Affiliations
    Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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  • Kana Wu
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Molin Wang
    Affiliations
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Wendy S. Garrett
    Affiliations
    Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts

    Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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  • Author Footnotes
    § Authors share co-senior authorship.
    Edward L. Giovannucci
    Footnotes
    § Authors share co-senior authorship.
    Affiliations
    Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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    § Authors share co-senior authorship.
    Charles S. Fuchs
    Footnotes
    § Authors share co-senior authorship.
    Affiliations
    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts

    Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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  • Author Footnotes
    § Authors share co-senior authorship.
    Andrew T. Chan
    Correspondence
    Reprint requests Address requests for reprints to: Andrew T. Chan, MD, MPH, Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. fax: (617) 726-3673.
    Footnotes
    § Authors share co-senior authorship.
    Affiliations
    Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

    Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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  • Author Footnotes
    § Authors share co-senior authorship.
    Shuji Ogino
    Correspondence
    Shuji Ogino, MD, PhD, MS, Division of MPE Molecular Pathological Epidemiology, Brigham and Women’s Hospital, 450 Brookline Avenue, DFCI Room M422, Boston, Massachusetts 02215. fax: (617) 582-8558.
    Footnotes
    § Authors share co-senior authorship.
    Affiliations
    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts

    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

    Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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  • Author Footnotes
    ∗ Authors share co-first authorship.
    § Authors share co-senior authorship.

      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.

      Keywords

      Abbreviations used in this paper:

      AHEI (Alternate Healthy Eating Index), CI (confidence interval), HPFS (Health Professionals Follow-up Study), MHT (menopausal hormone therapy), MSI (microsatellite instability), NHS (Nurses’ Health Study), NSAID (nonsteroidal anti-inflammatory drug), PTGS2 (prostaglandin-endoperoxide synthase 2), RR (relative risk), TIL (tumor-infiltrating lymphocytes)
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