Inflammatory Markers Are Associated With Risk of Colorectal Cancer and Chemopreventive Response to Anti-Inflammatory Drugs

  • Andrew T. Chan
    Correspondence
    Reprint requests Address requests for reprints to: Andrew T. Chan, MD, MPH, Gastrointestinal Unit, Massachusetts General Hospital GRJ-722, Boston, Massachusetts 02114. fax: (617) 726-3673
    Affiliations
    Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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  • Shuji Ogino
    Affiliations
    Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
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  • Edward L. Giovannucci
    Affiliations
    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

    Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts

    Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
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  • Charles S. Fuchs
    Affiliations
    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
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Published:November 29, 2010DOI:https://doi.org/10.1053/j.gastro.2010.11.041

      Background & Aims

      Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) lower the risk of colorectal cancer (CRC). We investigated whether plasma inflammatory markers were associated with risk of CRC and if use of anti-inflammatory drugs was differentially associated with risk of CRC according to levels of inflammatory markers.

      Methods

      We measured levels of high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, and the soluble tumor necrosis factor receptor 2 (sTNFR-2) in blood samples from 32,826 women, collected from 1989 to 1990. Through 2004, we documented 280 cases of incident CRC; each case was matched for age to 2 randomly selected participants without cancer (controls). Information on anti-inflammatory drug (aspirin and NSAIDs) use was collected biennially.

      Results

      Compared with women in the lowest quartile of plasma levels of sTNFR-2, women in the highest quartile had an increased risk of CRC (multivariate relative risk [RR], 1.67; 95% confidence interval [CI], 1.05–2.68; P for trend = .03). Among women with high baseline levels of sTNFR-2, those who initiated aspirin/NSAID use after blood collection had significant reductions in subsequent risk of CRC (multivariate RR, 0.39; 95% CI, 0.18–0.86). In contrast, among women with low baseline levels of sTNFR-2, initiation of aspirin/NSAID use was not associated with significant risk reduction (multivariate RR, 0.86; 95% CI, 0.41–1.79). Plasma levels of CRP and IL-6 were not significantly associated with CRC risk.

      Conclusions

      Plasma levels of sTNFR-2, but not CRP or IL-6, are associated with an increased risk of CRC. Anti-inflammatory drugs appear to reduce risk of CRC among women with high, but not low, baseline levels of sTNFR-2. Certain subsets of the population, defined by inflammatory markers, may obtain different benefits from anti-inflammatory drugs.

      Keywords

      Abbreviations used in this paper:

      CI (confidence interval), CRP (C-reactive protein), IL (interleukin), RR (relative risk), sTNFR-2 (soluble tumor necrosis factor receptor 2), TNF (tumor necrosis factor)
      Aspirin and NSAID use reduces the risk of colorectal adenoma and cancer.
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      • Giovannucci E.L.
      • Meyerhardt J.A.
      • et al.
      Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer.
      • Chan A.T.
      • Giovannucci E.L.
      • Meyerhardt J.A.
      • et al.
      Aspirin dose and duration of use and risk of colorectal cancer in men.
      • Chan A.T.
      • Ogino S.
      • Fuchs C.S.
      Aspirin and the risk of colorectal cancer in relation to the expression of COX-2.
      • Cole B.F.
      • Logan R.F.
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      • et al.
      Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials.
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      Nonsteroidal anti-inflammatory drug use after 3 years of aspirin use and colorectal adenoma risk: observational follow-up of a randomized study.
      This effect may be mediated through abrogation of chronic inflammation. Considerable experimental, epidemiologic, and clinical data provide strong evidence for a causative link between chronic inflammation and cancer, including the well-described association between inflammatory bowel disease and colonic dysplasia.
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      Chronic inflammation: a common and important factor in the pathogenesis of neoplasia.
      Beyond inflammatory bowel disease, however, the importance of inflammation in sporadic colorectal cancer remains undefined. Inflammation may predispose to cancer through enhanced cellular proliferation and mutagenesis, inability to adapt to oxidative stresses, promotion of angiogenesis, inhibition of apoptosis, and secretion of mediators that may promote tumorigenesis.
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      prospective studies specifically relating inflammatory markers to colorectal cancer have been equivocal. For CRP, some prospective studies have observed an increased risk of colorectal cancer,
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      Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort.
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      Plasma C-reactive protein and risk of cancer: a prospective study from Greece.
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      • Boeing H.
      • et al.
      Circulating C-reactive protein concentrations and risks of colon and rectal cancer: a nested case-control study within the European Prospective Investigation into Cancer and Nutrition.
      whereas other studies have shown an equivocal,
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      nonexistent,
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      • et al.
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      or somewhat inverse association.
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      • Buring J.E.
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      • et al.
      C-reactive protein levels are not associated with increased risk for colorectal cancer in women.
      The few studies that have also examined IL-6 have not observed strong relationships.
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      • Colbert L.H.
      • Harris T.B.
      • et al.
      Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort.
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      • Harris R.
      • Lowe G.
      • et al.
      Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis.
      To our knowledge, no studies have specifically investigated sTNFR-2 in relation to risk.
      Thus, to further elucidate the role of inflammation and anti-inflammatory drugs in relation to colorectal carcinogenesis, we examined whether CRP, IL-6, or sTNFR-2 levels are independently associated with risk of colorectal cancer in a nested case-control analysis among women enrolled in the Nurses' Health Study who provided a blood sample at baseline and were followed up for 14 years. Because women provided aspirin/nonsteroidal anti-inflammatory drug (NSAID) data both before and after collection of plasma, we also had the unique opportunity to prospectively evaluate the relationship between baseline levels of inflammatory markers and subsequent response to aspirin and NSAIDs on risk of colorectal cancer.

      Subjects and Methods

       Study Participants

      Participants were drawn from the Nurses' Health Study, which began in 1976 when 121,701 US female registered nurses aged 30 to 55 years completed a mailed questionnaire about their health history. We have mailed follow-up questionnaires to the participants every 2 years to update information on lifestyle factors, medication use, and diagnoses of colorectal cancer and other diseases. In 1989 through 1990, we collected a blood specimen from 32,826 participants.
      • Hankinson S.E.
      • Willett W.C.
      • Manson J.E.
      • et al.
      Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women.
      As previously detailed,
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      • Hankinson S.E.
      • Hough H.
      • et al.
      A prospective study of NAT2 acetylation genotype, cigarette smoking, and risk of breast cancer.
      women who provided a blood specimen were generally similar to women who did not; however, the proportion of women who were current smokers was lower among women who gave a blood specimen (14.4%) than among women who did not (25.0%). Subsequent follow-up of this sub-cohort of women has been greater than 96%. The Human Research Committee at the Brigham and Women's Hospital and the Harvard School of Public Health approved this study.

       Selection of Colorectal Cancer Cases and Control Participants

      Eligible women for this study provided a blood specimen and were free from inflammatory bowel disease or cancer (except nonmelanoma skin cancer). When a participant reported a diagnosis of colorectal cancer, we asked for permission to obtain hospital records and pathology reports. We identified deaths through the National Death Index and next of kin. For all deaths, we sought information to determine the cause, including death certificates, and, when appropriate, requested permission from next of kin to review medical records. Mortality follow-up was more than 98% complete.
      • Stampfer M.J.
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      Test of the National Death Index.
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      • Corsano K.A.
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      Test of the National Death Index and Equifax Nationwide Death Search.
      Study physicians, blinded to exposure data, reviewed all medical records to confirm cases of colorectal cancer. After blood collection through June 1, 2004, we confirmed 286 incident cases of colorectal cancer. Using risk set sampling, we randomly selected controls in a 2:1 ratio who were matched on year of birth and month/year of blood sampling (n = 572) from participants who were free of colorectal cancer at the same time the colorectal cancer was diagnosed in the cases.
      • Pai J.K.
      • Pischon T.
      • Ma J.
      • et al.
      Inflammatory markers and the risk of coronary heart disease in men and women.
      We excluded 6 cases and 15 controls due to insufficient plasma volume. Thus, we included 280 cases and 555 control participants in the final analysis.

       Laboratory Procedures

      We sent a phlebotomy kit to all women willing to provide a blood specimen in 1989 through 1990. After receipt by overnight courier, the chilled heparinized blood was immediately centrifuged, aliquoted into plasma, and stored in continuously monitored liquid nitrogen freezers. More than 97% of the blood samples arrived in our laboratory within 26 hours of phlebotomy. Quality control samples were routinely frozen along with study samples to monitor for changes associated with storage and assay variability. To examine the stability of plasma biomarkers according to our storage techniques, we previously compared the concentrations in samples taken from 17 female volunteers that were processed and plasma frozen immediately after venipuncture (the standard processing methods) with samples that were stored as heparinized whole blood for 24 to 36 hours before processing (mimicking our collection conditions). The mean IL-6, CRP, and sTNFR-2 values were almost identical and the intraclass correlations between results of the 2 collection methods were 0.99 for CRP, 0.93 for IL-6, and 0.91 for sTNFR-2, showing that our collection methods did not adversely affect sample integrity.
      • Pai J.K.
      • Curhan G.C.
      • Cannuscio C.C.
      • et al.
      Stability of novel plasma markers associated with cardiovascular disease: processing within 36 hours of specimen collection.
      In a core laboratory facility, we used a highly sensitive immunoturbidimetric assay (Denka Seiken Co, Tokyo, Japan) to measure CRP levels and enzyme-linked immunosorbent assays (R&D Systems, Minneapolis, MN) to measure IL-6 and sTNFR-2 levels. Personnel blinded to quality control and case-control status conducted all assays. The intra-assay coefficients of variations from blinded quality control samples for each analyte were as follows: CRP, 2.2%; IL-6, 10.6%; sTNFR-2, 6.7%.

       Assessment of Aspirin/NSAID Use

      Assessment of aspirin and NSAID use in the Nurses' Health Study has been described in detail previously. Briefly, since 1980, we assessed intake of aspirin biennially except in 1986 with specific questions on the number of standard aspirin tablets (325 mg) taken. Women were specifically asked to record their typical pattern of aspirin use in most weeks over the prior 2-year period. Early in the study, most women used standard-dose aspirin tablets of 325 mg; however, to reflect overall secular trends in consumption of low-dose or baby aspirin, questionnaires after 1992 asked participants to convert intake of 4 baby aspirin to 1 adult tablet. Beginning in 1990, we also asked about the use of “other anti-inflammatory drugs (eg, Ibuprofen, Naprosyn, Advil),” which we classified as NSAIDs.
      • Chan A.T.
      • Giovannucci E.L.
      • Meyerhardt J.A.
      • et al.
      Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer.
      • Chan A.T.
      • Ogino S.
      • Fuchs C.S.
      Aspirin and the risk of colorectal cancer in relation to the expression of COX-2.
      • Chan A.T.
      • Ogino S.
      • Fuchs C.S.
      Aspirin use and survival after diagnosis of colorectal cancer.
      There were no important differences in baseline characteristics comparing regular aspirin users with NSAID users.

       Statistical Analysis

      We first calculated means (±SD), medians (±interquartile ranges), and proportions of baseline characteristics for the case subjects and control subjects at the time of blood draw. We used Wilcoxon signed rank and χ2 tests for comparisons of the means and proportions of the baseline characteristics. We calculated Spearman coefficients to estimate the correlation between mean levels of plasma biomarkers and lifestyle factors.
      We divided the inflammatory markers into quartiles, from the lowest to highest levels, on the basis of the distribution among the controls. Because postmenopausal hormone use elevates CRP levels,
      • Ridker P.M.
      • Hennekens C.H.
      • Rifai N.
      • et al.
      Hormone replacement therapy and increased plasma concentration of C-reactive protein.
      consistent with prior studies, we categorized women into quartiles of CRP based on the CRP distribution among never-users or ever-users of postmenopausal hormones at baseline.
      • Zhang S.M.
      • Buring J.E.
      • Lee I.M.
      • et al.
      C-reactive protein levels are not associated with increased risk for colorectal cancer in women.
      We estimated the relative risk (RR) and corresponding 95% confidence intervals (CIs) for associations between quartile-specific markers using logistic regression models. Tests for trend were conducted using the median values for each quartile of plasma biomarker as a continuous variable in the regression models. We obtained similar results using conditional logistic regression models or unconditional logistic regression models adjusting for matching factors. Because both analyses provided similar results, we present the results of unconditional logistic regression, which parallel the results in the subgroup analyses. We also examined the possibility of a nonlinear association between each plasma analyte and colorectal cancer risk using restricted cubic splines.
      • Durrleman S.
      • Simon R.
      Flexible regression models with cubic splines.
      We selected 3 knot splines, consistent with prior analyses in this cohort and the frequency distribution of each analyte.
      • Baba Y.
      • Nosho K.
      • Shima K.
      • et al.
      Relationship of CDX2 loss with molecular features and prognosis in colorectal cancer.
      We tested for overall significance of the spline curve using a likelihood ratio test that compared the −2 log likelihood of a model with the analytes expressed as spline terms with that of a model without these terms (only the covariates).
      In our multivariate model, we further adjusted for known or suspected risk factors for colorectal cancer listed in Table 1. We have previously shown each of these covariates to be related to colorectal cancer within the overall cohort from which this study was nested.
      • Chan A.T.
      • Giovannucci E.L.
      • Meyerhardt J.A.
      • et al.
      Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer.
      To reflect the participants' characteristics at the time of the measurement of the plasma biomarker, we used baseline data for all lifestyle covariate data at the time of blood collection. For our analyses evaluating the influence of aspirin/NSAID use after measurement of plasma biomarkers, we derived aspirin and NSAID use data from the biennial questionnaire after blood collection. Consistent with our prior analyses, regular aspirin use was defined as at least 2 standard (325-mg) aspirin tablets per week and NSAID use was defined as at least 2 tablets per week.
      • Chan A.T.
      • Giovannucci E.L.
      • Meyerhardt J.A.
      • et al.
      Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer.
      • Chan A.T.
      • Giovannucci E.L.
      • Meyerhardt J.A.
      • et al.
      Aspirin dose and duration of use and risk of colorectal cancer in men.
      • Chan A.T.
      • Ogino S.
      • Fuchs C.S.
      Aspirin and the risk of colorectal cancer in relation to the expression of COX-2.
      Consistent with prior analyses in this cohort,
      • Karlson E.W.
      • Chang S.C.
      • Cui J.
      • et al.
      Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis.
      we assessed additive interaction based on the work of Rothman, which showed that independent risk factors adhere to an additive model and biological interaction results in the departure from additivity.
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      • et al.
      Calculating measures of biological interaction.
      We also assessed multiplicative interaction by using a cross-product term. We used SAS version 9.1.3 (SAS Institute, Inc, Cary, NC) for all analyses. All P values are 2 sided.
      Table 1Baseline Characteristics of Study Participants
      Baseline characteristicCase participants (n = 280)Control participants (n = 555)
      Mean age at blood draw ± SD (y)59.3 ± 6.659.3 ± 6.6
      Nonwhite (%)9 (3)6 (1)
      Current or past smoker, no. (%)161 (56)317 (57)
      Postmenopausal, no. (%)244 (87)490 (88)
       Current use of hormones, no. (%)
      Percentage is among postmenopausal women.
      86 (35)213 (44)
      Body mass index (kg/m2), mean (SD)26.0 (6.0)25.5 (5.8)
      Physical activity (METs), mean (SD)19.1 (19.7)17.4 (18.6)
      Regular aspirin use (≥2 325-mg tablets/wk), no. (%)114 (41)253 (46)
      Regular NSAID use (≥2 tablets/wk), no. (%)43 (15)107 (19)
      Multivitamin use, no. (%)102 (36)208 (37)
      Colorectal cancer in a parent or sibling, no. (%)40 (14)72 (13)
      History of previous endoscopy, no. (%)34 (12)89 (16)
      History of colon polyp, no. (%)21 (8)25 (5)
       Calcium (mg/d)995 (546)1069 (573)
       Folate (mg/d)436 (277)470 (238)
       Beef, pork, or lamb as main dish (servings/d)0.30 (0.18)0.30 (0.17)
       Alcohol (g/d)5.8 (9.9)5.4 (9.6)
      CRP (mg/L), median (IQR)
      Among 118 case participants and 224 control participants who never used postmenopausal hormones.
      1.02 (0.59–2.29)1.24 (0.55–3.14)
      IL-6 (pg/mL), median (IQR)1.28 (0.86–2.05)1.22 (0.84–1.98)
      sTNF-R2 (pg/mL), median (IQR)2636 (2202–3083)2528 (2116–2997)
      METs, metabolic equivalent task score hours per week.
      a Percentage is among postmenopausal women.
      b Among 118 case participants and 224 control participants who never used postmenopausal hormones.

      Results

      The baseline characteristics of the 280 colorectal cancer case participants and 555 matched control participants at the time of blood collection are presented in Table 1. The mean age of the study cohort was 59.3 years at the time of blood draw. The median values of baseline plasma CRP were 1.24 mg/L among 224 control women who never used postmenopausal hormones and 1.99 mg/L among 331 control women who had ever used postmenopausal hormones (P < .0001). For IL-6, the corresponding median values were 1.22 pg/mL for women who never used postmenopausal hormones and 1.23 for women who had ever used postmenopausal hormones (P = .88). For sTNFR-2, the corresponding median values were 2598 pg/mL for women who never used postmenopausal hormones and 2502 pg/mL for women who had ever used postmenopausal hormones (P = .13). Overall, women who were subsequently diagnosed with colorectal cancer were significantly less likely to have used postmenopausal hormones (P = .03) and had nonsignificantly higher levels of baseline plasma sTNFR-2 (P = .07). Plasma levels of CRP (among women who never used postmenopausal hormones) and IL-6 did not appear to significantly differ between cases and controls (P = .24 for CRP and P = .44 for IL-6).
      The Spearman correlation coefficients between plasma inflammatory markers, age, body mass index, and metabolic equivalent task score hours per week of physical activity are shown in Table 2. Plasma inflammatory markers directly correlated with age and body mass index and negatively correlated with physical activity. Levels of plasma CRP appeared to correlate more strongly with levels of IL-6 than sTNFR-2.
      Table 2Spearman Correlation Coefficients Between CRP, IL-6, sTNFR-2, Age, BMI, and METs of Physical Activity at Blood Draw Among Control Subjects
      VariableCRPIL-6sTNFR-2AgeBMIMETs
      CRP1.000.46
      P < .0001.
      0.29
      P < .0001.
      0.12
      P = .004.
      0.37
      P < .0001.
      −0.17
      P < .0001.
      IL-60.46
      P < .0001.
      1.000.40
      P < .0001.
      0.09
      P = .04.
      0.24
      P < .0001.
      −0.12
      P = .007.
      sTNFR-20.29
      P < .0001.
      0.40
      P < .0001.
      1.000.24
      P < .0001.
      0.24
      P < .0001.
      −0.03
      Age0.12
      P = .004.
      0.09
      P = .04.
      0.24
      P < .0001.
      1.00−0.040.07
      BMI0.37
      P < .0001.
      0.24
      P < .0001.
      0.24
      P < .0001.
      −0.041.00−0.14
      METs−0.17
      P < .0001.
      −0.12
      P = .007.
      −0.030.07−0.141.00
      BMI, body mass index; METs, metabolic equivalent task score hours per week.
      a P < .0001.
      b P = .004.
      c P = .04.
      d P = .007.
      We examined the relationship between baseline plasma inflammatory markers and risk of colorectal cancer based on the quartile distribution of each marker in the controls (Table 3). Consistent with prior studies and the known effect of postmenopausal hormones in raising CRP levels, we assigned quartile categories of CRP according to separate cut points derived for women who never used hormones and women who ever used hormones. The highest quartile of plasma sTNFR-2 compared with the lowest quartile was significantly associated with colorectal cancer, even after adjustment for other traditional lifestyle and dietary risk factors (multivariate RR, 1.67; 95% CI, 1.05–2.68; Ptrend= .03). In contrast, there was no association observed comparing extreme quartiles for CRP (multivariate RR, 0.65; 95% CI, 0.40–1.05; Ptrend = .17) or IL-6 (multivariate RR, 1.18; 95% CI, 0.75–1.85; Ptrend = .55).
      Table 3RR of Colorectal Cancer According to Plasma Inflammatory Markers
      AnalyteQuartilesPtrend
      Tests for linear trend were conducted using the median values for each quartile of analyte.
      1234
      CRP
       Median (mg/L)0.390.952.135.37
       No. of cases/controls77/13368/13875/14260/142
       Age-adjusted RR (95% CI)
      Age-adjusted models including adjustment for matching factors (age at blood draw, date of blood draw).
      1.00 (referent)0.85 (0.57–1.27)0.91 (0.61–1.35)0.73 (0.48–1.10).13
       Multivariate-adjusted RR (95% CI)
      Multivariate models were adjusted for age at blood draw, date of blood draw, body mass index (quintiles), physical activity (quintiles of metabolic equivalent task score hours per week), current or past smoking (yes or no), menopause status, current postmenopausal hormone use (yes or no), prior lower gastrointestinal endoscopy (yes or no), colorectal cancer in parent or sibling (yes or no), regular use of multivitamins (yes or no), regular use of aspirin or NSAIDs (≥2 tablets/week), energy-adjusted intake (including supplements) of calcium and folate (quintiles), servings of beef, pork, or lamb as a main dish (0–3 times/month, 1 time/week, 2–4 times/week, 5+ times/week), and alcohol consumption (0, 0.1–4.9, 5.0–14.9, or +15 g/day).
      1.00 (referent)0.79 (0.51–1.21)0.89 (0.57–1.39)0.65 (0.40–1.05).17
      IL-6
       Median (pg/mL)0.651.021.453.04
       No. of cases/controls63/13870/13871/13875/139
       Age-adjusted RR (95% CI)
      Age-adjusted models including adjustment for matching factors (age at blood draw, date of blood draw).
      1.00 (referent)1.11 (0.73–1.68)1.13 (0.74–1.70)1.17 (0.78–1.78).52
       Multivariate-adjusted RR (95% CI)
      Multivariate models were adjusted for age at blood draw, date of blood draw, body mass index (quintiles), physical activity (quintiles of metabolic equivalent task score hours per week), current or past smoking (yes or no), menopause status, current postmenopausal hormone use (yes or no), prior lower gastrointestinal endoscopy (yes or no), colorectal cancer in parent or sibling (yes or no), regular use of multivitamins (yes or no), regular use of aspirin or NSAIDs (≥2 tablets/week), energy-adjusted intake (including supplements) of calcium and folate (quintiles), servings of beef, pork, or lamb as a main dish (0–3 times/month, 1 time/week, 2–4 times/week, 5+ times/week), and alcohol consumption (0, 0.1–4.9, 5.0–14.9, or +15 g/day).
      1.00 (referent)1.13 (0.73–1.74)1.11 (0.72–1.72)1.18 (0.75–1.85).55
      sTNFR-2
       Median (pg/mL)1900234527433463
       No. of cases/controls54/13863/13980/13980/139
       Age-adjusted RR (95% CI)
      Age-adjusted models including adjustment for matching factors (age at blood draw, date of blood draw).
      1.00 (referent)1.18 (0.76–1.82)1.50 (0.98–2.30)1.51 (0.98–2.33).04
       Multivariate-adjusted RR (95% CI)
      Multivariate models were adjusted for age at blood draw, date of blood draw, body mass index (quintiles), physical activity (quintiles of metabolic equivalent task score hours per week), current or past smoking (yes or no), menopause status, current postmenopausal hormone use (yes or no), prior lower gastrointestinal endoscopy (yes or no), colorectal cancer in parent or sibling (yes or no), regular use of multivitamins (yes or no), regular use of aspirin or NSAIDs (≥2 tablets/week), energy-adjusted intake (including supplements) of calcium and folate (quintiles), servings of beef, pork, or lamb as a main dish (0–3 times/month, 1 time/week, 2–4 times/week, 5+ times/week), and alcohol consumption (0, 0.1–4.9, 5.0–14.9, or +15 g/day).
      1.00 (referent)1.22 (0.78–1.92)1.53 (0.98–2.40)1.67 (1.05–2.68).03
      NOTE. Quartiles of plasma inflammatory markers are based on the distribution in the controls. For CRP, women were categorized according to cut points of never-users or ever-users of postmenopausal hormones. For CRP, the median values in the table represent never-users of postmenopausal hormones. The corresponding values for ever-users of postmenopausal hormones were 0.68 mg/L for quartile 1, 1.62 mg/L for quartile 2, 3.15 mg/L for quartile 3, and 6.71 mg/L for quartile 4. One case and 2 controls had insufficient plasma for IL-6 measurements. Three cases had insufficient plasma for sTNFR-2 measurements.
      a Tests for linear trend were conducted using the median values for each quartile of analyte.
      b Age-adjusted models including adjustment for matching factors (age at blood draw, date of blood draw).
      c Multivariate models were adjusted for age at blood draw, date of blood draw, body mass index (quintiles), physical activity (quintiles of metabolic equivalent task score hours per week), current or past smoking (yes or no), menopause status, current postmenopausal hormone use (yes or no), prior lower gastrointestinal endoscopy (yes or no), colorectal cancer in parent or sibling (yes or no), regular use of multivitamins (yes or no), regular use of aspirin or NSAIDs (≥2 tablets/week), energy-adjusted intake (including supplements) of calcium and folate (quintiles), servings of beef, pork, or lamb as a main dish (0–3 times/month, 1 time/week, 2–4 times/week, 5+ times/week), and alcohol consumption (0, 0.1–4.9, 5.0–14.9, or +15 g/day).
      We also examined the possibility of a nonlinear relation between each plasma marker and colorectal cancer using restricted cubic splines. This flexible method allowed us to examine the relation to colorectal cancer risk without any categorization of each plasma marker or an assumption of linearity. A test for overall significance of the curve showed a significant relationship between colorectal cancer and plasma sTNFR-2 level (P = .02; Figure 1). In contrast, there was no significant association between colorectal cancer and CRP level (P = .32; Figure 2) or IL-6 level (P = .49; Figure 3). Based on these analyses, we calculated multivariate RRs at specific values on the spline plots that have been previously shown to be clinically relevant. Because no prior studies have examined sTNFR-2 in relation to colorectal cancer, we selected a plasma level that has been previously associated with risk of coronary heart disease in this cohort.
      • Pai J.K.
      • Pischon T.
      • Ma J.
      • et al.
      Inflammatory markers and the risk of coronary heart disease in men and women.
      A plasma sTNFR-2 level of 3408 pg/mL was associated with a multivariate RR of colorectal cancer of 1.92 (95% CI, 1.12–3.30). In addition, for sTNFR-2, the relationship with colorectal cancer appeared linear; a 100-pg/mL increase in sTNFR-2 level was associated with a multivariate RR of colorectal cancer of 1.04 (95% CI, 1.01–1.08). Prior studies have related IL-6 to risk of total cancer;
      • Il'yasova D.
      • Colbert L.H.
      • Harris T.B.
      • et al.
      Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort.
      a plasma IL-6 level of 3.0 pg/mL was associated with a multivariate RR of colorectal cancer of 1.25 (95% CI, 0.72–2.17) in our cohort. Finally, for CRP, we selected a value that has been specifically associated with risk of colorectal cancer;
      • Erlinger T.P.
      • Platz E.A.
      • Rifai N.
      • et al.
      C-reactive protein and the risk of incident colorectal cancer.
      a plasma CRP level of 5.33 mg/L was associated with a multivariate RR of colorectal cancer of 0.58 (95% CI, 0.33–1.01) in our cohort.
      Figure thumbnail gr1
      Figure 1Restricted cubic spline plot for sTNFR-2 and risk of colorectal cancer. RR of colorectal cancer is plotted according to plasma sTNFR-2 level (pg/mL). Hatched lines represent 95% CIs. Spline was adjusted for the same factors as the multivariate model in . A test for overall significance of the curve was statistically significant (P = .02).
      Figure thumbnail gr2
      Figure 2Restricted cubic spline plot for CRP and risk of colorectal cancer. RR of colorectal cancer is plotted according to plasma CRP level (mg/L). Hatched lines represent 95% CIs. Spline was adjusted for the same factors as the multivariate model in . A test for overall significance of the curve was nonsignificant (P = .32).
      Figure thumbnail gr3
      Figure 3Restricted cubic spline plot for IL-6 and risk of colorectal cancer. RR of colorectal cancer is plotted according to plasma IL-6 level (pg/mL). Hatched lines represent 95% CIs. Spline was adjusted for the same factors as the multivariate model in . A test for overall significance of the curve was nonsignificant (P = .49).
      To address the potential bias that undiagnosed colorectal cancer itself could influence levels of plasma inflammatory markers at the time of blood collection, we excluded incident cases of colorectal cancer that were diagnosed within 2 years of follow-up. The multivariate RR of colorectal cancer for the highest quartile of plasma sTNFR-2 compared with the lowest quartile was not materially changed (multivariate RR, 1.61; 95% CI, 0.98–2.62; Ptrend = .04). There remained no significant association between plasma CRP (Ptrend = .08) or plasma IL-6 (Ptrend = .86) level after excluding cases within 2 years of blood collection.
      We conducted analyses (including spline-based models) of plasma inflammatory markers according to selected subgroups, including age, body mass index, aspirin/NSAID use, multivitamin use, or folate intake at the time of blood collection. For each marker, there were no significant differences in the associations we observed within each subgroup, including those who were nonusers of aspirin/NSAIDs and those who were regular users of aspirin/NSAIDs at the time of blood draw. We also performed analyses adjusting for the presence of coronary heart disease or diabetes mellitus, and our results were not materially altered. Because current use of postmenopausal hormones increases plasma CRP levels, we also conducted separate spline-based analyses of CRP using a model that did not include a term for current use of postmenopausal hormones. The spline plot was essentially unchanged; a test for overall significance of the curve relating CRP to colorectal cancer remained nonsignificant (P = .15; Supplementary Figure s1). In addition, we observed consistent results for spline analyses conducted among women who currently used postmenopausal hormones (P = .75; Supplementary Figure s2) and women who did not currently use postmenopausal hormones (P = .44; Supplementary Figure s3).
      We have previously shown that aspirin and NSAID use in this cohort is associated with a lower risk of colorectal cancer.
      • Chan A.T.
      • Giovannucci E.L.
      • Meyerhardt J.A.
      • et al.
      Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer.
      • Chan A.T.
      • Ogino S.
      • Fuchs C.S.
      Aspirin and the risk of colorectal cancer in relation to the expression of COX-2.
      Thus, in an exploratory analysis, we considered the possibility that initiating aspirin or NSAID use may be differentially associated with risk of colorectal cancer according to baseline levels of sTNFR-2 among the 286 women who were not using aspirin or NSAIDs at the time of blood draw (Table 4). Among women with high baseline levels of plasma sTNFR-2 (greater than or equal to the median), women who began using aspirin (≥2 standard 325-mg tablets/week) or NSAIDs (≥2 tablets/week) after blood collection had a multivariate RR of colorectal cancer of 0.39 (95% CI, 0.18–0.86). In contrast, among women with low baseline plasma sTNFR-2 levels (less than the median), women who began using aspirin or NSAIDs had a multivariate RR of colorectal cancer of 0.86 (95% CI, 0.41–1.79). A formal test of additive interaction between sTNFR-2, use of aspirin/NSAIDs, and risk of colorectal cancer was statistically significant (P = .03). A formal test of multiplicative interaction between sTNFR-2, use of aspirin/NSAIDs, and risk of colorectal cancer approached statistical significance (P = .10).
      Table 4RR of Colorectal Cancer According to Initiation of Regular Aspirin or NSAID Use After Blood Draw, Stratified by sTNFR-2 Level
      CharacteristicNonuser after blood drawRegular user after blood draw
      All sTNF-R2 levels
       No. of cases/controls109/17734/84
       Age-adjusted RR (95% CI)
      Age-adjusted models including adjustment for matching factors (age at blood draw, date of blood draw).
      1.000.65 (0.41–1.04)
       Multivariable-adjusted RR (95% CI)
      Multivariate RRs and 95% CIs were adjusted for the same factors as the multivariate model in Table 3 with the exception of regular use of aspirin/NSAIDs.
      1.000.67 (0.41–1.09)
      sTNFR-2 level greater than or equal to the median (2636 pg/mL)
       No. of cases/controls59/8315/43
       Age-adjusted RR (95% CI)
      Age-adjusted models including adjustment for matching factors (age at blood draw, date of blood draw).
      1.000.49 (0.25–0.97)
       Multivariable-adjusted RR (95% CI)
      Multivariate RRs and 95% CIs were adjusted for the same factors as the multivariate model in Table 3 with the exception of regular use of aspirin/NSAIDs.
      1.000.39 (0.18–0.86)
      sTNFR-2 level less than the median (2636 pg/mL)
       No. of cases/controls48/9419/41
       Age-adjusted RR (95% CI)
      Age-adjusted models including adjustment for matching factors (age at blood draw, date of blood draw).
      1.000.91 (0.48–0.74)
       Multivariable-adjusted RR (95% CI)
      Multivariate RRs and 95% CIs were adjusted for the same factors as the multivariate model in Table 3 with the exception of regular use of aspirin/NSAIDs.
      1.000.86 (0.41–1.79)
      NOTE. This analysis was restricted to the 404 participants who denied regular use of aspirin (≥2 standard 325-mg tablets/week) or NSAIDs (≥2 tablets/week) on the most recent questionnaire before blood draw. Nonusers after blood draw denied regular use of aspirin on any questionnaire after blood draw but before diagnosis. Regular users after blood draw reported regular use after the most recent questionnaire after blood draw but before diagnosis.
      a Age-adjusted models including adjustment for matching factors (age at blood draw, date of blood draw).
      b Multivariate RRs and 95% CIs were adjusted for the same factors as the multivariate model in Table 3 with the exception of regular use of aspirin/NSAIDs.

      Discussion

      Our results show an association between baseline plasma sTNFR-2 level, but not CRP or IL-6 level, and subsequent risk of colorectal cancer. Moreover, the inverse association between regular aspirin and NSAID use on risk of colorectal cancer appeared to be restricted to women with high baseline levels of sTNFR-2. To our knowledge, this study is the first to directly examine the role of sTNFR-2 in relation to risk of colorectal cancer.
      Our data support a role for chronic inflammation in the pathogenesis of sporadic colorectal cancer but suggest that circulating biomarkers of inflammation have varying ability to predict risk of incident cancer. Specifically, we did not find an association between colorectal cancer and CRP or IL-6 level, consistent with several other studies.
      • Siemes C.
      • Visser L.E.
      • Coebergh J.W.
      • et al.
      C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study.
      • Heikkila K.
      • Harris R.
      • Lowe G.
      • et al.
      Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis.
      • Allin K.H.
      • Bojesen S.E.
      • Nordestgaard B.G.
      Baseline C-reactive protein is associated with incident cancer and survival in patients with cancer.
      • Ito Y.
      • Suzuki K.
      • Tamakoshi K.
      • et al.
      Colorectal cancer and serum C-reactive protein levels: a case-control study nested in the JACC Study.
      • Allin K.H.
      • Nordestgaard B.G.
      • Zacho J.
      • et al.
      C-reactive protein and the risk of cancer: a mendelian randomization study.
      • Zhang S.M.
      • Buring J.E.
      • Lee I.M.
      • et al.
      C-reactive protein levels are not associated with increased risk for colorectal cancer in women.
      In contrast, prior studies have observed an increased risk of colorectal cancer associated with CRP level.
      • Gunter M.J.
      • Stolzenberg-Solomon R.
      • Cross A.J.
      • et al.
      A prospective study of serum C-reactive protein and colorectal cancer risk in men.
      • Erlinger T.P.
      • Platz E.A.
      • Rifai N.
      • et al.
      C-reactive protein and the risk of incident colorectal cancer.
      • Otani T.
      • Iwasaki M.
      • Sasazuki S.
      • et al.
      Plasma C-reactive protein and risk of colorectal cancer in a nested case-control study: Japan Public Health Center-based prospective study.
      • Il'yasova D.
      • Colbert L.H.
      • Harris T.B.
      • et al.
      Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort.
      • Trichopoulos D.
      • Psaltopoulou T.
      • Orfanos P.
      • et al.
      Plasma C-reactive protein and risk of cancer: a prospective study from Greece.
      Each of these positive studies examined populations that included a significant proportion of men, with the strongest associations observed in a cohort composed entirely of male smokers.
      • Gunter M.J.
      • Stolzenberg-Solomon R.
      • Cross A.J.
      • et al.
      A prospective study of serum C-reactive protein and colorectal cancer risk in men.
      In contrast, our null results for CRP level and colorectal cancer were most consistent with those observed in the only other cohort composed entirely of women.
      • Zhang S.M.
      • Buring J.E.
      • Lee I.M.
      • et al.
      C-reactive protein levels are not associated with increased risk for colorectal cancer in women.
      Thus, it is possible that some of the divergent results across studies of CRP may be related to sex. In support of this hypothesis, several studies have shown significant differences in the inflammatory marker profile among women compared with men.
      • Pai J.K.
      • Pischon T.
      • Ma J.
      • et al.
      Inflammatory markers and the risk of coronary heart disease in men and women.
      • Ridker P.M.
      • Hennekens C.H.
      • Buring J.E.
      • et al.
      C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.
      Animal data also show sex-based differences in cytokines associated with inflammation-related cancers.
      • Naugler W.E.
      • Sakurai T.
      • Kim S.
      • et al.
      Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production.
      Nonetheless, the precise reasons for the different results for CRP and colorectal cancer across studies remain largely speculative.
      Although our results for CRP and IL-6 were null, we did find an association between sTNFR-2 and risk of colorectal cancer. In support of our findings, previous studies in this cohort have shown that sTNFR-2 is associated with risk of coronary heart disease and diabetes mellitus,
      • Hu F.B.
      • Meigs J.B.
      • Li T.Y.
      • et al.
      Inflammatory markers and risk of developing type 2 diabetes in women.
      • Pai J.K.
      • Pischon T.
      • Ma J.
      • et al.
      Inflammatory markers and the risk of coronary heart disease in men and women.
      • Shai I.
      • Schulze M.B.
      • Manson J.E.
      • et al.
      A prospective study of soluble tumor necrosis factor-alpha receptor II (sTNF-RII) and risk of coronary heart disease among women with type 2 diabetes.
      conditions related to systemic inflammation and also associated with risk of colorectal cancer.
      • Hu F.B.
      • Manson J.E.
      • Liu S.
      • et al.
      Prospective study of adult onset diabetes mellitus (type 2) and risk of colorectal cancer in women.
      • Chan A.O.
      • Jim M.H.
      • Lam K.F.
      • et al.
      Prevalence of colorectal neoplasm among patients with newly diagnosed coronary artery disease.
      sTNFR-2 is considered a reliable surrogate marker for tumor necrosis factor (TNF)-α because it is more stable in stored frozen samples and less influenced by diurnal variation.
      • Liu S.
      • Tinker L.
      • Song Y.
      • et al.
      A prospective study of inflammatory cytokines and diabetes mellitus in a multiethnic cohort of postmenopausal women.
      • Diez-Ruiz A.
      • Tilz G.P.
      • Zangerle R.
      • et al.
      Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis.
      • DeRijk R.
      • Michelson D.
      • Karp B.
      • et al.
      Exercise and circadian rhythm-induced variations in plasma cortisol differentially regulate interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) production in humans: high sensitivity of TNF alpha and resistance of IL-6.
      • Ohgushi M.
      • Taniguchi A.
      • Fukushima M.
      • et al.
      Soluble tumor necrosis factor receptor 2 is independently associated with pulse wave velocity in nonobese Japanese patients with type 2 diabetes mellitus.
      • Hotamisligil G.S.
      • Arner P.
      • Atkinson R.L.
      • et al.
      Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance.
      • Aderka D.
      The potential biological and clinical significance of the soluble tumor necrosis factor receptors.
      Compared with CRP and IL-6, sTNFR-2 may be more strongly associated with colorectal cancer because TNF-α not only independently promotes cellular proliferation and inhibits apoptosis but is also a key upstream regulator of CRP and IL-6.
      • de Visser K.E.
      • Eichten A.
      • Coussens L.M.
      Paradoxical roles of the immune system during cancer development.
      Thus, sTNFR-2 may be a superior marker of the specific proinflammatory milieu that predisposes to long-term development of cancer. Moreover, sTNFR-2 may also be a biomarker of deranged insulin resistance pathways through TNF-α–mediated inhibition of insulin signaling. Insulin resistance may represent an independent mechanistic pathway that promotes colorectal carcinogenesis.
      • Slattery M.L.
      • Samowitz W.
      • Hoffman M.
      • et al.
      Aspirin, NSAIDs, and colorectal cancer: possible involvement in an insulin-related pathway.
      Our results for sTNFR-2 are also consistent with findings from the North Carolina Diet and Health Study. In this cross-sectional study, TNF-α levels were positively associated with prevalent colorectal adenomas.
      • Kim S.
      • Keku T.O.
      • Martin C.
      • et al.
      Circulating levels of inflammatory cytokines and risk of colorectal adenomas.
      However, our findings contrast with a secondary analysis of a clinical trial of aspirin and/or folic acid in the prevention of recurrent colorectal adenomas.
      • Ho G.Y.
      • Xue X.
      • Cushman M.
      • et al.
      Antagonistic effects of aspirin and folic acid on inflammation markers and subsequent risk of recurrent colorectal adenomas.
      In that study, changes over 3 years in plasma levels of sTNFR-2 were not associated with adenoma recurrence among high-risk patients with prior adenoma. The discordant findings in the aspirin trial compared with our study or the North Carolina Diet and Health Study may reflect the inability of inflammatory markers to determine risk of recurrent adenoma rather than initial adenoma or cancer.
      We also observed that initiation of aspirin or NSAID therapy was more strongly associated with lower risk of colorectal cancer among women with high levels of baseline sTNFR-2 than among women with low levels of sTNFR-2. This supports the hypothesis that aspirin and NSAIDs, at least in part, reduce risk of colorectal neoplasia through anti-inflammatory pathways. This is consistent with prior findings in this cohort in which we observed that aspirin use specifically reduced risk of colorectal cancers that overexpressed the proinflammatory COX-2 (PTGS2) isoenzyme.
      • Chan A.T.
      • Ogino S.
      • Fuchs C.S.
      Aspirin and the risk of colorectal cancer in relation to the expression of COX-2.
      Other data examining the role of inflammatory markers in determining responsiveness to anti-inflammatory drugs are limited. Most prior studies relating anti-inflammatory drug use to inflammatory markers only examined drug exposure at the time of blood collection.
      • Gunter M.J.
      • Stolzenberg-Solomon R.
      • Cross A.J.
      • et al.
      A prospective study of serum C-reactive protein and colorectal cancer risk in men.
      • Erlinger T.P.
      • Platz E.A.
      • Rifai N.
      • et al.
      C-reactive protein and the risk of incident colorectal cancer.
      • Il'yasova D.
      • Colbert L.H.
      • Harris T.B.
      • et al.
      Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort.
      • Trichopoulos D.
      • Psaltopoulou T.
      • Orfanos P.
      • et al.
      Plasma C-reactive protein and risk of cancer: a prospective study from Greece.
      • Siemes C.
      • Visser L.E.
      • Coebergh J.W.
      • et al.
      C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study.
      • Kim S.
      • Keku T.O.
      • Martin C.
      • et al.
      Circulating levels of inflammatory cytokines and risk of colorectal adenomas.
      However, it is difficult to interpret these studies because the concurrent use of aspirin and NSAIDs directly influences the baseline level of inflammatory markers,
      • Kim S.
      • Keku T.O.
      • Martin C.
      • et al.
      Circulating levels of inflammatory cytokines and risk of colorectal adenomas.
      • Ho G.Y.
      • Xue X.
      • Cushman M.
      • et al.
      Antagonistic effects of aspirin and folic acid on inflammation markers and subsequent risk of recurrent colorectal adenomas.
      precluding an evaluation of the effect of these drugs according to pretreatment levels. In the clinical trial of aspirin/folic acid, neither baseline levels nor changes in posttreatment levels of sTNFR-2 modified the association of aspirin treatment with risk of recurrent adenoma.
      • Ho G.Y.
      • Xue X.
      • Cushman M.
      • et al.
      Antagonistic effects of aspirin and folic acid on inflammation markers and subsequent risk of recurrent colorectal adenomas.
      However, these results may reflect the potential limitation of using sTNFR-2 levels among high-risk patients with established neoplasia. Moreover, the dosage of aspirin used by the women in our study (mean, 7 standard aspirin tablets/week) was considerably higher than the dosage of aspirin (81 mg/day) that was effective in preventing recurrence in this randomized trial.
      • Chan A.T.
      • Giovannucci E.L.
      • Meyerhardt J.A.
      • et al.
      Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer.
      • Baron J.A.
      • Cole B.F.
      • Sandler R.S.
      • et al.
      A randomized trial of aspirin to prevent colorectal adenomas.
      Finally, sTNFR-2 may influence the effect of aspirin/NSAID use on initial risk of invasive cancer but not recurrent adenoma.
      The strengths of our study include its prospective design and high follow-up rate. Our measures of plasma inflammatory markers before diagnosis of cancer minimize potential bias related to elevation of these markers by the cancer itself. Moreover, because our risk estimates were essentially unchanged after excluding cases within 2 years of blood draw, our results are unlikely to be related to occult malignancy. We also had prospectively collected data on aspirin/NSAID use as well as potential lifestyle factors that could confound the relationship between colorectal cancer and inflammation. Notably, our associations between aspirin/NSAID use and risk of colorectal cancer have been validated by the results of randomized control trials.
      • Flossmann E.
      • Rothwell P.M.
      Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies.
      Finally, because we obtained data on aspirin/NSAID use both before and after blood collection, we were able to disentangle the effect of concurrent anti-inflammatory drug use on inflammatory marker levels with the specific influence of these drugs on colorectal cancer risk among treatment-naïve individuals.
      We acknowledge several limitations to our study. First, we obtained only one baseline measure of inflammatory markers. However, others have shown that these markers are generally consistent over several years among the same individual.
      • Allin K.H.
      • Nordestgaard B.G.
      • Zacho J.
      • et al.
      C-reactive protein and the risk of cancer: a mendelian randomization study.
      • Platz E.A.
      • Sutcliffe S.
      • De Marzo A.M.
      • et al.
      Intra-individual variation in serum C-reactive protein over 4 years: an implication for epidemiologic studies.
      Moreover, intraindividual variation in levels over time would tend to attenuate our observed associations.
      • Platz E.A.
      • Sutcliffe S.
      • De Marzo A.M.
      • et al.
      Intra-individual variation in serum C-reactive protein over 4 years: an implication for epidemiologic studies.
      • Clarke R.
      • Shipley M.
      • Lewington S.
      • et al.
      Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies.
      Second, plasma inflammatory markers are likely to be a relatively nonspecific assessment of the tissue-specific inflammatory pathways most relevant for colorectal carcinogenesis. Third, our cohort was composed entirely of women. Thus, additional studies are needed to generalize our findings to men. Fourth, because our cohort was a case-control study of incident colorectal cancer nested within a prospective cohort, our study design did not permit an examination of adenoma, colorectal cancer–specific mortality, overall mortality, or the adverse consequences of aspirin use. However, we have previously shown significant relationships between aspirin use and risk of adenoma, colorectal cancer–specific mortality, overall mortality, and cardiovascular and gastrointestinal side effects in detailed, separate analyses of the larger cohort.
      • Chan A.T.
      • Ogino S.
      • Fuchs C.S.
      Aspirin use and survival after diagnosis of colorectal cancer.
      • Chan A.T.
      • Giovannucci E.L.
      • Schernhammer E.S.
      • et al.
      A prospective study of aspirin use and the risk of colorectal adenoma.
      • Chan A.T.
      • Manson J.E.
      • Feskanich D.
      • et al.
      Long-term aspirin use and mortality in women.
      • Chan A.T.
      • Manson J.E.
      • Albert C.M.
      • et al.
      Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events.
      • Huang E.S.
      • Strate L.L.
      • Ho W.W.
      • et al.
      Long-term use of aspirin and the risk of gastrointestinal bleeding in a prospective, population-based cohort.
      Finally, we cannot exclude the possibility that our associations with sTNFR-2 may reflect residual confounding resulting from imperfectly measured lifestyle risk factors. However, even if sTNFR-2 is not causally related to colorectal carcinogenesis, this would not diminish its potential as a surrogate biomarker for relevant proinflammatory, procarcinogenic lifestyle factors or exclude inflammation as a mechanistic basis for colorectal cancer.
      In conclusion, plasma sTNFR-2, but not CRP or IL-6, is associated with the development of colorectal cancer. Anti-inflammatory drugs appear to reduce risk of colorectal cancer among women with high baseline levels of sTNFR-2 but not among women with low levels of sTNFR-2. Although these results should be viewed as exploratory and require confirmation, they support a role for chronic inflammation in the pathogenesis of colorectal cancer and the potential of using inflammatory markers to define subsets of the population that may obtain differential benefit from anti-inflammatory drugs.

      Acknowledgments

      The authors thank the participants in the Nurses' Health Study for their continued dedication; Donna Spiegelman, ScD, for statistical expertise; Ellen Hertzmark for assistance in programming; and Gary Bradwin and Nader Rifai, PhD, for measurements of the inflammatory analytes.

      Supplementary material

      Figure thumbnail grs1
      Supplementary Figure s1Restricted cubic spline plot for CRP and risk of colorectal cancer. RR of colorectal cancer is plotted according to plasma CRP level (mg/L). Hatched lines represent 95% CIs. Spline was adjusted for the same factors as the multivariate model in with the exception of current use of postmenopausal hormones. A test for overall significance of the curve was nonsignificant (P = .15).
      Figure thumbnail grs2
      Supplementary Figure s2Restricted cubic spline plot for CRP and risk of colorectal cancer among women who currently used postmenopausal hormones. RR of colorectal cancer is plotted according to plasma CRP level (mg/L). Hatched lines represent 95% CIs. Spline was adjusted for the same factors as the multivariate model in with the exception of current use of postmenopausal hormones. A test for overall significance of the curve was nonsignificant (P = .75).
      Figure thumbnail grs3
      Supplementary Figure s3Restricted cubic spline plot for CRP and risk of colorectal cancer among women who did not currently use postmenopausal hormones. RR of colorectal cancer is plotted according to plasma CRP level (mg/L). Hatched lines represent 95% CIs. Spline was adjusted for the same factors as the multivariate model in with the exception of current use of postmenopausal hormones. A test for overall significance of the curve was nonsignificant (P = .44).

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