Original Article
Aspirin and the Risk of Colorectal Cancer in Relation to the Expression of COX-2
N Engl J Med 2007; 356:2131-2142May 24, 2007
- Abstract
Background
Regular use of aspirin reduces the risk of a colorectal neoplasm, but the mechanism by which aspirin affects carcinogenesis in the colon is not well understood.
Methods
We estimated cyclooxygenase-2 (COX-2) expression by immunohistochemical assay of sections from paraffin-embedded colorectal-cancer specimens from two large cohorts of participants who provided data on aspirin use from a questionnaire every 2 years. We applied Cox regression to a competing-risks analysis to compare the effects of aspirin use on the relative risk of colorectal cancer in relation to the expression of COX-2 in the tumor.
Results
During 2,446,431 person-years of follow-up of 82,911 women and 47,363 men, we found 636 incident colorectal cancers that were accessible for determination of COX-2 expression. Of the tumors, 423 (67%) had moderate or strong COX-2 expression. The effect of aspirin use differed significantly in relation to COX-2 expression (P for heterogeneity=0.02). Regular aspirin use conferred a significant reduction in the risk of colorectal cancers that overexpressed COX-2 (multivariate relative risk, 0.64; 95% confidence interval [CI], 0.52 to 0.78), whereas regular aspirin use had no influence on tumors with weak or absent expression of COX-2 (multivariate relative risk, 0.96; 95% CI, 0.73 to 1.26). The age-standardized incidence rate for cancers that overexpressed COX-2 was 37 per 100,000 person-years among regular aspirin users, as compared with 56 per 100,000 person-years among those who did not use aspirin regularly; in contrast, the rate for cancers with weak or absent COX-2 expression was 27 per 100,000 person-years among regular aspirin users, as compared with 28 per 100,000 person-years among nonregular aspirin users.
Conclusions
Regular use of aspirin appears to reduce the risk of colorectal cancers that overexpress COX-2 but not the risk of colorectal cancers with weak or absent expression of COX-2.
Media in This Article
Figure 1
COX-2 Expression in Immunohistochemical Assays of Colorectal-Cancer Tissue and Mucosa.Table 1
Baseline Characteristics of the Study Cohort.Article Activity
- Article
Observational studies and randomized intervention trials have found that regular use of aspirin reduces the risk of colorectal neoplasms.1-4 The mechanism by which aspirin influences the risk of colorectal cancer is not well understood. Aspirin inhibits cyclooxygenase, which catalyzes the rate-limiting step in the metabolic conversion of arachidonic acid to prostaglandins and related eicosanoids.5 One form of cyclooxygenase, termed cyclooxygenase-2 (COX-2), promotes inflammation and cell proliferation, and colorectal cancers often overexpress this enzyme.6-9 Randomized trials have demonstrated that selective inhibitors of COX-2 reduce the risk of recurrent adenoma in participants at high risk.10-13 However, aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) decrease proliferation and increase apoptosis of colorectal cancer cell lines that have no detectable cyclooxygenase activity.14 Aspirin has other effects that are unrelated to cyclooxygenase, including inhibition of nuclear factor-κB,15 induction of apoptosis by activation of p38 kinase,16 and catabolism of polyamines.17 If aspirin exerts its effect on the formation of adenomas and cancers by inhibiting COX-2 or its downstream effectors, then the use of aspirin should preferentially reduce the risk of tumors for which growth depends on COX-2 function.
We investigated whether the influence of aspirin on the risk of colorectal cancer varied with the expression of COX-2 in the tumor. For this purpose, we used tumor specimens from two large prospective studies in which an association was found between the regular use of aspirin and a reduced risk of colorectal cancer.18-20
Methods
Study Population
The Nurses' Health Study (NHS) was initiated in 1976 when 121,701 U.S. female registered nurses, 30 through 55 years of age, completed a mailed questionnaire.19,20 The Health Professionals Follow-up Study (HPFS) was established in 1986 with a parallel cohort of 51,529 U.S. male dentists, optometrists, osteopaths, podiatrists, pharmacists, and veterinarians who were 40 through 75 years of age at entry.18 The cohorts had a follow-up rate of 92%. We mailed questionnaires every 2 years to obtain updated information and identify new cases of cancer. In 1980, the NHS questionnaire was expanded to include a validated assessment of diet and aspirin use21; a similar instrument had been used in the 1986 HPFS questionnaire.22 The overall response rate for these questionnaires was 90%. The institutional review boards at Brigham and Women's Hospital and the Harvard School of Public Health approved this study; completion of the questionnaire was considered to imply informed consent.
Assessment of Medication Use
Assessment of aspirin use in both the NHS and the HPFS has been described in detail previously.18-20,23 Briefly, in 1980 we asked NHS participants whether they used aspirin, the number of pills taken each week, and the number of years of use. We updated this information every 2 years except for 1986 with specific questions on the number of aspirin tablets taken per week (in categories of number taken). In the 1986 HPFS questionnaire and in questionnaires every 2 years thereafter, we inquired whether the men in the study used aspirin two or more times per week. Beginning in 1992, we also asked these men the average number of tablets taken per week (in categories of number taken). In both cohorts, we specifically inquired about standard-dose (325-mg) aspirin tablets. However, to reflect secular trends in consumption of low-dose (baby) aspirin, the questionnaires after 1992 asked participants to convert four baby aspirin tablets to one adult standard-dose tablet when responding. We did not collect consistent data on use of nonaspirin NSAIDs in either cohort. We did not evaluate the use of selective inhibitors of COX-2 that were introduced in the United States in 1999.
Ascertainment of Cases
We requested permission to acquire medical records and pathology reports from participants who reported colorectal cancer on our biennial questionnaire. We identified deaths from the National Death Index and from next of kin.24 A study physician who was unaware of information on the participants' intake of aspirin reviewed medical and pathological records to extract information on histologic types and anatomic locations of the cancers. A single study pathologist reviewed all of the cases that were retrieved for determination of COX-2 expression.
Assessment of COX-2 Expression
Beginning in 1997 in the HPFS and 2001 in the NHS, we began retrieving, from the pathology departments of treating hospitals, available pathological specimens from participants whom we confirmed had received a diagnosis of colorectal cancer. We obtained specimens from 648 cases (76%) over 16 years of follow-up in the HPFS and 662 cases (58%) over 22 years of follow-up in the NHS. We limited our analysis of the expression of COX-2 to unstained paraffin blocks with amounts of tumor tissue and adjacent mucosa that were sufficient for immunohistochemical analysis (636 cases: 368 from the NHS and 268 from the HPFS). The baseline characteristics of participants with colorectal cancer whose tumors we analyzed were similar to those of participants whose tumors we did not analyze (mean age, 54.4 vs. 54.9 years; nonwhite, 3% vs. 3%; former or current smoker, 60% vs. 58%; mean body-mass index [the weight in kilograms divided by the square of the height in meters], 25.5 vs. 25.3; mean metabolic equivalent [MET; i.e., exercise intensity] score per week, 16.6 vs. 15.3; current multivitamin use, 36% vs. 33%; previous lower gastrointestinal endoscopy, 13% vs. 12%; folate intake, 401 vs. 408 μg per day; calcium intake, 798 vs. 786 mg per day; alcohol intake, 9.9 vs. 10.2 g per day; P>0.25 for all comparisons).
We used a previously described method for COX-2 immunostaining on whole tissue sections or on microassays constituted from specimens.25,26 We incubated deparaffinized tissue sections with citrate buffer (BioGenex) in a microwave oven for 15 minutes, then cooled them for 40 minutes. Tissue sections were then incubated with 3% hydrogen peroxide for 20 minutes, avidin block for 15 minutes, and biotin block for 15 minutes. A mouse anti–COX-2 antibody (Cayman Chemical) diluted 1:300 in phosphate-buffered saline was applied, and the slides were maintained overnight at 4°C. Next, we applied an antimouse horse IgG antibody (Vector Laboratories) for 20 minutes, followed by an avidin–biotin complex conjugate (Vector Laboratories). The immunochemical reaction was revealed by diaminobenzidine and methyl-green counterstain. For each assay run, we included a cancer tissue with COX-2 overexpression and a negative control (normal colonic tissue). We also examined a specimen with known COX-2 overexpression treated with phosphate-buffered saline, but not the anti-COX-2 antibody, as a control for nonspecific binding of the immunohistochemical marker.
A pathologist who was unaware of any data concerning the participants interpreted COX-2 expression, using a standardized grading system (absent, weak, moderate, or strong). The pathologist classified staining of tumor cells as “absent” if COX-2 expression was at the same level of intensity as that in adjacent normal colonic epithelium; weak, moderate, or strong staining indicated progressively increasing degrees of overexpression. A random sample of 108 cancers was reread by a second pathologist unaware of data on the participants; the concordance between the two pathologists was 0.92 (κ=0.62, P<0.001).26 If the intensity of immunostaining was moderate or strong, tumors were classified as cancers with COX-2 overexpression (COX-2–positive). If immunostaining intensity was weak or absent, tumors were classified as negative for COX-2 overexpression (COX-2–negative) (Figure 1Figure 1
COX-2 Expression in Immunohistochemical Assays of Colorectal-Cancer Tissue and Mucosa.).Statistical Analysis
At baseline, we excluded men and women who did not complete the baseline dietary questionnaire or medication questions, who recorded implausible dietary or aspirin data (e.g., responded “yes” to use but then recorded use of zero aspirin tablets per week), or reported a baseline history of cancer (except nonmelanoma skin cancer). We also excluded participants with inflammatory bowel disease, familial polyposis, or hereditary nonpolyposis colon cancer. After these exclusions, 82,911 women and 47,363 men were eligible for analysis. They accrued follow-up time beginning on the month of return of their baseline questionnaire and ending on the month of diagnosis of colorectal cancer, death from other causes, or June 2002, whichever came first. Participants in whom colorectal cancer was adjudicated as the cause of death by study physicians after review of medical records were included as cases. Data from cases of colorectal cancer for which we were unable to assay COX-2 expression in the tumor were censored from the analysis at the date of diagnosis.
To reduce within-person variation and to better estimate long-term intake, we used the cumulative average intake of aspirin as reported on all available questionnaires up to the start of each 2-year follow-up interval.27 In the NHS, women who reported taking two or more standard (325-mg) aspirin tablets per week were classified as regular users, whereas those who reported less aspirin use were classified as nonusers. We also estimated the duration of the regular use of aspirin by NHS participants from the number of years of regular use reported in 1980, with updating of this variable every 2 years.19,20,23 In the HPFS, men who reported using aspirin at least two times per week were classified as regular users, whereas those who did not report aspirin use at least two times per week were classified as nonusers.18 For our main analyses, we pooled data from both cohorts. We conducted tests of heterogeneity using the Q statistic before pooling.28 In this analysis, we observed no heterogeneity between the cohorts regarding the association of regular aspirin use and risk of colorectal cancer (P=0.33 for Cochran's Q test).
We calculated the incidence rates of colorectal cancer for participants in a specific category of aspirin use by dividing the number of incident cases by the number of person-years of follow-up. We calculated relative risks by dividing the incidence rate in one category by the incidence rate in the reference category; we used Cox proportional-hazards modeling to control for multiple variables simultaneously and to calculate 95% confidence intervals. Multivariate relative risks are adjusted for age, sex, smoking before the age of 30 years (0, 1 to 4, 5 to 10, 11 to 15, or more than 15 pack-years); body-mass index (in quintiles); regular vigorous exercise (in quintiles of MET task score per week); colorectal cancer in a parent or sibling (yes or no); previous lower gastrointestinal endoscopy (yes or no); history of polyps (yes or no); current multivitamin use (yes or no); consumption of beef, pork, or lamb as a main dish (0 to 3 times per month, 1 time per week, 2 to 4 times per week, or 5 or more times per week); alcohol consumption (0, 0.1 to 4.9, 5.0 to 14.9, or 15 g or more per day); and energy-adjusted folate and calcium intake (in quintiles). For the analyses restricted to women, the multivariate models additionally adjusted for postmenopausal hormone-replacement therapy (premenopausal women and postmenopausal women who never used, formerly used, or were currently using hormone-replacement therapy) and did not include sex. For the analyses restricted to men, the multivariate models also did not include sex. We used the most recent information for all covariates.
To compare the association between aspirin use and the risk of colorectal cancer in relation to COX-2 expression in the cancer, we used a competing-risk analysis that uses a duplication-method Cox regression.29,30 This method permits estimation of separate regression coefficients for aspirin use stratified according to the type of outcome (e.g., cancer with COX-2 overexpression vs. cancer with weak or absent COX-2 expression). We assessed the statistical significance of the difference between the risk estimates according to tumor type by a likelihood-ratio test that compared the model that allowed for separate associations of aspirin according to COX-2 expression with a model that assumed a common association. We used SAS software (version 9.1.3) for all analyses. All P values are two-sided.
Results
Among the 82,911 eligible women and 47,363 eligible men at the time of the baseline questionnaire, participants reporting the regular use of aspirin (taking two or more standard aspirin tablets per week or using aspirin at least two times per week) were older, were slightly less physically active, were more likely to be current or former smokers, were more likely to use multivitamins regularly, were more likely to use postmenopausal hormones (among women), consumed more alcohol, and consumed more folate (P<0.001 for all unadjusted comparisons) (Table 1Table 1
Baseline Characteristics of the Study Cohort.). On the basis of the updated data on aspirin use we obtained on biennial questionnaires, we observed that patterns of aspirin use changed over time. Averaged over the total number of person-years of follow-up (2,446,431), the difference in mean age between regular aspirin users and nonusers gradually increased (59.0 years for regular aspirin users and 56.5 years for nonusers, P<0.001). For this analysis, we identified 636 incident cases of colorectal cancer among users and nonusers of aspirin that were available for analysis of COX-2 expression (Table 1). Among these 636 tumors, 423 (67%) had moderate or strong COX-2 expression (i.e., were COX-2–positive), whereas 213 (33%) had weak or absent COX-2 expression (i.e., were COX-2–negative).As in our previous studies,18-20 we observed in both cohorts a significantly lower risk of colorectal cancer among regular aspirin users than among participants who did not regularly use aspirin, after controlling for other known or suspected colorectal cancer risk factors (Table 2Table 2
Relative Risk of Colorectal Cancer in Relation to COX-2 Expression and Regular Aspirin Use.). For the combined cohorts, regular aspirin use was associated with a multivariate relative risk of colorectal cancer of 0.73 (95% confidence interval [CI], 0.62 to 0.86) for cases with tissue available for COX-2 analysis. Inclusion of all documented cases of colorectal cancer that were found during follow-up, irrespective of the availability of tissue for analysis of COX-2 expression, did not materially alter these results (multivariate relative risk, 0.76; 95% CI, 0.70 to 0.84 for 1142 cases in the NHS and 853 cases in the HPFS; P<0.001). Regular aspirin use was associated with a multivariate relative risk of 0.78 (95% CI, 0.69 to 0.87; P<0.001) among participants with colorectal cancer in whom COX-2 expression was not assayed.We evaluated the influence of aspirin on the risk of colorectal cancer according to overexpression of COX-2 in the tumor (Table 2). The benefit of regular aspirin use appeared to be confined to cancers with COX-2 overexpression (multivariate relative risk, 0.64; 95% CI, 0.52 to 0.78). In contrast, aspirin use did not appear to be associated with the risk of colorectal cancer with weak or absent COX-2 expression (multivariate relative risk, 0.96; 95% CI, 0.73 to 1.26). A test for heterogeneity for the association of regular aspirin use with COX-2–positive or COX-2–negative tumors found a statistically significant association (P for heterogeneity=0.02).
Table 3Table 3
Relative Risk of Colorectal Cancer in Relation to COX-2 Expression and Duration of Regular Aspirin Use. shows the association between the duration of regular use of aspirin and the risk of a COX-2–positive or COX-2–negative colorectal cancer. A statistically significant reduction in the number of cases of COX-2–positive cancer was not evident until aspirin had been used regularly for more than 10 years (multivariate relative risk, 0.59; 95%, CI, 0.42 to 0.82; P for trend, <0.001); there was no statistically significant reduction in the number of COX-2–negative cancers with increasing duration of aspirin use (P for trend=0.25).Table 4Table 4
Relative Risk of Colorectal Cancer in Relation to COX-2 Expression and Aspirin Dose. shows the association between the dose of aspirin (tablets per week) and the risk of colorectal cancer. A reduction in the multivariate relative risk of colorectal cancer became apparent with an intake of more than five tablets per week, and the relative risk was further reduced as the number of tablets per week increased (P for trend=0.001). This association was also noted among participants with COX-2–positive tumors (P for trend, <0.001) but not among those with COX-2–negative tumors (P for trend=0.52). After adjustment for the number of years of use of aspirin, the association between dose and COX-2–negative tumors remained nonsignificant (P for trend=0.91).On the basis of the overall incidence of colorectal cancer in these cohorts and the prevalence of COX-2–positive and COX-2–negative tumors among participants in whom we assessed COX-2 expression, we estimated the age-standardized incidence rate for COX-2–positive and COX-2–negative colorectal cancers in relation to aspirin use in the entire cohort. The age-standardized incidence rate of COX-2–positive tumors was 37 per 100,000 person-years for regular aspirin users as compared with 56 per 100,000 person-years for nonusers. In contrast, the age-standardized incidence rate of COX-2–negative tumors was 27 per 100,000 person-years for regular aspirin users as compared with 28 per 100,000 person-years for nonusers.
Discussion
We found that participants in two large prospective cohorts who reported long-term, regular aspirin use (at least two standard tablets per week or use of aspirin at least two times per week) had a significant reduction in the relative risk of colorectal cancer, as compared with participants who reported less use of aspirin. This reduction in risk was due almost entirely to a reduction in the number of COX-2–positive colorectal cancers among regular aspirin users. In contrast, the difference in the incidence of COX-2–negative colorectal cancers between regular users and nonusers of aspirin was not statistically significant. A reduction of the risk of COX-2–positive tumors was also found with increasing aspirin dose and increasing duration of use. No significant dose or duration effect was observed for COX-2–negative tumors.
These results are consistent with a cross-sectional case–control study in which the association of NSAIDs with a reduced risk of adenomatous polyps was strongest in cases with high expression of COX-2 messenger RNA.31 Our finding that the association with a reduced risk of colorectal cancer is most apparent at intakes of more than five aspirin tablets per day is consistent with the results of studies in which higher doses of aspirin were required to inhibit COX-2 than to inhibit COX-1.1,5 Moreover, the association with a reduction in cancer risk was found only after several years of aspirin use, a finding that suggests an effect of aspirin on the early stages of colorectal adenoma or cancer.1-4
COX-2 is progressively overexpressed during the stepwise sequence from adenoma to carcinoma,7 and randomized, placebo-controlled trials have shown that selective COX-2 inhibitors prevent recurrence of adenoma among patients with a history of adenoma or familial polyposis.10-13 Our data suggest that the anticancer benefit of aspirin is mediated, at least in part, by inhibition of COX-2. Experimental studies have shown that aspirin and NSAIDs, especially at high doses, have a range of other potentially antineoplastic actions15-17,32-37; these results indicate that further work is needed to elucidate the effects of these agents and COX-2 (or its downstream effectors) on the development of colorectal cancer.38,39 COX-2, possibly through production of inflammatory prostaglandins or eicosanoids, may regulate angiogenesis, apoptosis, or tumor-cell invasiveness.6
Our study has several strengths. First, because we collected detailed, updated information on aspirin use during 22 years of follow-up, we were able to evaluate the effects of long-term use across a broad range of intakes. Second, we obtained aspirin data prospectively, before the diagnosis of colorectal cancer. Any errors in recall would have tended to attenuate rather than exaggerate true associations. Third, because the participants were all health professionals, the accuracy of self-reported aspirin use is likely to be high. Fourth, we collected detailed data on potential confounders and had a high follow-up rate (92% of participants returned questionnaires or were identified as deceased). Finally, our results were remarkably consistent between the two independent cohorts.
There are several limitations to our study. The study was observational, and aspirin use was self-selected; thus, among aspirin users and nonusers, there were small, albeit statistically significant, differences in risk factors for colorectal cancer, including smoking history, physical activity, and use of multivitamins. However, adjustment for these characteristics, as well as for a wide range of other potential risk factors, had minimal influence on our findings, suggesting little potential for residual or uncontrolled confounding. We did not have sufficient data on use of nonaspirin NSAIDs in both cohorts to reliably examine their use in relation to COX-2–expressing tumors. However, it is improbable that use of nonaspirin NSAIDs influenced our findings with aspirin; our previous study did not demonstrate any modification by NSAID use of the reduced risk of colorectal cancer observed with aspirin.20 We were unable to obtain tumor tissue from all cases of confirmed colorectal cancer detected in the two cohorts, but the risk factors in these cases did not appreciably differ from those in cases with tumor tissue available.
Another limitation of our study is the lack of a widely accepted, standardized classification scheme for COX-2 expression in colorectal cancer. Nevertheless, previous studies have demonstrated that the results of Western and Northern blot analyses correlate well with immunohistochemical grading of COX-2.40 With our classification of COX-2 expression, we found, in our overall population, a proportion of tumors that overexpressed COX-2 similar to those found by other investigators.8,9,41 In validation studies of the central, blinded review of tumor specimens, we observed substantial interobserver agreement (92%). Any significant misclassification of COX-2 overexpression would be expected to bias our results toward finding no significant differences in the effect of aspirin on tumors in relation to COX-2 expression.
Our results support the importance of continued investigation into COX-2 and related pathways for the development of new treatments and the potential use of COX-2 as a molecular marker for tailoring chemoprevention in participants with a history of colorectal cancer.
Supported by grants from the National Cancer Institute (CA87969, CA55075), the National Institutes of Health, the Marshall S. Kates Memorial Fund, the Bennett Family Fund for Targeted Therapies Research, and the Entertainment Industry Foundation National Colorectal Cancer Research Alliance. Dr. Chan is a recipient of the American Gastroenterological Association/Foundation for Digestive Health and Nutrition Research Scholar Award and a career development award from the National Cancer Institute (CA10741). The National Cancer Institute, the National Institutes of Health, the Marshall S. Kates Memorial Fund, the Bennett Family Fund for Targeted Therapies Research, the Entertainment Industry Foundation National Colorectal Cancer Research Alliance, the American Gastroenterological Association, and the Foundation for Digestive Health and Nutrition had no role in the collection, management, analysis, or interpretation of the data and had no role in the preparation, review, or approval of the manuscript.
Dr. Chan reports receiving a career development award from the Glaxo Institute for Digestive Health for an unrelated study. No other potential conflict of interest relevant to this article was reported.
We thank Mr. Gregory Kirkner for assistance in accessing tumor specimens, Ms. Mami Cantor for assistance in immunohistochemical assays, Dr. Reiko Dehari for interobserver variability studies, Dr. Eva Schernhammer for statistical expertise, and Dr. Edward Giovannucci and Dr. Walter Willett for scientific insights.
Source Information
From the Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School (A.T.C.); the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School (S.O.); the Department of Medical Oncology, Dana–Farber Cancer Institute (S.O., C.S.F.); and the Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (A.T.C., C.S.F.) — all in Boston.
Address reprint requests to Dr. Chan at the Gastrointestinal Unit, Massachusetts General Hospital, 55 Fruit St., GRJ 728A, Boston, MA 02114, or at achan@partners.org.
- References
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- Citing Articles (121)
Citing Articles
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Doran Avivi, Menachem Moshkowitz, Elmar Detering, Nadir Arber. (2012) The role of low-dose aspirin in the prevention of colorectal cancer. Expert Opinion on Therapeutic Targets1-12
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A. Kuchiba, T. Morikawa, M. Yamauchi, Y. Imamura, X. Liao, A. T. Chan, J. A. Meyerhardt, E. Giovannucci, C. S. Fuchs, S. Ogino. (2012) Body Mass Index and Risk of Colorectal Cancer According to Fatty Acid Synthase Expression in the Nurses' Health Study. JNCI Journal of the National Cancer Institute
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D. Wang, R. N. DuBois. (2012) Associations Between Obesity and Cancer: The Role of Fatty Acid Synthase. JNCI Journal of the National Cancer Institute
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H. Shime, M. Matsumoto, H. Oshiumi, S. Tanaka, A. Nakane, Y. Iwakura, H. Tahara, N. Inoue, T. Seya. (2012) Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors. Proceedings of the National Academy of Sciences
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Barbara C. Pence, Eric J. Belasco, Conrad P. Lyford. (2012) Prevention of Colorectal Cancer by Aspirin and/or Calcium: Efficacy, Mechanisms, and Cost Effectiveness. Current Colorectal Cancer Reports
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Mark F. McCarty. (2012) Minimizing the cancer-promotional activity of cox-2 as a central strategy in cancer prevention. Medical Hypotheses 78:1, 45-57
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Ting Luo, Hua-Mei Yan, Ping He, Yong Luo, Yuan-Fu Yang, Hong Zheng. (2012) Aspirin use and breast cancer risk: a meta-analysis. Breast Cancer Research and Treatment 131:2, 581-587
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Mary-Clare Cathcart, Kenneth J. O'Byrne, John V. Reynolds, Jacintha O'Sullivan, Graham P. Pidgeon. (2012) COX-derived prostanoid pathways in gastrointestinal cancer development and progression: Novel targets for prevention and intervention. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1825:1, 49-63
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Teppei Morikawa, Aya Kuchiba, Zhi Rong Qian, Mari Mino-Kenudson, Jason L. Hornick, Mai Yamauchi, Yu Imamura, Xiaoyun Liao, Reiko Nishihara, Jeffrey A. Meyerhardt, Charles S. Fuchs, Shuji Ogino. (2011) Prognostic Significance and Molecular Associations of Tumor Growth Pattern in Colorectal Cancer. Annals of Surgical Oncology
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John Burn, Anne-Marie Gerdes, Finlay Macrae, Jukka-Pekka Mecklin, Gabriela Moeslein, Sylviane Olschwang, Diane Eccles, D Gareth Evans, Eamonn R Maher, Lucio Bertario, Marie-Luise Bisgaard, Malcolm G Dunlop, Judy WC Ho, Shirley V Hodgson, Annika Lindblom, Jan Lubinski, Patrick J Morrison, Victoria Murday, Raj Ramesar, Lucy Side, Rodney J Scott, Huw JW Thomas, Hans F Vasen, Gail Barker, Gillian Crawford, Faye Elliott, Mohammad Movahedi, Kirsi Pylvanainen, Juul T Wijnen, Riccardo Fodde, Henry T Lynch, John C Mathers, D Timothy Bishop. (2011) Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. The Lancet 378:9809, 2081-2087
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Soon Young Shin, Jiye Hyun, Yoongho Lim, Young Han Lee. (2011) 3′-Chloro-5,7-dimethoxyisoflavone inhibits TNFα-induced CXCL10 gene transcription by suppressing the NF-κB pathway in HCT116 human colon cancer cells. International Immunopharmacology 11:12, 2104-2111
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Valerie A. McCormack, Rayjean J. Hung, Darren R. Brenner, Heike Bickeböller, Albert Rosenberger, Joshua E. Muscat, Philip Lazarus, Anne Tjønneland, Søren Friis, David C. Christiani, Eun-mi Chun, Loic Marchand, Gad Rennert, Hedy S. Rennert, Angeline S. Andrew, Irene Orlow, Bernard Park, Paolo Boffetta, Eric J. Duell. (2011) Aspirin and NSAID use and lung cancer risk: a pooled analysis in the International Lung Cancer Consortium (ILCCO). Cancer Causes & Control 22:12, 1709-1720
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Ludovica Tagliabue, Mariateresa Pugliano. (2011) Will aspirin rescue us from cancer?. Internal and Emergency Medicine 6:5, 449-451
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Abhay Kumar Singh, Rajinder Parshad, Shweta Pasi, Thirumurthy Madhavan, Satya N. Das, Biswajit Mishra, Kamaldeep Gill, Krishna Dalal, Sharmistha Dey. (2011) Prognostic Significance of Cyclooxygenase-2 and Response to Chemotherapy in Invasive Ductal Breast Carcinoma Patients by Real Time Surface Plasmon Resonance Analysis. DNA and Cell Biology 30:10, 801-807
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X. Zhang, S. A. Smith-Warner, A. T. Chan, K. Wu, D. Spiegelman, C. S. Fuchs, W. C. Willett, E. L. Giovannucci. (2011) Aspirin Use, Body Mass Index, Physical Activity, Plasma C-Peptide, and Colon Cancer Risk in US Health Professionals. American Journal of Epidemiology 174:4, 459-467
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Shuji Ogino, Jérôme Galon, Charles S. Fuchs, Glenn Dranoff. (2011) Cancer immunology—analysis of host and tumor factors for personalized medicine. Nature Reviews Clinical Oncology 8:12, 711-719
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Marco Erreni, Alberto Mantovani, Paola Allavena. (2011) Tumor-associated Macrophages (TAM) and Inflammation in Colorectal Cancer. Cancer Microenvironment 4:2, 141-154
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Denis Gingras, Richard Béliveau. (2011) Colorectal Cancer Prevention Through Dietary and Lifestyle Modifications. Cancer Microenvironment 4:2, 133-139
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A. Filipovic, G. Giamas, J. Stebbing. (2011) The potential role of cyclooxygenase-2 (COX-2) during early breast cancer therapy. Annals of Oncology 22:8, 1700-1702
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X. Garcia-Albeniz, A.T. Chan. (2011) Aspirin for the prevention of colorectal cancer. Best Practice & Research Clinical Gastroenterology 25:4-5, 461-472
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Nicole Beauchemin. (2011) The Colorectal Tumor Microenvironment: The Next Decade. Cancer Microenvironment 4:2, 181-185
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Karsten Schrör. (2011) Pharmacology and cellular/molecular mechanisms of action of aspirin and Non-aspirin NSAIDs in colorectal cancer. Best Practice & Research Clinical Gastroenterology 25:4-5, 473-484
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A.-M. Katsori, M. Chatzopoulou, K. Dimas, C. Kontogiorgis, A. Patsilinakos, T. Trangas, D. Hadjipavlou-Litina. (2011) Curcumin analogues as possible anti-proliferative & anti-inflammatory agents. European Journal of Medicinal Chemistry 46:7, 2722-2735
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Katherine Van Loon, Alan P Venook. (2011) Adjuvant treatment of colon cancer: what is next?. Current Opinion in Oncology 23:4, 403-409
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Nadir Arber, Julius Spicak, István Rácz, Miroslav Zavoral, Aurora Breazna, Paola Gerletti, Maria J Lechuga, Neal Collins, Rebecca B Rosenstein, Craig J Eagle, Bernard Levin. (2011) Five-Year Analysis of the Prevention of Colorectal Sporadic Adenomatous Polyps Trial. The American Journal of Gastroenterology 106:6, 1135-1146
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Wen-liang Zhang. (2011) The role of inflammation in breast cancer and prostate cancer. Clinical Oncology and Cancer Research 8:2, 77-84
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Preet K. Dhillon, Stacey A. Kenfield, Meir J. Stampfer, Edward L. Giovannucci. (2011) Long-term aspirin use and the risk of total, high-grade, regionally advanced and lethal prostate cancer in a prospective cohort of health professionals, 1988-2006. International Journal of Cancer 128:10, 2444-2452
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Shiu-Dong Chung, Jiunn-Horng Kang, Chun-Hou Liao, Kuan-Ming Chiu, Herng-Ching Lin. (2011) Increased Risk for Cancer Following Erectile Dysfunction: A Nationwide Population-Based Follow-Up Study. The Journal of Sexual Medicine 8:5, 1513-1520
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Edward S. Huang, Lisa L. Strate, Wendy W. Ho, Salina S. Lee, Andrew T. Chan. (2011) Long-Term Use of Aspirin and the Risk of Gastrointestinal Bleeding. The American Journal of Medicine 124:5, 426-433
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Yoshifumi Baba, Katsuhiko Nosho, Kaori Shima, Marika Hayashi, Jeffrey A. Meyerhardt, Andrew T. Chan, Edward Giovannucci, Charles S. Fuchs, Shuji Ogino. (2011) Phosphorylated AKT expression is associated with PIK3CA mutation, low stage, and favorable outcome in 717 colorectal cancers. Cancer 117:7, 1399-1408
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Sarah Kraus, Nadir Arber. (2011) Cyclooxygenase-2 Expression and Recurrence of Colorectal Adenomas: Effect of Aspirin Chemoprevention. Current Colorectal Cancer Reports 7:1, 5-7
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Robert Benamouzig, Bernard Uzzan, Jacques Deyra, Antoine Martin, Stanislas Chaussade. (2011) Prevention by Aspirin of Colorectal Adenoma Recurrence: Some Advances and Latest Results of the APACC Trial. Current Colorectal Cancer Reports 7:1, 33-41
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Andrew T. Chan, Shuji Ogino, Edward L. Giovannucci, Charles S. Fuchs. (2011) Inflammatory Markers Are Associated With Risk of Colorectal Cancer and Chemopreventive Response to Anti-Inflammatory Drugs. Gastroenterology 140:3, 799-808.e2
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A E Coghill, P A Newcomb, V M Chia, Y Zheng, K J Wernli, M N Passarelli, J D Potter. (2011) Pre-diagnostic NSAID use but not hormone therapy is associated with improved colorectal cancer survival in women. British Journal of Cancer 104:5, 763-768
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Kaori Shima, Katsuhiko Nosho, Yoshifumi Baba, Mami Cantor, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Charles S. Fuchs, Shuji Ogino. (2011) Prognostic significance of CDKN2A (p16) promoter methylation and loss of expression in 902 colorectal cancers: Cohort study and literature review. International Journal of Cancer 128:5, 1080-1094
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Marianne Berg, Kjetil Søreide. (2011) Prevention: Will an aspirin a day keep the colorectal cancer away?. Nature Reviews Clinical Oncology 8:3, 130-131
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Kaori Shima, Teppei Morikawa, Yoshifumi Baba, Katsuhiko Nosho, Maiko Suzuki, Mai Yamauchi, Marika Hayashi, Edward Giovannucci, Charles S. Fuchs, Shuji Ogino. (2011) MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers. Cancer Causes & Control 22:2, 301-309
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Peter M Rothwell, F Gerald R Fowkes, Jill FF Belch, Hisao Ogawa, Charles P Warlow, Tom W Meade. (2011) Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. The Lancet 377:9759, 31-41
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Teppei Morikawa, Aya Kuchiba, Xiaoyun Liao, Yu Imamura, Mai Yamauchi, Zhi Rong Qian, Reiko Nishihara, Kaori Sato, Jeffrey A. Meyerhardt, Charles S. Fuchs, Shuji Ogino. (2011) Tumor TP53 expression status, body mass index and prognosis in colorectal cancer. International Journal of Cancern/a-n/a
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Byeong Do Yi, Young Pil Bae, Bong Gun Kim, Jong Wha Park, Dong Hyun Kim, Ja Young Park, Seong Ho Choi, Hee Seung Park, Jae Seung Lee, Chang Won Lee, Sang Soo Kim, Bo Hyun Kim, Moon Ki Choi, In Joo Kim. (2011) The Association between Type 2 Diabetes Mellitus and Colorectal Cancer. Endocrinology and Metabolism 26:2, 126
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Yoshifumi Baba, Katsuhiko Nosho, Kaori Shima, Curtis Huttenhower, Noriko Tanaka, Aditi Hazra, Edward L. Giovannucci, Charles S. Fuchs, Shuji Ogino. (2010) Hypomethylation of the IGF2 DMR in Colorectal Tumors, Detected by Bisulfite Pyrosequencing, Is Associated With Poor Prognosis. Gastroenterology 139:6, 1855-1864
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Noriko Tanaka, Curtis Huttenhower, Katsuhiko Nosho, Yoshifumi Baba, Kaori Shima, John Quackenbush, Kevin M. Haigis, Edward Giovannucci, Charles S. Fuchs, Shuji Ogino. (2010) Novel Application of Structural Equation Modeling to Correlation Structure Analysis of CpG Island Methylation in Colorectal Cancer. The American Journal of Pathology 177:6, 2731-2740
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Mee Sook Lee, Yun-Kyoung Lee, Ock Jin Park. (2010) Cherry silver berry (Elaeagnus multiflora) extracts exert antiinflammatory effects by inhibiting COX-2 and Akt signals in HT-29 colon cancer cells. Food Science and Biotechnology 19:6, 1673-1677
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Katsuhiko Nosho, Yoshifumi Baba, Noriko Tanaka, Kaori Shima, Marika Hayashi, Jeffrey A Meyerhardt, Edward Giovannucci, Glenn Dranoff, Charles S Fuchs, Shuji Ogino. (2010) Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. The Journal of Pathology 222:4, 350-366
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Peter M Rothwell, Michelle Wilson, Carl-Eric Elwin, Bo Norrving, Ale Algra, Charles P Warlow, Tom W Meade. (2010) Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. The Lancet 376:9754, 1741-1750
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Pedro Figueiredo, Maria Donato. (2010) Cyclooxygenase-2 is overexpressed in aberrant crypt foci of smokers. European Journal of Gastroenterology & Hepatology 22:10, 1271-1271
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Y Baba, K Nosho, K Shima, J A Meyerhardt, A T Chan, J A Engelman, L C Cantley, M Loda, E Giovannucci, C S Fuchs, S Ogino. (2010) Prognostic significance of AMP-activated protein kinase expression and modifying effect of MAPK3/1 in colorectal cancer. British Journal of Cancer 103:7, 1025-1033
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Natsumi Irahara, Yoshifumi Baba, Katsuhiko Nosho, Kaori Shima, Liying Yan, Dora Dias-Santagata, Anthony John Iafrate, Charles S. Fuchs, Kevin M. Haigis, Shuji Ogino. (2010) NRAS Mutations Are Rare in Colorectal Cancer. Diagnostic Molecular Pathology 19:3, 157-163
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William Ka Kei Wu, Joseph Jao Yiu Sung, Chung Wa Lee, Jun Yu, Chi Hin Cho. (2010) Cyclooxygenase-2 in tumorigenesis of gastrointestinal cancers: An update on the molecular mechanisms. Cancer Letters 295:1, 7-16
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Shuanglin Xiang, Zhenhua Sun, Qiongzhi He, Feng Yan, Yijun Wang, Jian Zhang. (2010) Aspirin inhibits ErbB2 to induce apoptosis in cervical cancer cells. Medical Oncology 27:2, 379-387
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Carina Pereira, Pedro Pimentel-Nunes, Catarina Brandão, Luís Moreira-Dias, Rui Medeiros, Mário Dinis-Ribeiro. (2010) COX-2 polymorphisms and colorectal cancer risk: a strategy for chemoprevention. European Journal of Gastroenterology & Hepatology 22:5, 607-613
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Yoshifumi Baba, Katsuhiko Nosho, Kaori Shima, Natsumi Irahara, Andrew T. Chan, Jeffrey A. Meyerhardt, Daniel C. Chung, Edward L. Giovannucci, Charles S. Fuchs, Shuji Ogino. (2010) HIF1A Overexpression Is Associated with Poor Prognosis in a Cohort of 731 Colorectal Cancers. The American Journal of Pathology 176:5, 2292-2301
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Sandra Demaria, Eli Pikarsky, Michael Karin, Lisa M. Coussens, Yen-Ching Chen, Emad M. El-Omar, Giorgio Trinchieri, Steven M. Dubinett, Jenny T. Mao, Eva Szabo, Arthur Krieg, George J. Weiner, Bernard A. Fox, George Coukos, Ena Wang, Robert T. Abraham, Michele Carbone, Michael T. Lotze. (2010) Cancer and Inflammation: Promise for Biologic Therapy. Journal of Immunotherapy 33:4, 335-351
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S. Ogino, M. Stampfer. (2010) Lifestyle Factors and Microsatellite Instability in Colorectal Cancer: The Evolving Field of Molecular Pathological Epidemiology. JNCI Journal of the National Cancer Institute 102:6, 365-367
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Sharon G. Curhan, Roland Eavey, Josef Shargorodsky, Gary C. Curhan. (2010) Analgesic Use and the Risk of Hearing Loss in Men. The American Journal of Medicine 123:3, 231-237
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Dingzhi Wang, Raymond N. DuBois. (2010) Eicosanoids and cancer. Nature Reviews Cancer 10:3, 181-193
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D Wang, R N DuBois. (2010) The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene 29:6, 781-788
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Shuji Ogino, Katsuhiko Nosho, Natsumi Irahara, Kaori Shima, Yoshifumi Baba, Gregory J Kirkner, Mari Mino-Kenudson, Edward L Giovannucci, Jeffrey A Meyerhardt, Charles S Fuchs. (2010) Negative Lymph Node Count Is Associated With Survival of Colorectal Cancer Patients, Independent of Tumoral Molecular Alterations and Lymphocytic Reaction. The American Journal of Gastroenterology 105:2, 420-433
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Ron Firestein, Kaori Shima, Katsuhiko Nosho, Natsumi Irahara, Yoshifumi Baba, Emeric Bojarski, Edward L. Giovannucci, William C. Hahn, Charles S. Fuchs, Shuji Ogino. (2010) CDK8 expression in 470 colorectal cancers in relation to β-catenin activation, other molecular alterations and patient survival. International Journal of CancerNA-NA
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Hui Cao, Zhong Xu, Hao Long, Xiao-Qing Li, Shao-Lin Li. (2010) The -765C Allele of the Cyclooxygenase-2 Gene as a Potential Risk Factor of Colorectal Cancer: A Meta-Analysis. The Tohoku Journal of Experimental Medicine 222:1, 15-21
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Geom Seog Seo. (2010) Long-term Effect of Aspirin on Colorectal Cancer Incidence and Mortality: 20-year Follow-up of Five Randomised Trials (Lancet 2010;376:1741-1750). Intestinal Research 8:2, 205
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Sarah Kraus, Nadir Arber. (2010) Insights From the Adenoma Prevention With Celecoxib Trial and Risk for Cardiovascular Adverse Events. Current Colorectal Cancer Reports 6:1, 1-3
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Jason A. Zell, Argyrios Ziogas, Leslie Bernstein, Christina A. Clarke, Dennis Deapen, Joan A. Largent, Susan L. Neuhausen, Daniel O. Stram, Giske Ursin, Hoda Anton-Culver. (2009) Nonsteroidal anti-inflammatory drugs. Cancer 115:24, 5662-5671
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Katsuhiko Nosho, Shoko Kure, Natsumi Irahara, Kaori Shima, Yoshifumi Baba, Donna Spiegelman, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Charles S. Fuchs, Shuji Ogino. (2009) A Prospective Cohort Study Shows Unique Epigenetic, Genetic, and Prognostic Features of Synchronous Colorectal Cancers. Gastroenterology 137:5, 1609-1620.e3
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Daniel Iglesias, Nargisse Nejda, Mariano Moreno Azcoita, Simó Schwartz, Juan J. González-Aguilera, Antonia M. Fernández-Peralta. (2009) Effect of COX2 -765G>C and c.3618A>G polymorphisms on the risk and survival of sporadic colorectal cancer. Cancer Causes & Control 20:8, 1421-1429
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Sarah Kraus, Nadir Arber. (2009) Colorectal cancer chemoprevention: Ready for practice?. European Journal of Cancer 45, 360-366
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Theofilos Poutahidis, Varada P. Rao, Werner Olipitz, Christie L. Taylor, Erin A. Jackson, Tatiana Levkovich, Chung Wei Lee, James G. Fox, Zhongming Ge, Susan E. Erdman. (2009) CD4+ lymphocytes modulate prostate cancer progression in mice. International Journal of Cancer 125:4, 868-878
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Shuji Ogino, Katsuhiko Nosho, Yoshifumi Baba, Shoko Kure, Kaori Shima, Natsumi Irahara, Saori Toyoda, Li Chen, Gregory J Kirkner, Brian M Wolpin, Andrew T Chan, Edward L Giovannucci, Charles S Fuchs. (2009) A Cohort Study of STMN1 Expression in Colorectal Cancer: Body Mass Index and Prognosis. The American Journal of Gastroenterology 104:8, 2047-2056
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B. M. Wolpin, M. J. Stampfer. (2009) Defining Determinants of Pancreatic Cancer Risk: Are We Making Progress?. JNCI Journal of the National Cancer Institute 101:14, 972-973
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Katsuhiko Nosho, Kaori Shima, Natsumi Irahara, Shoko Kure, Ron Firestein, Yoshifumi Baba, Saori Toyoda, Li Chen, Aditi Hazra, Edward L Giovannucci, Charles S Fuchs, Shuji Ogino. (2009) SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Modern Pathology 22:7, 922-932
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Shuji Ogino, Kaori Shima, Yoshifumi Baba, Katsuhiko Nosho, Natsumi Irahara, Shoko Kure, Li Chen, Saori Toyoda, Gregory J. Kirkner, Y. Lynn Wang, Edward L. Giovannucci, Charles S. Fuchs. (2009) Colorectal Cancer Expression of Peroxisome Proliferator-Activated Receptor γ (PPARG, PPARgamma) Is Associated With Good Prognosis. Gastroenterology 136:4, 1242-1250
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