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Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors
© Harris et al; licensee BioMed Central Ltd. 2006
Received: 20 October 2005
Accepted: 30 January 2006
Published: 30 January 2006
Epidemiologic and laboratory investigations suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects against breast cancer due to their activity against cyclooxygenase-2 (COX-2), the rate-limiting enzyme of the prostaglandin cascade.
We conducted a case control study of breast cancer designed to compare effects of selective and non-selective COX-2 inhibitors. A total of 323 incident breast cancer patients were ascertained from the James Cancer Hospital, Columbus, Ohio, during 2003–2004 and compared with 649 cancer free controls matched to the cases at a 2:1 ratio on age, race, and county of residence. Data on the past and current use of prescription and over the counter medications and breast cancer risk factors were ascertained using a standardized risk factor questionnaire. Effects of COX-2 inhibiting agents were quantified by calculating odds ratios (OR) and 95% confidence intervals.
Results showed significant risk reductions for selective COX-2 inhibitors as a group (OR = 0.29, 95% CI = 0.14–0.59), regular aspirin (OR = 0.49, 95% CI = 0.26–0.94), and ibuprofen or naproxen (0.36, 95% CI = 0.18–0.72). Acetaminophen, a compound with negligible COX-2 activity and low dose aspirin (81 mg) produced no significant change in the risk of breast cancer.
Selective COX-2 inhibitors (celecoxib and rofecoxib) were only recently approved for use in 1999, and rofecoxib (Vioxx) was withdrawn from the marketplace in 2004. Nevertheless, even in the short window of exposure to these compounds, the selective COX-2 inhibitors produced a significant (71%) reduction in the risk of breast cancer, underscoring their strong potential for breast cancer chemoprevention.
The recent recall of rofecoxib (Vioxx) from the marketplace due its alleged association with increased risk for cardiovascular disease has severely compromised further testing of all selective cyclooxygenase-2 (COX-2) inhibitors in the chemoprevention and therapy of cancer. Despite compelling evidence that COX-2 inhibitors have powerful anti-cancer effects, several clinical trials designed to evaluate these compounds in the chemoprevention and therapy of neoplasms have been discontinued or suspended [1, 2].
Both the magnitude and the direction of effect of selective COX-2 blockers on the risk of cardiovascular disease is the subject of controversy. Risk increases have been observed with use of rofecoxib and celecoxib in clinical trials that were designed to evaluate their potential for treating arthritis or reducing colonic polyp recurrence [3–5], whereas risk decreases have been observed in observational studies that were designed to evaluate effects of these same compounds on cardiovascular diseases [6–8]. Still other investigations suggest that COX-2 inhibitors have no effect on the risk of myocardial infarction and related cardiovascular events [9, 10].
Among American women, breast cancer is the most frequently diagnosed malignancy and second leading cause of cancer death . Despite intensive efforts aimed primarily at early detection and therapy, the mortality rates of breast cancer have remained virtually constant for several decades. Innovative research efforts must therefore be redirected towards chemoprevention of the early stages of carcinogenesis. Among twenty published epidemiologic studies that focused on the association between intake of nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of human breast cancer, 13 reported statistically significant risk reductions. Meta-analysis of these data suggests that regular NSAID intake significantly reduces the risk of breast cancer .
Two selective COX-2 inhibitors, celecoxib (Celebrex) and rofecoxib (Vioxx), were approved for the treatment of arthritis by the United States Food and Drug Administration (FDA) in 1999. Until the recall of Vioxx in September, 2004, these two compounds plus other selective COX-2 inhibitors valdecoxib (Bextra) and meloxicam (Mobic) were widely utilized in the United States for pain relief and treatment of osteoarthritis and rheumatoid arthritis. The time period between approval of Celebrex to the recall of Vioxx provides an approximate six-year window for evaluation of exposure to such compounds by a case control approach. The current case control study was designed to test the chemopreventive value of selective COX-2 blockade against human breast cancer.
We studied 323 cases of invasive breast cancer with histological verification based upon review of the pathology records, and 649 group-matched controls with no personal history of cancer and no current breast disease based on screening mammography. Cases were sequentially ascertained for interview at the time of their diagnosis during 2003 through September, 2004 at The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (CHRI), Columbus, Ohio. There were no refusals to participate among cases. The controls were ascertained from the mammography service of the cancer hospital during the same time period and frequency matched to the cases at a rate of 2:1 by five-year age interval, race, and place (county) of residence. Controls were sequentially ascertained for each matching category resulting in a stratified random sample. Among women eligible for participation, 95% completed the questionnaire.
Critical information on exposure to NSAIDs and other factors were obtained utilizing a standardized risk factor questionnaire. The questionnaires were administered in person by trained medical personnel prior to definitive surgery or treatment for the cases and at the time of screening mammography for controls. The data variables collected consisted of demographic characteristics, height, weight, menstrual and pregnancy history, family history of breast and ovarian cancer, comprehensive information on cigarette smoking, alcohol intake, pre-existing medical conditions (arthritis, chronic headache, cardiovascular conditions including hypertension, angina, ischemic attacks, stroke, and myocardial infarction, lung disease, and diabetes mellitus), and medication history including over the counter (OTC) and prescription NSAIDs, and exogenous hormones. Regarding selective COX-2 inhibitors and other NSAIDs, the use pattern (frequency, dose, and duration), and the type, (celecoxib, valdecoxib, rofecoxib, meloxicam, aspirin, ibuprofen, naproxen, indomethacin) were recorded. Data on the related analgesic, acetaminophen were collected for comparison with selective COX-2 inhibitors and other NSAIDs.
Case-control differences in means and frequencies were checked for statistical significance by t-tests and chi square tests, respectively. Effects of the selective COX-2 inhibitors as a group were quantified by estimating odds ratios and their 95% confidence intervals. Odds ratios were adjusted for age and classical breast cancer risk factors (parity, family history, body mass, menopausal status, chronic smoking, and regular alcohol intake) by logistic regression analysis [13, 14]. Adjusted estimates were obtained for specific types of compounds, e.g., over the counter NSAIDs, selective COX-2 inhibitors, and acetaminophen.
Characteristics of breast cancer cases and controls.
Cases (N = 323)
Controls (N = 649)
< 12 yrs
> 12 yrs
First Pregnancy <30 yrs
First Pregnancy >30 yrs
7 (p < 0.05)
84 (p < 0.01)
BMI < 22
BMI > 28
53 (p < 0.05)
31 (p < 0.05)
20 (p < 0.02)
1–2 drinks per week
> 2 drinks per week
Odds ratios with 95% confidence intervals for breast cancer and selective cyclooxygenase-2 (COX-2) inhibitors, and over the counter nonsteroidal anti-inflammatory drugs (OTC NSAIDS).
Number of Cases
Number of Controls
Age Adjusted OR (95% CI)
Multivariate OR d (95% CI)
None/Infrequent Use a
COX-2 Inhibitors b
OTC NSAIDs c
Odds ratios for breast cancer by dose, frequency, and duration of exposure to celecoxib, rofecoxib, aspirin, and ibuprofen.
Frequency of Use
Multivariate OR b (95% CI)
trend (p < 0.05)
trend (p < 0.01)
This is the first observation of a significant risk reduction in human breast cancer due to intake of selective COX-2 inhibitors. Standard daily dosages of celecoxib (200 mg) or rofecoxib (25 mg) taken for two or more years were associated with a 71% reduction in breast cancer risk. Comparator NSAIDs with non-selective COX-2 activity (325 mg aspirin, 200 mg ibuprofen or 250 mg naproxen) also produced significant risk reductions, although their observed effects were not as strong as selective compounds. In contrast, neither acetaminophen nor 81 mg (baby) aspirin changed the risk of breast cancer.
In general, NSAIDs inhibit cyclooyxgenase which is the key rate-limiting enzyme of prostaglandin biosynthesis [15–17]. Molecular studies show that the inducible COX-2 gene is over-expressed in human breast cancer and that COX-2 genetic expression in cancer cells is correlated with mutagenesis, mitogenesis, angiogenesis, and deregulation of apoptosis [18–20]. Over the counter NSAIDs have consistently shown antitumor effects in animal models of carcinogenesis , and in recent studies, striking antitumor effects of the specific COX-2 inhibitor, celecoxib, have been observed against breast cancer . In breast cancer cells, COX-2 over-expression is also associated with CYP-19 P-450arom genetic expression and local estrogen biosynthesis [23–25]. The current study coupled with existing preclinical and molecular evidence suggest that aberrant induction of COX-2 and up-regulation of the prostaglandin cascade play a significant role in mammary carcinogenesis, and that blockade of this process has strong potential for intervention.
Enthusiasm for the use of selective COX-2 blocking agents in the chemoprevention of breast cancer and other malignancies has been tempered by reports of adverse effects on the cardiovascular system leading to the recall of popular anti-arthritic compounds, rofecoxib (Vioxx) and valdecoxib (Bextra). However, such studies involved supra-therapeutic dosages given over long periods of time without consideration of body size or individual differences in metabolism .
We observed a significant reduction in the risk of human breast cancer due to intake of selective COX-2 inhibitors. Chemopreventive effects against breast cancer were associated with recommended daily doses of celecoxib (median dose = 200 mg) or rofecoxib (median dose = 25 mg) for an average duration of 3.6 years. Notably, selective COX-2 inhibitors (celecoxib and rofecoxib) were only recently approved for use in 1999, and rofecoxib (Vioxx) was withdrawn from the marketplace in 2004. Nevertheless, even in the short window of exposure to these compounds, the selective COX-2 inhibitors produced a significant (71%) reduction in the risk of breast cancer, underscoring their strong potential for breast cancer chemoprevention.
The authors thank Elvira M. Garofalo, Program Manager of the James Cancer Mammography Unit, and Julie M. Coursey, Assistant Director of the James Cancer Medical Records Registry, for their assistance in the conduct of this investigation.
- Couzin J: Withdrawal of Vioxx casts a shadow over COX-2 inhibitors. Science. 2004, 306: 384-385.View ArticlePubMedGoogle Scholar
- Couzin J: Clinical Trials: Nail-biting time for trials of drugs. Science. 2004, 306: 1673-1675.View ArticlePubMedGoogle Scholar
- Mukherjee D, Nissen SE, Topol EJ: Risk of cardiovascular events associated with selective COX-2 inhibitors. J Am Med Assoc. 2001, 286 (8): 954-959.View ArticleGoogle Scholar
- Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005, 352 (11): 1092-1102.View ArticlePubMedGoogle Scholar
- Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005, 352 (11): 1071-1080.View ArticlePubMedGoogle Scholar
- White WB, Faich G, Whelton A, Maurath C, Ridge NJ, Verburg KM, Geis GS, Lefkowith JB: Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol. 2002, 89 (4): 425-430.View ArticlePubMedGoogle Scholar
- White WB, Faich G, Borer JS, Makuch RW: Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor, celecoxib. Am J Cardiol. 2003, 92 (4): 411-418.View ArticlePubMedGoogle Scholar
- Reicin AS, Shapiro D, Sperling RS, Barr E, Yu Q: Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabumetone). Am J Cardiol. 2002, 89 (2): 204-209.View ArticlePubMedGoogle Scholar
- Mamdani M, Rochon P, Juurlink DN, Anderson GM, Kopp A, Naglie G, Austin PC, Laupaci A: Effect of selective cyclooxygenase-2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med. 2003, 163 (4): 481-486.View ArticlePubMedGoogle Scholar
- Shaya FT, Blume SW, Blanchette CM, Weir MR, Mullin CD: Selective cyclooxygenase-2 inhibition and cardiovascular effects: an observational study of a Medicaid population. Arch Intern Med. 2005, 165 (2): 181-186.View ArticlePubMedGoogle Scholar
- Cancer Statistics, Incidence and Mortality. American Cancer Society. 2004Google Scholar
- Harris RE, Beebe-Donk J, Doss H, Burr-Doss D: Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (Review). Oncology Reports. 2004, 13: 559-583.Google Scholar
- Schlesselman JJ: Case Control Studies. 1982, Oxford University Press, New YorkGoogle Scholar
- Harrell F: Logistic Regression Procedure. Statistical Analysis System (SAS). 2005Google Scholar
- Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature. 1971, 231: 323-235.Google Scholar
- Herschman HR: Regulation of prostaglandin synthase-1 and prostaglandin synthase-2. Cancer and Metas Rev. 1994, 13: 241-256.View ArticleGoogle Scholar
- Hla T, Neilson K: Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci USA. 1992, 89: 7384-7388.View ArticlePubMedPubMed CentralGoogle Scholar
- Harris RE: Epidemiology of breast cancer and nonsteroidal anti-inflammatory drugs. COX-2 Blockade in Cancer Prevention and Therapy. Edited by: Harris RE. 2002, Humana Press, Totowa, NJ, 57-68.View ArticleGoogle Scholar
- Parrett ML, Harris RE, Joarder FS, Ross MS, Clausen KP, Robertson FM: Cyclooxygenase-2 gene expression in human breast cancer. International Journal of Oncology. 1997, 10: 503-507.PubMedGoogle Scholar
- Masferrer JL, Leahy KM, Koki AT, Aweifel BS, Settle SL, Woerner BM, Edwards DA, Flickinger AG, Moore RJ, Seibert K: Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 2000, 60 (5): 1306-1311.PubMedGoogle Scholar
- Abou-Issa HM, Alshafie GA, Harris RE: Chemoprevention of breast cancer by nonsteroidal anti-inflammatory drugs and selective COX-2 blockade in animals. COX-2 Blockade in Cancer Prevention and Therapy. Edited by: Harris RE. 2002, Humana Press, Totowa, NJ, 85-98.View ArticleGoogle Scholar
- Harris RE, Alshafie GA, Abou-Issa H, Seibert K: Chemoprevention of breast cancer in rats by Celecoxib, a specific cyclooygenase-2 (COX-2) inhibitor. Cancer Res. 2000, 60: 2101-2103.PubMedGoogle Scholar
- Harris RE, Robertson FM, Farrar WB, Brueggemeier RW: Genetic induction and upregulation of cyclooxygenase (COX) and aromatase (CYP-19): an extension of the dietary fat hypothesis of breast cancer. Medical Hypotheses. 1999, 52 (4): 292-293.View ArticleGoogle Scholar
- Zhao Y, Agarwal VR, Mendelson CR, Simpson ER: Estrogen biosynthesis proximal to a breast tumor is stimulated by PGE2 via cyclic AMP, leading to activation of promoter II of the CYP19 (aromatase) gene. Endocrinology. 1996, 137 (12): 5739-5742.PubMedGoogle Scholar
- Brueggemeier RW, Quinn AL, Parrett ML, Joarder FS, Harris RE, Robertson FM: Correlation of aromatase and cyclooxygenase gene expression in human breast cancer specimens. Cancer Letters. 1999, 140 (1–2): 27-35.View ArticlePubMedGoogle Scholar
- Harris RE: Does the dose make the poison?. Science. 2005, 308: 203-View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/6/27/prepub
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