Affiliations of authors: Department of Medical Oncology, Ankara University School of Medicine, Sihhiye, Ankara, Turkey (BY, AB, GU, HD); Department of Internal Medicine (MD, MA) and Department of General Surgery (SY), Ankara University School of Medicine, Sihhiye, Ankara, Turkey
Correspondence to: Bulent Yalcin, MD, Department of Medical Oncology, Ankara University School of Medicine, TR-06100, Sihhiye, Ankara, Turkey (e-mail: bulyalcin{at}yahoo.com).
In their recent article, Martino et al. (1) concluded that raloxifene treatment reduces the incidence of estrogren receptor (ER)positive invasive breast cancer in postmenopausal women with osteoporosis. However, venous thromboembolic events were two times higher in the raloxifene group than in the placebo group (2). We have a comment about this study.
Nonsteroidal anti-inflammatory drugs, such as cyclooxygenase-1 and -2 (COX-1 and -2) inhibitors, are frequently used to alleviate bone pain due to osteoporosis in postmenopausal women. COX-2 inhibitors have been shown to be chemopreventive agents in patients with familial polyposis coli (3). However, it has also been shown that overexpression of COX-2 is associated with increased expression of aromatase in breast cancer cells (4). The expression of COX-2 promotes the growth of microvessels within the tumor through increased expression of prostaglandin E2, which induces the expression of vascular endothelial growth factor and basic fibroblast growth factor in cancer cells and directly modulates endothelial cell proliferation (5,6). Because both an abundant vasculature and accelerated estrogen synthesis are thought to contribute to unfavorable conditions for response to endocrine therapy, it is likely that COX-2 inhibition may be a promising strategy to potentiate the effectiveness of endocrine therapy.
Martino et al. (1) did not report any information about the use of analgesics, especially COX-2 inhibitors, by the patients in their study. It is possible that patients in the placebo and raloxifene groups differed in their use of COX-2 inhibitors, which may have had a preventive effect on the development of ER-positive breast cancer. We recommend that a subgroup analysis that considers the use of nonsteroidal anti-inflammatory agents should be performed.
REFERENCES
(1) Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 2004;96:175161.
(2) Grady D, Ettinger B, Moscarelli E, Plouffe L Jr, Sarkar S, Ciaccia A, et al. Safety and adverse effects associated with raloxifene: Multiple Outcomes of Raloxifene Evaluation. Obstet Gynecol 2004;104:83744.
(3) Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 2002;94:25266.
(4) Brodie AM, Lu Q, Long BJ, Fulton A, Chen T, Macpherson N, et al. Aromatase and COX-2 expression in human breast cancers. J Steroid Biochem Mol Biol 2001;79:417.[CrossRef][ISI][Medline]
(5) Leung WK, To KF, Go MY, Chan KK, Chan FK, Ng EK, et al. Cyclooxygenase-2 upregulates vascular endothelial growth factor expression and angiogenesis in human gastric carcinoma. Int J Oncol 2003;23:131722.[ISI][Medline]
(6) Linderholm BK, Lindh B, Beckman L, Erlanson M, Edin K, Travelin B, et al. Prognostic correlation of basic fibroblast growth factor and vascular endothelial growth factor in 1307 primary breast cancers. Clin Breast Cancer 2003;4:3407.[Medline]
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