Journal of the National Cancer Institute Advance Access originally published online on March 11, 2008
JNCI Journal of the National Cancer Institute 2008 100(6):421-427; doi:10.1093/jnci/djn036
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Association Between Cyclooxygenase-2 Expression in Atypical Hyperplasia and Risk of Breast Cancer
Affiliations of authors: Department of Surgical Pathology, University of Michigan, Ann Arbor, MI (DWV); Divisions of Biostatistics (VSP, RAV), Medical Oncology (MS, MHF, LCH), Anatomic Pathology (CR), and Experimental Pathology (WLL), Mayo Clinic, Rochester, MN; Department of Pathology, HUSLAB/Helsinki University Central Hospital and Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland (AR)
Correspondence to: Lynn C. Hartmann, MD, Division of Medical Oncology, Mayo Clinic, 200 1st St Southwest, Rochester, MN 55905 (e-mail: hartmann.lynn{at}mayo.edu).
Background: The cyclooxygenase-2 (COX-2) enzyme, which is induced by inflammatory and mitogenic stimuli, plays a protumorigenic role in several human cancers. COX-2 is overexpressed in invasive and in situ breast cancers. Atypical hyperplasia in breast tissue, although benign, is associated with a high risk of breast cancer. We investigated whether COX-2 overexpression in atypical hyperplasia is associated with the risk of subsequent breast cancer.
Methods: COX-2 expression was assessed immunohistochemically in archival sections from 235 women with atypia whose biopsy specimens were obtained at the Mayo Clinic from January 1, 1967, through December 31, 1991. COX-2 expression was scored as 0 (negative), 1+ (weak), 2+ (moderate), or 3+ (strong). Risk factor information and follow-up for breast cancer events were obtained via a study questionnaire and the medical records. All statistical tests were two-sided.
Results: Forty-one (17%) of the 235 women developed breast cancer during a median follow-up of 15 years. Moderate (category 2+) or strong (category 3+) COX-2 expression was identified in 71 (30%) and 34 (14%) of the 235 samples, respectively. The risk for developing breast cancer, relative to a control population (the Iowa Surveillance, Epidemiology, and End Results registry), increased with increasing COX-2 expression (relative risk [RR] = 2.63, 95% confidence interval [CI] = 1.56 to 4.15, for those with negative or weak COX-2 expression; RR = 3.56, 95% CI = 1.94 to 5.97, for those with moderate expression; and RR = 5.66, 95% CI = 2.59 to 10.75, for those with strong expression; P = .07). Overexpression of COX-2 was statistically significantly associated with the type of atypia (lobular vs ductal, P < .001), number of foci of atypia in the biopsy (P = .02), and older age at time of biopsy (>45 years, P = .01).
Conclusions: COX-2 appears to be a biomarker that further stratifies breast cancer risk among women with atypia and may be a relevant target for chemoprevention strategies.
| CONTEXT AND CAVEATS Prior knowledge Cyclooxygenase-2 (COX-2) plays a protumorigenic role in several human cancers and is overexpressed in invasive and in situ breast cancers. Atypical hyperplasia in breast tissue, although benign, is associated with a high risk of breast cancer. Study design The relationship between the risk of breast cancer and COX-2 expression in archival specimens from women with atypical hyperplasia and a 15-year follow-up was assessed. Contribution
The risk for developing breast cancer, relative to a control population (the Iowa Surveillance, Epidemiology, and End Results registry), increased with increasing COX-2 expression, in a borderline statistically significant manner. Overexpression of COX-2 was statistically significantly associated with the type of atypia (lobular vs ductal), with number of foci of atypia in the biopsy, and with older age at time of biopsy ( Implications COX-2 may be a biomarker that further stratifies breast cancer risk among women with atypia and may be a relevant target for chemoprevention strategies. Limitations Tissue-based biomarker studies, such as this study, are limited by semiquantitative and subjective evaluation of COX-2 status, which is further complicated by the variable nature of immunoreactivity.
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45 years).Manuscript received August 28, 2007; revised January 8, 2008; accepted January 25, 2008.
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J Natl Cancer Inst 2008 100: 375.