Abstract
BackgroundCyclooxygenases (COX) play a key role in prostaglandin metabolism and are important for tumor development and progression. The aim of this study was to analyze the prognostic impact of COX-2 expression in a cohort of lymph node-negative breast cancer patients not treated in the adjuvant setting.MethodsCOX-2 expression was determined by immunohistochemistry (IHC) in tumor tissue of 193 node-negative breast cancer patients. Additionally, mRNA expression was determined in corresponding tumor samples using microarray based gene-expression data. Univariate and multivariate Cox regression analyses adjusted for age at diagnosis, tumor size, histological grade, human epithelial growth factor receptor 2 (HER2), estrogen receptor (ER) and progesterone receptor (PR) were performed to evaluate the association of both COX-2 protein and mRNA expression with survival. Survival rates were determined by the Kaplan-Meier method. Correlations between COX-2 expression and established prognostic factors were analyzed using the Chi-square test. A potential correlation between COX-2 protein expression and COX-2 mRNA expression was assessed utilizing the Kruscal-Wallis-H-test.ResultsCOX-2 protein expression was positive in 24.9% of the breast cancer samples. Univariate analysis showed that COX-2 protein expression was associated with shorter disease-free survival (DFS) (P = 0.0001), metastasis-free survival (MFS) (P = 0.002) as well as breast cancer specific overall survival (OS) (P = 0.043). In multivariate analysis COX-2 expression retained its significance independent of established prognostic factors for shorter DFS (P < 0.001, HR = 2.767, 95% CI = 1.563-4.901) and for inferior MFS (P = 0.002, HR = 2.7, 95% CI = 1.469-5.263) but not for OS (P = 0.096, HR = 1.929, 95% CI = 0.889-4.187). In contrast, COX-2 mRNA expression was not related to survival and failed to show a correlation with protein expression (P = 0.410).ConclusionsThe present findings support the hypothesis that COX-2 protein but not mRNA expression is associated with an unfavorable outcome in node-negative breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-952) contains supplementary material, which is available to authorized users.
Highlights
Cyclooxygenases (COX) play a key role in prostaglandin metabolism and are important for tumor development and progression
The association between COX-2 immunostaining and disease-free survival did not depend on a specific mode of dichotomization of the patients into two groups but all previously reported strategies of immunostaining interpretation resulted in significant results: (i) Intensity and proportion scores were multiplied resulting in an “immunostaining score” (0-12) which was significantly associated with DFS in the multivariate Cox model (P = 0.020; hormone receptor status (HR) = 1.1, Additional file 1: Table S1). (ii) It has been reported that for some prognostic factors only the highest immunostaining score is relevant with respect to prognosis
In conclusion, our results provide further evidence that increased COX-2 protein expression is associated with poor disease-free survival and metastasis-free survival independent of other prognostic factors
Summary
Cyclooxygenases (COX) play a key role in prostaglandin metabolism and are important for tumor development and progression. The aim of this study was to analyze the prognostic impact of COX-2 expression in a cohort of lymph node-negative breast cancer patients not treated in the adjuvant setting. The studies mentioned above used cohorts of breast cancer patients treated with different adjuvant systemic therapies. Because of this it is hardly possible to clarify whether the impact of COX-2 overexpression is purely prognostic in nature or confounded by predictive effects. The aim of the present study was to examine COX-2 expression on the protein as well as on the mRNA level in an untreated cohort of lymph node-negative breast cancer patients in the context of other established prognostic factors
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