COX2 expression in prognosis and in prediction to endocrine therapy in early breast cancer patients

Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 04/2010; 125(3):671-85. DOI: 10.1007/s10549-010-0854-7
Source: PubMed


In breast cancer, the prognostic impact of COX2 expression varies widely between studies. We examined the prognostic value of COX2 expression in a large cohort of breast cancer patients treated with primary surgery between 1985 and 1994 and explained the variable results of COX2 expression found in the literature. A tissue microarray was constructed of available tumour material, and ER, PgR, HER2, Ki67 and COX2 were examined by immunohistochemistry. Median follow-up was 19 years. Fifty-five percent (n = 369/677) of patients received no systemic treatment. COX2 was scored using a weighted histoscore. Analysis of COX2 expression in two groups based on the median (148; below vs. above) showed an increased hazard ratio (HR) of 1.35 (95% CI 1.05-1.75, P = 0.021) for disease-free survival (DFS) and of 1.39 (95% CI 1.03-1.82, P = 0.016) for overall survival (OS). However, COX2 did not remain independent in multivariate analysis. In patients with hormone receptor positive tumours, COX2 expression had a negative influence on outcome (low vs. high: DFS: HR 1.37, 95% CI 1.07-1.76, P = 0.013). This effect disappeared when endocrine therapy was administered (low vs. high: DFS: HR 0.93, 95% CI 0.51-1.70, P = 0.811) while it remained statistically significant when endocrine therapy was omitted (low vs. high: DFS: HR 1.48, 95% CI 1.12-1.94, P = 0.005). Our results show that COX2 plays a role in hormonal pathways. Our results can explain the results found in previously published studies.

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    • "Although some studies indicated prognostic value of COX-2 expression for the breast cancer using univariate statistical analyses such conclusions were not confirmed by multivariate analyses including several significant variables [3, 12–14]. Only Denkert et al. [4] found a correlation between COX-2 expression and survival in multivariate analysis. "
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    ABSTRACT: Background Prognostic value of enhanced COX-2 expression in breast cancer has been controversial for a long time. The opinions vary widely between studies. Moreover, significant majority of studies considered only COX-2 expression in cancer epithelial cells. Methods We examined the prognostic value of COX-2 expression in both epithelial and stromal cells using three different antibodies and three algorithms of immunohistochemical scoring and categorizing the tumours into COX-2 overexpressing groups. Results Our results demonstrate that COX-2 expression in stromal cells is independent prognostic factor indicating worse overall survival of patients. Such a result was obtained using each of the three antibodies and two of the algorithms used for evaluations of COX-2 expression levels. We also show that immunohistochemical assessment of the prognostic value of COX-2 expression in cancer epithelial cells depends to a large extent on a combination of primary antibodies and algorithms used for determination of the COX-2 over-expressing tumours. Conclusions Our results indicate that stromal expression of COX-2 is independent prognostic parameter relatively insensitive to variations in sensitivity of antibodies used for its determination. Wide scatter of the published results concerning prognostic value of COX-2 expression in breast cancer tissues seems to be due to a large extent to multitude of antibodies and scoring algorithms used by different groups.
    Full-text · Article · Sep 2014 · BMC Cancer
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    • "All antibodies have validated for use in immunohistochemistry by Western blot [27]–[30]. All primary antibodies were used at predetermined optimal dilutions and IHC was performed using a standard IHC protocol [31]. Briefly, endogenous peroxidase was blocked by incubating the sections in a 0.3% solution of hydrogen peroxide (in PBS) for 20 min. "
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    ABSTRACT: Numerous changes in epigenetic mechanisms have been described in various types of tumors. In search for new biomarkers, we investigated the expression of Polycomb-group (PcG) proteins EZH2, BMI1 and SUZ12 and associated histone modification H3K27me3 in colorectal cancer. Nuclear expression of PcG proteins and histone modification H3K27me3 were immunohistochemically (IHC) stained on a tissue microarray (TMA), including 247 tumor tissues and 47 normal tissues, and scored using the semi-automated Ariol system. Tumor tissues showed higher expression of EZH2 (p = 0.05) and H3K27me3 (p<0.001) as compared to their normal counterparts. Combined marker trend analyses indicated that an increase in the number of markers showing high expression was associated with better prognosis. High expression of all four markers in the combined marker analyses was correlated with the best patient survival and the longest recurrence-free survival, with overall survival (p = 0.01, HR 0.42(0.21-0.84)), disease-free survival (p = 0.007, HR 0.23(0.08-0.67) and local recurrence-free survival (p = 0.02, HR 0.30(0.11-0.84)). In conclusion, we found that expression of PcG proteins and H3K27me3 showed prognostic value in our study cohort. Better stratification of patients was obtained by combining the expression data of the investigated biomarkers as compared to the individual markers, underlining the importance of investigating multiple markers simultaneously
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "These findings have potential clinical significance, as COX2 is a known mediator of breast cancer progression and metastasis that has been an important clinical target of inhibitory therapies [21-23]. Indeed, both non-steroidal anti-inflammatory drugs (NSAIDs) and agents that selectively target COX2 (i.e., celecoxib, rofecoxib, valdecoxib) have been developed [24-26]. However, some COX2 inhibitors produce serious side effects such as gastrointestinal, cardiovascular, liver and kidney complications [27-29], resulting in their voluntary withdrawal from the market in some cases [30,31]. "
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    ABSTRACT: Background Expression of integrin α3β1 is associated with tumor progression, metastasis, and poor prognosis in several cancers, including breast cancer. Moreover, preclinical studies have revealed important pro-tumorigenic and pro-metastatic functions for this integrin, including tumor growth, survival, invasion, and paracrine induction of angiogenesis. Our previously published work in a preclinical breast cancer model showed that integrin α3β1 promotes expression of cyclooxygenase-2 (COX2/PTGS2), a known driver of breast cancer progression. However, the clinical significance of this regulation was unknown. The objective of the current study was to assess the clinical relevance of the relationship between integrin α3β1 and COX2 by testing for their correlated expression among various forms of human breast cancer. Methods Immunohistochemistry was performed to assess co-expression of α3 and COX2 in specimens of human invasive ductal carcinoma (IDC), either on a commercial tissue microarray (n = 59 samples) or obtained from Albany Medical Center archives (n = 68 samples). Immunostaining intensity for the integrin α3 subunit or COX2 was scored, and Spearman’s rank correlation coefficient analysis was performed to assess their co-expression across and within different tumor subtypes or clinicopathologic criteria. Results Although expression of integrin α3 or COX2 varied among clinical IDC samples, a statistically significant, positive correlation was detected between α3 and COX2 in both tissue microarrays (rs = 0.49, p < 0.001, n = 59) and archived samples (rs = 0.59, p < 0.0001, n = 68). In both sample sets, this correlation was independent of hormone receptor status, histological grade, or disease stage. Conclusions COX2 and α3 are correlated in IDC independently of hormone receptor status or other clinicopathologic features, supporting the hypothesis that integrin α3β1 is a determinant of COX2 expression in human breast cancer. These results support the clinical relevance of α3β1-dependent COX2 gene expression that we reported previously in breast cancer cells. The findings also suggest that COX2-positive breast carcinomas of various subtypes might be vulnerable to therapeutic strategies that target α3β1, and that α3 expression might serve as an independent prognostic biomarker.
    Full-text · Article · Jun 2014 · BMC Cancer
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