Prognostic Significance Of Cyclooxygenase-2 Expression Research Articles

Abstract 729: Prognostic significance of COX-2 over-expression in BRAF mutated Middle Eastern PTC

Abstract The cyclooxygenase-2 (COX-2) - prostaglandin E2 (PGE2) pathway has been implicated in carcinogenesis with BRAF mutation shown to promote PGE2 synthesis. This study was conducted to evaluate COX-2 expression in a large cohort of Middle Eastern Papillary Thyroid Carcinoma (PTC) and further evaluate the prognostic significance of COX-2 expression in strata of BRAF mutation status. BRAF mutation analysis was performed by Sanger sequencing and COX-2 expression was evaluated immunohistochemically using tissue microarray. COX-2 over-expression was noted in 43.2% (567/1314) of cases and was significantly associated with poor prognostic markers such as extra-thyroidal extension, lymph node metastasis and higher tumor stage. COX-2 was also an independent predictor of poor disease-free survival (DFS). Most notably, the association of COX-2 expression with DFS differed by BRAF mutation status. COX-2 over-expression was associated with poor DFS in BRAF mutant but not BRAF wild-type PTCs with the multivariate-adjusted hazard ratio of 2.10 (95% CI = 1.52 - 2.92; p < 0.0001) for COX-2 over-expressed tumors in BRAF mutant PTC. In conclusion, the current study shows that COX-2 plays a key role in prognosis of PTC patients. Furthermore, a significant association of COX-2 expression with poor DFS was noted in BRAF mutated tumors. Our data suggests the potential therapeutic role of COX-2 inhibition in patients with BRAF mutated PTC. Citation Format: Rong Bu, Sandeep K. Parvathareddy, Abdul K. Siraj, Padmanaban Annaiyappanaidu, Kaleem Iqbal, Maha Al Rasheed, Wael Haqawi, Khawla S. Al-Kuraya. Prognostic significance of COX-2 over-expression in BRAF mutated Middle Eastern PTC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 729.

Prognostic Significance of COX-2 Overexpression in BRAF-Mutated Middle Eastern Papillary Thyroid Carcinoma.

The cyclooxygenase-2 (COX-2)–prostaglandin E2 (PGE2) pathway has been implicated in carcinogenesis, with BRAF mutation shown to promote PGE2 synthesis. This study was conducted to evaluate COX-2 expression in a large cohort of Middle Eastern papillary thyroid carcinoma (PTC), and further evaluate the prognostic significance of COX-2 expression in strata of BRAF mutation status. BRAF mutation analysis was performed using Sanger sequencing, and COX-2 expression was evaluated immunohistochemically using tissue microarray (TMA). COX-2 overexpression, noted in 43.2% (567/1314) of cases, was significantly associated with poor prognostic markers such as extra-thyroidal extension, lymph-node metastasis, and higher tumor stage. COX-2 was also an independent predictor of poor disease-free survival (DFS). Most notably, the association of COX-2 expression with DFS differed by BRAF mutation status. COX-2 overexpression was associated with poor DFS in BRAF-mutant but not BRAF wild-type PTCs, with a multivariate-adjusted hazard ratio of 2.10 (95% CI = 1.52–2.92; p < 0.0001) for COX-2 overexpressed tumors in BRAF-mutant PTC. In conclusion, the current study shows that COX-2 plays a key role in prognosis of PTC patients, especially in BRAF-mutated tumors. Our data suggest the potential therapeutic role of COX-2 inhibition in patients with BRAF-mutated PTC.

Clinicopathological and prognostic significance of cyclooxygenase-2 expression in head and neck cancer: A meta-analysis.

Several studies have assessed the clinicopathological and prognostic value of cyclooxygenase-2 (COX-2) expression in patients with head and neck cancer (HNC), but their results remain controversial. To address this issue, a meta-analysis was carried out. A total of 29 studies involving 2430 patients were subjected to final analysis. Our results indicated that COX-2 expression was not statistically associated with advanced tumor stage (OR, 1.23; 95% CI, 0.98–1.55) but correlated with high risk of lymph node metastasis (OR, 1.28; 95% CI, 1.03–1.60) and advanced TNM stage (OR, 1.33; 95% CI, 1.06–1.66). Moreover, COX-2 expression had significant effect on poor OS (HR, 1.93; 95% CI, 1.29–2.90), RFS (HR, 2.02; 95% CI, 1.00–4.08) and DFS (HR, 5.14; 95% CI, 2.84–9.31). The results of subgroup analyses revealed that COX-2 expression was related with high possibility of lymph node metastasis in oral cancer (OR, 1.49; 95% CI, 1.01–2.20) and advanced TNM stage in oral cancer (OR, 1.58; 95% CI, 1.05–2.37) and no site-specific HNC (OR, 1.64; 95% CI, 1.02–2.62). However, subgroup analyses only showed a tendency without statistically significant association between COX-2 expression and survival. Significant heterogeneity was not found when analyzing clinicopathological data, but it appeared when considering survival data. No publication bias was detected in this study. This meta-analysis suggested that COX-2 expression could act as a prognostic factor for patients with HNC.

COX-2 expression pattern is related to ovarian cancer differentiation and prognosis, but is not consistent with new model of pathogenesis.

Numerous studies suggest that cyclooxygenase-2 (COX-2) is overexpressed in cancer. Our objective was to investigate the relationship between COX-2 expression in ovarian carcinoma and clinicopathological factors. An emphasis was put on the association with the new pattern of tumorigenesis that divides tumors into type I--less aggressive, and type II--more aggressive one. The prognostic significance of COX-2 expression was evaluated. Ovarian cancer tissues were obtained from 65 patients in FIGO III stage (23 with type I and 42 with type II ovarian cancer). COX-2 expression was evaluated by immunohistochemistry. The statistical analysis was performed in order to assess the connection between COX-2 expression and characteristic factors of ovarian cancer patients as well as the new division for type I and type II ovarian cancer COX-2 expression was detected in 91% of tissue samples. It was markedly elevated in well differentiated tumors (p = 0.0041). The platinum-resistant tumors had significantly higher expression of COX-2 (p = 0.0337). There was no difference between COX-2 expression in type I and type II ovarian cancer (p = 0.6720). The COX-2 staining was not associated to age, CA125 level, the presence of ascites or any special histological type. An increased expression of COX-2 was an unfavorable prognostic factor for overall survival (p = 0.0369) and progression-free survival (p = 0.0218). Multivariate analysis confirmed that COX-2 overexpression is an independent unfavorable prognostic factor of shorter progression-free survival (p = 0.048). COX-2 expression is an unfavorable prognostic factor for progression-free survival and overall survival in ovarian cancer There is no relationship between COX-2 expression in ovarian cancer tissue and the examined model of ovarian cancer pathogenesis.

Prognostic Significance of COX-2 Expression and Correlation With Bcl-2 and VEGF Expression, Microvessel Density, and Clinical Variables in Classical Hodgkin Lymphoma

Vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) play important roles in tumor angiogenesis. Recent reports found that COX-2 expression had prognostic value in classical Hodgkin lymphoma (cHL). The purpose of this study was to measure the expression of COX-2, B-cell lymphoma-2 (Bcl-2), VEGF, and CD31 and assess their prognostic significance and potential correlation with clinical variables in cHL. A total of 167 cHL specimens were evaluated retrospectively by immunohistochemical methods for COX-2, Bcl-2, and VEGF expression and for CD31 to measure the microvessel density (MVD). Correlations between COX-2, Bcl-2, VEGF, MVD, and clinicopathologic factors were assessed, and prognostic significance was determined. COX-2, Bcl-2, and VEGF were expressed in 27.5%, 8.3%, and 33.5% of the specimens, respectively. A positive correlation was found between COX-2 and VEGF expression (P<0.001). The MVD was significantly higher in tumors positive for both COX-2 and VEGF compared with that in tumors negative for both markers (P=0.047). COX-2 expression was associated with a lower overall survival rate (P=0.015). High MVD was associated with a lower event-free survival rate (P=0.014). COX-2 was an independent prognostic factor for overall survival on multivariate analysis (P=0.013). COX-2 and VEGF correlated with angiogenesis and tumor progression in cHL. The findings support targeting COX-2 as a potential new therapeutic approach in cHL.

Overexpression of COX-2 in oral squamous cell carcinoma patients undergoing chemoradiotherapy.

Aims and Objectives:To evaluate the prognostic significance of cyclooxygenase-2 (COX-2) overexpression in oral squamous cell carcinoma (OSCC) patients undergoing chemoradiation therapy. Purpose of the study was to determine whether COX-2 could be used as a diagnostic and prognostic index in OSCC.Materials and Methods:Forty-four patients of SCC were included in the present study and immunohistochemical examination was done for COX-2 expression. Negative and <5% COX-2 positivity were taken as negative expression and ≥5% COX-2 positivity as positive expression group. ≥30% COX-2 positivity was taken as overexpressed group and <30% COX-2 positivity was taken as underexpressed group. All the data were analyzed statistically.Results:COX-2 overexpression in OSCC was found in 15.90% cases. The proportion of COX-2 overexpression was higher in patients with large tumor size than in those with small tumor size. The proportions of COX-2 positive expression cases were higher with cervical lymph node metastasis. Negative COX-2 expression was higher in well-differentiated OSCC and positive expression was higher in moderately differentiated tumors. COX-2 underexpressed cases had better response to chemoradiation therapy as compared to cases with overexpressed COX-2.Conclusion:COX-2 expression in OSCC can be used as a prognostic marker. Studies with large sample size and long-term follow-up are required to find out the exact role and prognostic significance of COX-2 expression in OSCC.

Meta‐analysis: clinicopathological and prognostic significance of cyclooxygenase‐2 expression on oesophageal squamous cell carinoma

Cyclooxygenase-2 (COX-2) is involved in oesophageal carcinogenesis, but the clinical and prognostic significance of COX-2 expression in oesophageal squamous cell carcinoma (ESCC) remains controversial. To evaluate the clinicopathological and prognostic role of COX-2 expression in ESCC. Studies assessing clinical or prognostic significance of COX-2 expression in ESCC published until December 2008 were selected. A meta-analysis was performed to clarify the impact of COX-2 expression on clinicopathological parameters or overall survival (OS) in ESCC. A total of 19 studies met the inclusion criteria, among which 17 studies were about the clinicopathological significance of COX-2 expression in ESCC, 12 studies were dealing with prognostic role of COX-2 expression in ESCC and 10 studies evaluated both of them. Overexpression of COX-2 was significantly correlated with not only the depth of invasion and TNM stage, with a combined odds ratio (OR) of 0.55 (95%CI: 0.34-0.90, Z = 2.41, P = 0.02) and 0.55 (95%CI: 0.32-0.95, Z = 2.13, P = 0.03) respectively but also the reduced OS with relative risk (RR) 1.42, 95% CI: 1.07-1.90, Z = 2.43, P = 0.02). COX-2 might play an important role in the progress of ESCC, overexpression of COX-2 correlates with not only the depth of invasion and TNM stage but also the reduced OS. COX-2 might be a potential therapy target for ESCC and work as a prognostic factor for ESCC patients, yet the clinicopathological and prognostic role of COX-2 in ESCC still needs further confirmation by well-designed prospective studies.

Estrogen-Dependent Prognostic Significance of Cyclooxygenase-2 Expression in Early-Stage Invasive Breast Cancers Treated With Breast-Conserving Surgery and Radiation

To evaluate the prognostic significance of cyclooxygenase-2 (COX-2) in breast cancer patients treated with conservative surgery and radiation therapy (CS+RT). Between 1975 and 2003, we retrieved specimens from 504 breast cancer patients treated with CS+RT. The specimens were constructed into tissue microarrays processed and stained for estrogen receptor (ER), progesterone receptor, Her2/neu, and COX-2. Each core was scored as positive or negative. All data including demographics, clinical, pathologic, staging, and outcome variables were entered into a computerized database. Expression of COX-2 was positive in 58% of cases and correlated with younger age (p = 0.01) and larger tumor size (p = 0.001). Expression of COX-2 was predictive of local relapse (relative risk[RR], 3.248; 95% confidence interval [CI], 1.340-7.871; p = 0.0091), distant metastasis (RR, 2.21; 95% CI, 1.259-3.896; p = 0.0058), and decreased survival (RR, 2.321; 95% CI, 1.324-4.071; p = 0.0033). Among ER-positive patients, COX-2 expression was predictive of worse local control (85% vs. 93%, p = 0.04), distant metastasis (75% vs. 95%, p = 0.002) and worse survival (65% vs. 94%, p = 0.002). Among ER-negative tumors COX-2 expression was not significantly correlated with local control (87 vs. 95%, p = 0.12), distant metastasis (73% vs. 78%, p = 0.39), or survival (77% vs. 87%, p = 0.15). In breast cancer patients treated with CS+RT, COX-2 expression is associated with younger age, larger tumor size, worse local control, distant metastasis, and worse overall survival. The significance is limited to hormone receptor-positive tumors, consistent with the known effect of COX-2/PGE2 on aromatase activity. Use of COX-2 inhibitors in estrogen-dependent breast cancers warrants further investigation.

Prognostic significance of cyclooxygenase-2 expression in pediatric Hodgkin and non-Hodgkin lymphomas with or without Epstein–Barr virus latent infection

The aim of this study is to investigate the expression of cyclooxygenase-2 (COX-2) and the relationship between COX-2, prognosis and Epstein–Barr virus (EBV) in pediatric Hodgkin (pHL) and non-Hodgkin lymphomas (pNHL). Cyclooxygenase-2 is frequently overexpressed in various tumors. COX-2 inhibitors’ potential use as a therapeutic target in onco-hematology and its relation with EBV is a contemporary question. A potential role for COX-2 in EBV-associated human cancers was suggested. The role of COX-2 in EBV-related oncogenesis of pHL and pNHL is not studied. The expression of COX-2, latent membrane protein 1 and Epstein–Barr virus-encoded early RNA was detected by immunohistochemistry and in situ hybridization in 63 pHL and 70 pNHL. The results were scored as positive or negative. The statistical significance was assessed by correlation, survival analysis, and nonparametric tests. In pNHL cases, the mean age was 7.16 ± 3.72. EBV was positive in 18 cases, COX-2 in 16 cases (22.8%). Expression of COX-2 did not correlate with age, sex, stage, phenotype, histology, EBV positivity, and response rate to therapy. In pHL cases, the mean age was 8.46 ± 3.54. EBV was positive in 52(82.5%), COX-2 in 36(57.1%) cases. The expression of COX-2 protein did not correlate with age, sex, stage of disease, EBV positivity, and response to therapy. COX-2 expression was higher in nodular sclerosing and lymphocyte-rich histology. In log rank analysis, no statistical significance for prognosis was observed. In this series, COX-2 was found to be expressed in the minority of pNHL tissues and more than half in pHL cases especially in NS type. This might be related with fibrosis of NS cases. It did not correlate with prognosis. COX-2 expression did not seem to have a synergistic role with EBV in the pathogenesis of pediatric lymphomas. It will be useful studying the relationship of COX-2 expression with apoptotic and other factors in pediatric lymphomas.

Prevalence and prognostic significance of COX-2 expression in stage IB cervical cancer

Objectives. To evaluate the prevalence of cyclooxygenase-2 (COX-2), correlation with various clinicopathologic factors and prognostic significance of COX-2 in stage IB cervical cancer patients. Methods. 89 paraffin-embedded specimens of patients with stage IB cervical cancer underwent radical hysterectomy and pelvic lymphadenectomy at King Chulalongkorn Memorial Hospital during 1 January 1997–31 December 2002 and were stained with polyclonal goat antiserum against COX-2 using immunohistochemical method. Medical records were reviewed; clinicopathological variables were retrieved and used for analysis. Results. The prevalence of positive COX-2 expression in stage IB cervical cancer in this study was 49.4%. Positive COX-2 expression in cervical adenocarcinoma was higher than squamous cell carcinoma (86.7% versus 40.6%, P < 0.05) and significantly expressed when lymph node metastasis was presented (100% versus 46.4%, P < 0.05). However, COX-2 expression was possibly associated with parametrial involvement (80% versus 47.6%, P > 0.05). There was no correlation between COX-2 expression and patient's age, tumor size, depth of stromal invasion and lymphovascular space invasion. Five-year disease free survival and 5-year overall survival in patients with positive COX-2 expression were 81% and 98% which were not differed from patients with negative COX-2 expression (92% and 95%, P > 0.05). Conclusions. Strong correlation was found in cervical adenocarcinoma and lymph node metastasis. However, COX-2 expression failed to demonstrate as a significant prognostic factor in stage IB cervical cancer.

Prognostic importance of COX-2 expression in patients with colorectal cancer

A relationship between cyclooxygenase-2 (COX-2) expression and the pathogenesis of colorectal cancer has been reported in recent studies. Moreover, it has been indicated that COX-2 expression may have a prognostic role in colorectal cancer patients. In this study, we investigated the prognostic significance of COX-2 expression in 83 patients with colorectal cancer. COX-2 expression was assessed using immunohistochemical methods and was evaluated by grading both staining intensity and staining extension. The relationships between COX-2 expression and clinicopathological features of the patients and patient survival were evaluated. There was no relationships between COX-2 expression and tumor size (tm<3 cm or tm⩾3 cm), tumor histopathological differentiation (poorly differentiated or moderately+well differentiated), number of metastatic lymph nodes (<4 or ⩾4), histopathology of the tumor, localization of the tumor (colon or rectum), distant metastasis, and vascular invasion of the tumor. In the multivariate analysis, COX-2 expression was not found as an independent prognostic factor. We demonstrated that COX-2 expression was not correlated with clinicopathological characteristics of colon carcinoma and disease outcome.

Clinicopathologic and prognostic significance of cyclooxygenase-2 expression in endometrial carcinoma.

Endometrial carcinoma is the most common malignancy of the female genital tract in the Western world. COX-2 is highly expressed in endometrial carcinoma, but there is controversy regarding its clinical role and its possible prognostic role. COX-2 expression was determined by immuno-histochemistry and was correlated to standard clinico-pathologic variables in a series of primary untreated endometrial carcinoma patients. COX-2 as an accurate predictor of the disease was also analyzed. One-hundred and ten cases of primary untreated endometrial carcinoma hosts who were admitted to the Department of Obstetrics and Gynecology, University General Hospital of Alexandroupolis, were investigated. Immunohistochemistry was performed using rabbit polyclonal antiserum against human COX-2. Twenty-eight patients (25.5%) were scored as COX-2 positive. A statistically significant association was found between COX-2 overexpression and FIGO stage (p=0.010). A positive correlation was also found with histological grade (p=0.019) and myometrial invasion (p=0.026). No significant association was found with histologic type of the tumor (p=0.164). COX-2 positive patients had a significant association with sort survival (p=0.028). COX-2 expression is an independent clinicopathologic factor and an independent prognostic factor in endometrial carcinoma. It could be used to plan treatment modalities for hosts.

Tissue Microarray Analysis Reveals Prognostic Significance of COX‐2 Expression for Local Relapse in T1–2N0 Larynx Cancer Treated with Primary Radiation Therapy

The purpose of this analysis is to determine whether a significant correlation exists between cyclooxygenase-2 (COX-2) expression and local relapse in a large cohort of patients with T1 to 2N0 laryngeal cancer treated with primary radiation therapy. Clinical and molecular analyses were conducted on 123 patients with biopsy-proven T1 to 2N0 laryngeal cancer. Clinical prognostic factors included pretreatment hemoglobin, age, sex, race, T stage, tumor subsite, beam energy, biologically equivalent dose, therapy duration, and treatment date. Molecular prognostic factors included COX-2, p53, and Ki-67 expression. Expression levels were determined by immunohistochemistry on paraffin-embedded tissues arrayed on tissue microarrays. Multivariate analysis was done with the Cox proportional hazards model. Thirty-two patients have locally relapsed, for an actuarial 5-year local relapse-free rate of 70.4%. On multivariate analysis, positive COX-2 expression predicted local relapse after radiation therapy. The relative risk (RR) for local relapse with COX-2 positivity was 2.57 (95% CI, 1.21-5.47; P = .01). Other prognostic factors for local relapse included negative Ki-67 expression (RR = 5.72; 95% CI, 2.04-16.1; P < .001), T2 stage (RR = 2.98; 95% CI, 1.39-6.38; P = .005), and therapy duration greater than 43 days (RR = 6.04; 95% CI, 1.37-26.7; P = .02). Positive COX-2 expression predicts for local relapse in T1 to 2N0 larynx cancer in a multivariate model. This relationship may have potential therapeutic implications regarding the use of COX-2 inhibitors during radiation therapy for optimal outcome.

Differential cyclooxygenase-2 expression in squamous cell carcinoma and adenocarcinoma of the uterine cervix

Purpose To determine the differential expression of cyclooxygenase-2 (COX-2) in patients with squamous cell carcinoma (SCC) and adenocarcinoma (ADC) of the uterine cervix and the prognostic significance of COX-2 expression in these histologic types. Methods and materials A total of 105 International Federation of Gynecology and Obstetrics Stage IIB uterine cervical cancer patients were screened for COX-2 expression immunohistochemically. COX-2 expression was determined in invasive cervical SCC ( n = 84) and invasive cervical ADC ( n = 21). To determine the clinical significance of COX-2 expression by histologic type, the patients were arbitrarily divided into four groups: SCC/COX-2 negative ( n = 64); SCC/COX-2 positive ( n = 20); ADC/COX-2 negative ( n = 9); and ADC/COX-2 positive ( n = 12). The clinical response to treatment, patterns of treatment failure, and survival data by COX-2 expression were compared for these two major histologic types. Univariate and multivariate analyses were performed to identify the prognostic factors influencing survival. Results Immunohistochemical examination showed that COX-2 expression was more frequently observed in ADC than in SCC (57% vs. 24%, p = 0.007). Moreover, COX-2 expression was an important predictor of treatment response, irrespective of the histologic type. All COX-2–negative patients achieved complete remission after initial treatment; 17% of SCC patients and 33% of ADC patients with COX-2 expression did not have complete remission after the initial treatment. The incidence of local failure for those with COX-2 expression was significantly greater than for COX-2–negative patients, regardless of histologic type. With a minimal follow-up of 60 months, the overall 5-year actuarial survival rate for SCC and ADC patients was 79% and 62%, respectively ( p = 0.05). The 5-year disease-free survival rate for SCC and ADC patients was 73% and 56%, respectively ( p = 0.13). Irrespective of the pathologic type, COX-2–positive patients had an unfavorable prognosis. The overall 5-year actuarial survival rate was 57% for COX-2–positive patients and 83% for COX-2–negative patients ( p = 0.001). When patients were stratified into the four groups according to histologic type and COX-2 expression status, ADC/COX-2–positive patients had the worst prognosis, with an overall 5-year actuarial survival rate of 49% compared with 78% for ADC/COX-2–negative patients, 62% for SCC/COX-2–positive, and 84% for SCC/COX-2–negative patients ( p = 0.007, log–rank test). Irrespective of histologic type, COX-2 expression was an independent prognostic factor by univariate and multivariate analyses. Conclusion In uterine cervical cancer, COX-2 was expressed in a greater proportion of ADC patients than SCC patients. COX-2 expression was also identified as a major determiner of a poor response to treatment and of an unfavorable prognosis, irrespective of the histologic type, reflecting the importance of the COX-2 protein in the acquisition of biologic aggressiveness and more malignant phenotype or increased resistance to the standard chemotherapy and radiotherapy in both histologic types. Given these observations, we believe that that ADC/COX-2–positive patients might be appropriate candidates for future trials of selective COX-2 inhibitor adjunctive therapy.