Abstract P2-05-23: EP3-receptor expression is a prognostic marker for overall survival and progression-free survival in sporadic breast cancer

Abstract

Abstract Aim: Prostaglandins are tissue hormones with a variety of biological effects and are mainly associated with infection and inflammation. However, elevated prostaglandin synthesis, especially of prostaglandin E2 (PGE2) caused by overexpression of cyclooxygenase-2 (COX-2), has also been associated with the development and progression of different kinds of cancer. Clinical trials have shown the potential of non-steroidal anti-inflammatory drugs or specific COX-2 inhibitors (coxibs) in prevention and treatment of malignant disease, as they reduce prostaglandin levels via inhibition of COX-2. Unfortunately, the clinical use of these drugs is limited due to their various side effects. PGE2 exerts its effects by signaling through four specific membrane-bound receptors, the EP-receptors 1-4. In recent research, the relevance of EP-receptors in carcinogenesis is investigated in the attempt to find a more specific target for the reduction of prostaglandin-effects without inducing side effects. This study evaluates the expression of EP3-receptor on breast cancer tissue and its correlation to progression and survival Material and methods: A total of 277 sporadic breast cancer samples without primary distant metastases were immunohistochemically analyzed for EP3-receptor expression. Tissue samples were stained with primary anti-EP3 antibodies (monoclonal rabbit IgG). EP3-receptor-expression was quantified by the semi-quantitative immunoreactivity score (IRS); samples with an IRS ≥ 2 were scored as EP3 positive. Statistical analyses were performed with SPSS software using chi-squared test as well as Kaplan-Meier-estimates and Cox regression for survival analyses. Results: EP3-receptor was expressed in 71.1 % of all cases. EP3-receptor expression did not correlate with clinicopathological parameters such as tumor size or lymph node status at primary diagnosis or with the expression of other immunohistochemical markers (estrogen and progesterone receptor, Her2). Distant metastasis occurred in 49.1 % of EP3 negative cases but only in 32.8 % of EP3 positive cases in an observation period of up to ten years (p = 0.03). EP3 receptor positive cases also showed significantly improved progression-free survival rates (overall [p = 0.01], ten years [p = 0.002] and five years [p = 0.04]). Furthermore, EP3-receptor positivity was associated with an improved overall survival rate (p = 0.002) and ten years survival rate (p = 0.001), whereas short-time survival rate (five years) did not differ between both EP3-groups (p = 0.10). In a multivariate analysis comparing all factors with significant influence in univariate testing, EP3-receptor could be confirmed as an independent factor. Discussion: Our results show that EP3-receptor positivity is a relevant prognostic factor in sporadic breast cancer. Its correlation with a favorable course of disease is especially interesting as EP3 is known to regulate uPA, a well-known parameter which is – on the contrary - associated with unfavorable survival in breast cancer. Therefore, ongoing studies by our group aim to examine the correlation of EP3-receptor to the uPA/PAI1-pathway and to evaluate the possibility to target EP3-receptor in future anti-tumor therapy in breast cancer. Citation Format: Semmlinger A, von Schönfeldt V, Wolf V, Schmoeckel E, Mayr D, Meuter A, Mahner S, Jeschke U, Ditsch N. EP3-receptor expression is a prognostic marker for overall survival and progression-free survival in sporadic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-23.