Abstract 2641: The presence of Cyclooxygenase 2, tumor-associated macrophages, and collagen features as prognostic markers for invasive breast carcinoma patients
Authors: Esbona Karla , Yi Yanyao , Yu Menggang , Doorn Rachel Van , Conklin Matthew , Graham Douglas , Wisinski Kari , Ponik Suzanne , Eliceiri Kevin , Wilke Lee , Keely Patricia 
Published: August 2018

Abstract
Inflammation and the organization of collagen in the breast tumor microenvironment is an important mediator of tumor progression. The objective of this study was to assess whether the tissue localization of COX-2 and tumor-associated macrophages were associated with clinicopathological features of invasive carcinoma, including collagen deposition and patient survival outcome. A tumor microarray (TMA) of 371 biopsy specimens from patients with invasive breast carcinoma was analyzed for expression levels of COX-2, the macrophage marker CD68 and activated macrophage marker CD163 in either the tumor nest (TN) or the tumor-associated stroma (TS). The TMA cohort included females; age 18 to 80, with a median follow up of 8.4 years. Biomarkers were correlated against clinicopathological and collagen features. Additionally, survival curves were calculated according to the Kaplan-Meier method. We found that high expression of COX-2 was associated with tumor size (P = 0.006), grade (P &lt; 0.0001), proliferation (P &lt; 0.0001), ER+ (P = 0.001), collagen deposition (P &lt; 0.0001) and density (P = 0.001). One possible mechanism for this, is COX-2 dependent recruitment of macrophages to the tumor microenvironment. This is supported by our finding of high infiltration of both macrophage markers that were associated with tumor size and proliferation; however, only high levels of stromal CD163 were associated with collagen deposition. In order to better analyze patient survival data, samples were divided into quartiles based on their levels of COX-2 expression and/or macrophage infiltration. COX-2 localization in the TN (P = 0.016, HR = 1.71), perpendicular alignment of collagen to the tumor boundary (TACS-3) (P = 0.049, HR = 1.65) and macrophage recruitment were predictors of poor overall survival (OS). Furthermore, patient survival was worsened if patients had a high CD163 macrophage infiltration (TN: P &lt; 0.0001, HR = 2.86; TS: P = 0.002, HR = 2.54). This notion is further established by the finding of our multivariate analysis that high numbers of CD163+ macrophages in the TS as an independent prognostic factor (P = 0.001, HR = 2.90). These results suggest that in invasive carcinoma the localization of inflammatory markers within the tumor are biomarkers for patient survival outcome. Therefore, we propose that these patients may benefit from a selective COX-2 inhibitor and/or immune modulation therapies.
Citation Format: Karla Esbona, Yanyao Yi, Menggang Yu, Rachel Van Doorn, Matthew Conklin, Douglas Graham, Kari Wisinski, Suzanne Ponik, Kevin Eliceiri, Lee Wilke, Patricia Keely. The presence of Cyclooxygenase 2, tumor-associated macrophages, and collagen features as prognostic markers for invasive breast carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2641.