The Presence of Cyclooxygenase 2, Tumor-Associated Macrophages, and Collagen Alignment as Prognostic Markers for Invasive Breast Carcinoma Patients

Inflammation, and the organization of collagen in the breast tumor microenvironment, is an important mediator of breast tumor progression. However, a direct link between markers of inflammation, collagen organization, and patient outcome has yet to be established. A tumor microarray of 371 invasive breast carcinoma biopsy specimens was analyzed for expression of inflammatory markers, including cyclo-oxygenase 2 (COX-2), macrophages, and several collagen features in the tumor nest (TN) or the tumor-associated stroma (TS). The tumor microarray cohort included females, aged 18 to 80 years, with a median follow-up of 8.4 years. High expression of COX-2 (TN), CD68 (TS), and CD163 (TN and TS) predicted worse patient overall survival (OS). This notion was strengthened by the finding from the multivariate analysis that high numbers of CD163(+) macrophages in the TS is an independent prognostic factor. Overall collagen deposition was associated with high stomal expression of COX-2 and CD163; however, total collagen deposition was not a predictor for OS. Conversely, local collagen density, alignment and perpendicular alignment to the tumor boundary (tumor-associated collagen signature-3) were predictors of OS. These results suggest that in invasive carcinoma, the localization of inflammatory cells and aligned collagen orientation predict poor patient survival. Additional clinical studies may help validate whether therapy with selective COX-2 inhibitors alters expression of CD68 and CD163 inflammatory markers.