Abstract P4-12-13: High intratumoral and stromal S100A8 expression is prognostic of poor outcome in breast cancer

Background: S100A8 and S100A9 are members of a family of calcium binding proteins that regulate inflammatory response, and are biomarkers of inflammatory diseases, S100A8/A9 preferentially form heterodimers that interact with their receptor, RAGE, to activate signaling pathways (ERK1/2 MAPK, JNK, and NF-κB) and stimulate tumor cells. Elevated expression of S100A8/A9 has been observed in cancers of the bladder, esophagus, colon, ovary, and breast. S100A8/A9 are expressed intratumorally by cancer cells and in the stroma by infiltrating immune and myeloid cells as well. We investigated the associations of elevated expression of intratumoral and stromal S100A8 with survival outcomes in breast cancer. Methods: Tissue microarrays (TMA) were constructed from breast cancer specimens from patients with stage I-III breast cancer treated at the University of Michigan Comprehensive Cancer Center between 2004-2006, ensuring a minimum of 10-year follow-up. Each patient was represented on the TMA by representative regions of non-necrotic tumor and distant normal tissue. Automative Quantitative Immunofluorescence (AQUA) was performed for S100A8 protein, and samples were scored for intratumoral and stromal S100A8 expression. S100A8 staining was assessed as a continuous value and by exploratory dichotomous cutoffs. Associations with disease-free survival (DFS) or overall survival (OS) and S100A8 expression, either as continuous value or based on the exploratory cutoffs, were determined using the Kaplan-Meier method and Cox proportional hazards models. Results: In the entire patient cohort, high intratumoral S100A8 expression, as a continuous measure, was a significant prognostic factor for OS (univariable hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.02-1.56, p=0.036), and for DFS (multivariable HR [95%CI] = 1.24 [1.01-1.53], p = 0.043). Exploratory analyses demonstrated optimal cutoffs of intratumoral and intrastromal staining that greatly separated survival curves. We evaluated whether the prognostic significance of S100A8 expression is different in breast cancer patients based on hormone receptor status and determined that neither intratumoral nor stromal S100A8 expression were significantly associated with outcomes. Conclusions: Elevated intratumoral and stromal expression of S100A8 are significant indicators of poor outcome in breast cancer patients. These data further support a biological role for S100A8 signaling in mammary carcinogenesis and aggressive tumor behavior. Evaluation of S100A8 protein expression might provide additional prognostic information beyond traditional breast cancer prognostic biomarkers. Further validation is necessary to investigate these findings. Citation Format: Miller P, Kidwell K, Thomas D, Sabel M, Rae J, Hayes DF, Lippman ME, El-Ashry D. High intratumoral and stromal S100A8 expression is prognostic of poor outcome in 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 P4-12-13.