Abstract P3-06-16: The pattern of alpha- and beta- adrenergic receptor expression impacts breast cancer outcome
Authors: Elkhanany A , Katsuta E , Repasky E , Takabe K 
Published: May 2019

Abstract
BACKGROUND. Chronic stress promotes myriad of genomic changes collectively termed conserved transcriptional response to adversity (CTRA), contributing to a pro-tumorogenic and immunosuppressive tumor microenvironment (TME). Adrenergic stimulation is one mechanism of CTRA, and adrenergic receptor (AR) modulators are currently repurposed in cancer trials. However, the impact of AR expression on TME and overall survival outcome (OS) in breast cancer (BC) remains unclear. We asked whether AR expression in tumor samples predicts prognosis in BC patients (pts) and whether it correlated to expression in normal cells.
METHODS. Public RNA expression data accessed from The Cancer Genome Atlas (TCGA), and fed to deconvolutional algorithm CIBERSORT, estimating 22 immune cell proportions. Clinical and OS data were accessed from XENA. Differential gene expression obtained for 115 CTRA genes known to correlate with stress. Cytolytic activity (CY) appended from Rooney et al.
RESULTS. 1,211 pts had clinical and genomic data, including 114 pts with normal breast (BN) samples. When compared to BC, BN samples were enriched for ARG1, PTGS2, VCAM1, CSF1, as well as all ARs (ADR A1A, A1B, A1D, A2A, A2B, A2C, B1, B2, B3). There was significant correlation between BC and BN samples in A2A, B1, B2, IFN-γ, PTGS2 (Spearman ρ -0.2, -0.27, -0.2, 0.28, 0.29, P&lt;0.01). On survival analysis, worse OS was associated with higher expression of A1B and A2C (HR 1.1[1-1.22], 1.1[1-1.17]), while higher B1 predicted better OS (HR 0.86[0.79-0.93]). OS impact persisted after quantile separation (HR for higher to lower quantiles of A1B, A2C and B1 were 1.47[1.1-2], 1.38[1.01-1.9], 0.69[0.49-0.0.95]). Co-expression of A1B and A2C predicted significantly worse OS than either alone (HR 1.53[1.1-2.2]). Results persisted after adjusting for age. For TME analysis between quantiles, higher A1B and A2C expression correlated with higher regulatory T (Treg) cells (OR 1.42[1.1-1.86]), fewer resting and activated dendritic cells (DCs) and memory CD4+ cells, and lower CY (OR 0.81[0.64-0.9]). In comparison, higher B1 correlated with higher tumor infiltrating lymphocytes (TILs), M1 macrophages (M1), M1/M2 ratio (OR 1.45[1.14-1.84], 3.64[1.03-12.8], 1.86[1.46-2.36]), lower M2 and Treg (0.42[0.33-0.53], 0.65[0.49-0.85]), and higher CY (OR 1.89[1.49-2.38]). CY also correlated with IFN-γ, MMP9 and CSF1 (Spearman ρ 0.75, 0.59, 0.3 p&lt;0.001). Higher M2 and lower M1/M2 ratio were independently associated with a poorer OS, persisting after control for B1 (HR 1.78[1.27-2.47], 1.5[1.08-2.08]). T-cell exhaustion (Tex) genes CD274, PDCD1, CTLA4, IDO1, LAG3 and HAVCR2 were all lower in ADR-α (OR for A1B was 0.69, 0.73, 0.68, 0.87, 0.61, 0.69) and higher in ADR-β (OR for B1 was 1.46, 1.32, 1.29, 1.42, 1.26, 1.4).
CONCLUSIONS. AR genes were similarly expressed across normal and tumor samples from BC pts. Pts with higher ADR-α expression had worse OS (higher Treg, lower CY) while higher ADR-β expression pts had better OS (higher TILs, M1, M1/M2, lower Treg, M2). Tex genes were higher in ADR-β, likely due to higher TILs. These findings illustrate the potential impact of chronic stress on TME and clinical outcome, potentially helping to discern pts who can benefit most from AR modulation.
Citation Format: Elkhanany A, Katsuta E, Repasky E, Takabe K. The pattern of alpha- and beta- adrenergic receptor expression impacts breast cancer outcome [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-16.