Prognostic and Predictive Impact of Beta-2 Adrenergic Receptor Expression in HER2-Positive Breast Cancer

ADRB2 mediates trastuzumab resistance in preclinical models of HER2+ breast cancer. We evaluated ADRB2 gene expression as a prognostic and predictive biomarker in HER2+ early breast cancer patients. Opposing our initial hypothesis, a high ADRB2 expression may exert antiproliferative, antiangiogenic, and immunogenic effects, and thus be associated with a favorable prognosis in patients with HER2+ early breast cancer. Background: Beta-2 adrenergic receptor (ADRB2) mediates proliferation and treatment resistance in preclinical models of human epidermal growth factor receptor 2 positive (HER2+) breast cancer. We evaluated ADRB2 gene expression as a prognostic and predictive biomarker in patients with HER2+ early breast cancer. Methods: ADRB2 expression was retrieved from HER2+ patients enrolled in the FinHer study (N = 202), and 2 public datasets containing data from patients with HER2+ early breast cancer: one including patients who did not receive systemic treatment (disease-free survival [DFS] dataset; n = 175) and another including patients who received neoadjuvant treatment (pathologic complete response [pCR] dataset; n = 207). Survival was estimated with Kaplan-Meier method and Cox regression was used for uni-multivariate analyses. ADRB2 expression was correlated with several gene signatures. Results: ADRB2 high expression was associated with improved DFS rates in HER2+ patients (hazard ratio [HR] 0.52; 95% confidence interval [CI] 0.32-0.84; P =.0068). No association between ADRB2 expression and pCR was observed (odds ratio 1.14; 95% CI, 0.63-2.10; P =.67). No association between ADRB2 and relapse-free survival (RFS) was observed in HER2+ patients enrolled in the FinHer study (HR 0.93; 95% CI, 0.69-1.25; P =.61). ADRB2 was associated with a low expression of angiogenesis-related (vascular endothelial growth factor -0.38, P <.001) and proliferation-related (aurora kinase A -0.36, P <.001; genomic grade index -0.028, P <.001; signal transducers and activators of transcription -0.17, P <.001) genes; and a high expression of immune-related genes (Perez +0.45, P <.001; STAT1 +0.28, P <.001; immune response gene expression module +0.29, P <.001). Conclusions: Opposing our initial hypothesis, a high ADRB2 expression may be a favorable prognostic factor in patients with HER2+ early breast cancer. This association appears to be mediated by antiproliferative, antiangiogenic, and immunogenic effects of ADRB2. (C) 2020 Elsevier Inc. All rights reserved.