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

Clin Breast Cancer. 2020 Jun;20(3):262-273.e7. doi: 10.1016/j.clbc.2020.01.007. Epub 2020 Mar 4.

Abstract

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.

Keywords: ADRB2; Biomarker; Early breast cancer; Gene expression; HER2.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Breast / pathology*
  • Breast / surgery
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / therapy
  • Chemotherapy, Adjuvant / methods
  • Datasets as Topic
  • Disease-Free Survival
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Mastectomy
  • Middle Aged
  • Neoadjuvant Therapy / methods
  • Neoplasm Recurrence, Local / epidemiology*
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Predictive Value of Tests
  • Prognosis
  • Protective Factors
  • Receptor, ErbB-2 / analysis
  • Receptor, ErbB-2 / metabolism
  • Receptors, Adrenergic, beta-2 / analysis
  • Receptors, Adrenergic, beta-2 / genetics*
  • Receptors, Adrenergic, beta-2 / metabolism
  • Receptors, Estrogen / analysis
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / analysis
  • Receptors, Progesterone / metabolism
  • Risk Assessment / methods

Substances

  • ADRB2 protein, human
  • Biomarkers, Tumor
  • Receptors, Adrenergic, beta-2
  • Receptors, Estrogen
  • Receptors, Progesterone
  • ERBB2 protein, human
  • Receptor, ErbB-2