Preoperative β-Blockade with Propranolol Reduces Biomarkers of Metastasis in Breast Cancer: A Phase II Randomized Trial

Purpose: The majority of deaths from breast cancer occur following the development of metastatic disease, a process inhibited by beta-blockers in preclinical studies. This phase II randomized controlled trial evaluated the effect of preoperative beta-blockade with propranolol on biomarkers of metastatic potential and the immune cell profile within the primary tumor of patients with breast cancer. Patients and Methods: In this triple-blind placebo-controlled clinical trial, 60 patients were randomly assigned to receive an escalating dose of oral propranolol (n = 30; 80-160 mg daily) or placebo (n = 30) for 7 days prior to surgery. The primary endpoint investigated the effect of propranolol on prometastatic and proinflammatory gene expression within the primary tumor. Results: Propranolol downregulated primary tumor expression of mesenchymal genes (P = 0.002) without affecting epithelial gene expression (P = 0.21). Bioinformatic analyses implicated downregulation of Snail/Slug (P = 0.03), NF-kappa B/Rel (P < 0.01), and AP-1 (P < 0.01) transcription factors in structuring the observed transcriptome alterations, and identified changes in intratumoral neutrophil, natural killer cell, and dendritic cell recruitment (all P < 0.01). Patients with clinical evidence of drug response (lowered heart rate and blood pressure) demonstrated elevated tumor infiltration of CD68(+) macrophages and CD8(+) T cells. Conclusions: One week of beta-blockade with propranolol reduced intratumoral mesenchymal polarization and promoted immune cell infiltration in early-stage surgically-resectable breast cancer. These results show that beta-blockade reduces biomarkers associated with metastatic potential, and support the need for larger phase III clinical trials powered to detect the impact of beta-blockade on cancer recurrence and survival.