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

Abstract

The majority of deaths from breast cancer occur following the development of metastatic disease, a process inhibited by β-blockers in preclinical studies. This phase II randomized controlled trial evaluated the effect of preoperative β-blockade with propranolol on biomarkers of metastatic potential and the immune cell profile within the primary tumor of patients with breast cancer. In this triple-blind placebo-controlled clinical trial, 60 patients were randomly assigned to receive an escalating dose of oral propranolol (<i>n</i> = 30; 80-160 mg daily) or placebo (<i>n</i> = 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. Propranolol downregulated primary tumor expression of mesenchymal genes (<i>P</i> = 0.002) without affecting epithelial gene expression (<i>P</i> = 0.21). Bioinformatic analyses implicated downregulation of Snail/Slug (<i>P</i> = 0.03), NF-κB/Rel (<i>P</i> < 0.01), and AP-1 (<i>P</i> < 0.01) transcription factors in structuring the observed transcriptome alterations, and identified changes in intratumoral neutrophil, natural killer cell, and dendritic cell recruitment (all <i>P</i> < 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. One week of β-blockade with propranolol reduced intratumoral mesenchymal polarization and promoted immune cell infiltration in early-stage surgically-resectable breast cancer. These results show that β-blockade reduces biomarkers associated with metastatic potential, and support the need for larger phase III clinical trials powered to detect the impact of β-blockade on cancer recurrence and survival.<i>See related commentary by Blaes et al., p. 1781</i>.