β-Blockers Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta-Analysis

doi:10.1016/j.clbc.2015.07.001

Clinical Breast Cancer

Volume 15, Issue 6, December 2015, Pages 426-431

https://doi.org/10.1016/j.clbc.2015.07.001 Get rights and content

Abstract

The normal physiologic stress mechanism, mediated by the sympathetic nervous system, causes a release of the neurotransmitters epinephrine and norepinephrine. Preclinical data have demonstrated an effect on tumor progression and metastasis via the sympathetic nervous system mediated primarily through the β-adrenergic receptor (β-AR) pathway. In vitro data have shown an increase in tumor growth, migration, tumor angiogenesis, and metastatic spread in breast cancer through activation of the β-AR. Retrospective cohort studies on the clinical outcomes of β-blockers in breast cancer outcomes showed no clear consensus. The purpose of this study was to perform a systematic review and meta-analysis of the effect of β-blockers on breast cancer outcomes. A systematic review was performed using the Cochrane library and PubMed. Publications between the dates of January 2010 and December 2013 were identified. Available hazard ratios (HRs) were extracted for breast cancer recurrence, breast cancer death, and all-cause mortality and pooled using a random effects meta-analysis. A total of 7 studies contained results for at least 1 of the outcomes of breast cancer recurrence, breast cancer death, or all-cause mortality in breast cancer patients receiving β-blockers. In the 5 studies that contained results for breast cancer recurrence, there was no statistically significant risk reduction (HR, 0.67; 95% confidence interval [CI], 0.39-1.13). Breast cancer death results were contained in 4 studies, which also suggested a significant reduction in risk (HR, 0.50; 95% CI, 0.32-0.80). Among the 4 studies that reported all-cause mortality, there was no significant effect of β-blockers on risk (HR, 1.02; 95% CI, 0.75-1.37). Results of this systematic review and meta-analysis suggest that the use of β-blockers significantly reduced risk of breast cancer death among women with breast cancer.

Introduction

The body's natural reaction to acute psychosocial stress includes a ‘fight or flight’ response, which leads to an activation of the sympathetic nervous system and neuroendocrine stress hormones. However, in the realm of chronic behavioral stress, recent studies in hypothetical pathways and animal studies have shown an increased incidence and progression of cancer as a results of chronic stress.1, 2, 3 Norepinephrine has been closely scrutinized as a possible contributor to cancer progression via activation of its extracellular receptors.⁴ β-Adrenergic receptors have attracted much of the attention with its signaling found to contribute to cancer development, angiogenesis, and apoptosis.5, 6

β-Adrenoceptors have been identified throughout the body, including in immune cells, vascular endothelium, and normal breast tissue.⁷ Recent studies have identified β-adrenoceptors in breast cancer.8, 9, 10

Multiple preclinical studies have examined the context in which stress-induced catecholamine release of epinephrine and norepinephrine has affected tumorigenesis. Including ovarian, nasopharyngeal, prostate, colon, and pancreatic cancer, catecholamine has enhanced production of vascular endothelial growth factor, matrix metalloproteinase (MMP-2), and MMP-9, and increased tumor angiogenesis, growth, and rendered the cancer cells resistant to anoikis. In most of these studies, propranolol, a nonselective β-blocker, inhibited and/or suppressed the progrowth and proangiogenic effects of the catecholamines.11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21

With concomitant clinical and preclinical data that identified catecholamines as a mediator in breast cancer progression, further research is needed regarding the use of β-blockers as a means of prevention and therapy in breast cancer. A recent meta-analysis showed a statistically insignificant decrease in the incidence of breast cancer in patients receiving β-blockers.22, 23 In this meta-analysis, we reviewed existing studies and performed a meta-analysis on the end points of breast cancer recurrence, death from breast cancer, and all-cause mortality in patients receiving β-blockers.

Section snippets

Materials and Methods

A systematic review was performed using PubMed and the Cochrane library. The following search terms in the title and abstract fields were used: ‘beta-blockers, beta-adrenergic inhibitors, metoprolol, atenolol, propranolol, carvedilol’ and ‘breast cancer, breast cancer recurrence, breast malignancy, breast cancer metastasis.’ Searches were performed in August, September, and October of 2014. One author screened all abstracts and full-text articles. Discrepancies were discussed and resolved

Results

A total of 7 cohort studies met inclusion criteria and had formally published at least 1 end point of breast cancer recurrence, death from breast cancer, or all-cause mortality (Table 1). A total of 5 studies were included in the breast cancer recurrence meta-analysis. A total of 22,988 patients were included in the breast cancer recurrence analysis. Pooling studies that reported a HR for recurrence yielded an overall HR of 0.67, which was not statistically significant (95% CI, 0.39-1.13;

Discussion

One in 8 women will be diagnosed with breast cancer in their lifetime.³³ As the most commonly diagnosed cancer in women, and second most likely cancer to result in death in women, breast cancer is of vast interest and research. Surgical techniques, preventative screening programs, and chemotherapy remain the areas of research and refinement.

Various studies have been conducted on the phenomenon of native neurotransmitter receptors present on tumor cells, and the propensity of neurotransmitters

Conclusion

With preclinical data that provides further evidence of β-adrenoceptors contributing to the development and proliferation of breast cancer, follow-up clinical data have marginally provided uniform suggestion to their benefit. To our knowledge, this is the first meta-analysis on the benefit of β-blockers and death from breast cancer. With statistically significant results in support of the use of β-blockers, further research needs to be conducted to further examine the use of selective versus

Disclosure

The authors have stated that they have no conflicts of interest.

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Citation Excerpt :
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Reviewβ-Blockers Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta-Analysis

Abstract

Introduction

Section snippets

Materials and Methods

Results

Discussion

Conclusion

Disclosure

Brain Behav Immun

Trends Pharmacol Sci

Lancet Oncol

Cancer Epidemiol

Pharmacol Ther

Gynecol Oncol

Eur Urol

Ann Oncol

J Biol Chem

The neuroendocrine impact of chronic stress on cancer

Cell Cycle

The influence of biobehavioural factors on tumour biology: pathways and mechanisms

Nat Rev Cancer

Is norepinephrine an etiological factor in some types of cancer?

Int J Cancer

Molecular pathways: β-adrenergic signaling in cancer

Clin Cancer Res

Catecholamines regulate tumor angiogenesis

Cancer Res

Functional β-adrenergic receptors in breast cancer cells

J Cancer Res Clin Oncol

Possible association of β2 and β3-adrenergic receptor gene polymorphisms with susceptibility to breast cancer

Breast Cancer Res

Adrenoreceptors: nonconventional target for breast cancer?

Curr Med Chem

Norepinephrine upregulates the expression of vascular endothelial grow factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells

Cancer Res

The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by β-blockers

Int J Cancer

Inhibition of pancreatic cancer cell proliferation by propranolol occurs through apoptosis induction: the study of β-adrenoceptor antagonist's anticancer effect in pancreatic cancer cell

Pancreas

Prevention of pancreatic cancer by the β-blocker propranolol

Anticancer Drugs

Is β-blocker treatment associated with a decrease in the risk of cancer

Lett Drug Des Discov

Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by β-blockers

Cancer Res

β2-Adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NFkB and AP-1

Cancer Biol Ther

Review
β-Blockers Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta-Analysis