Reviewβ-Blockers Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta-Analysis
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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2023, Pharmacology and TherapeuticsCitation Excerpt :Antagonists for βARs, commonly termed β-blockers, have been used since the 1960s to treat cardiovascular disorders (Baker, Hill, & Summers, 2011; Black, Duncan, & Shanks, 1965). The use of β-blockers in the population has allowed retrospective clinical studies to look for an association between β-blocker use and improved breast cancer outcome, with mixed conclusions (Algazi, Plu-Bureau, Flahault, Dondon, & Le, 2006; Barron, Connolly, Sharp, Bennett, & Visvanathan, 2011; Barron, Sharp, & Visvanathan, 2012; Botteri et al., 2013; Cardwell et al., 2016; Childers, Hollenbeak, & Cheriyath, 2015; Le et al., 2016; Løfling et al., 2022; Melhem-Bertrandt et al., 2011). A recent meta-analysis of these retrospective studies concluded that the use of β-blockers was associated with a reduction of mortality only in patients with TNBC (Løfling et al., 2022).
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