β-Adrenergic Receptors : New Target in Breast Cancer

Breast cancer is the most common cancer in women in whole world (WHO, 2014). Although treatment of breast cancer has been in progress, global breast cancer mortality is still increasing annually (WHO, 2014). Therefore, new therapeutic options are needed. Recent studies had showed that β-Adrenergic signaling had an influence up on biological processes involved in the development of the carcinoma (Sood et al., 2006; Thaker et al., 2006; Chakroborty et al., 2009; Anil et al., 2010; Shahzad et al., 2010; Akbar and Alsharidah, 2014) by influencing tumor cells and the microenvironment of tumor cells (Entschladen et al., 2004; Antoni et al., 2006; ArmaizPena et al., 2008; Prema et al., 2008; Susan et al., 2010), including but not limited to the cancers of pancreas (Drell et al., 2003), breast (Barron et al., 2012 ; Diaz et al., 2012), ovary (Masu et al., 2001; Sood et al., 2006), colon (Masur et al., 2001), prostate (Grytli et al., 2013; Grytli et al., 2014). These effects can be removed by BBS (Masur et al., 2001; Drell et al., 2003; Zhang et al., 2010). Beta-adrenergic system is comprised of catecholamines (Tang et al., 2013), and beta-adrenergic receptor is composed of three subtypes, β1, β2 and β3 (Yamazaki et

Beta-adrenergic system is comprised of catecholamines (Tang et al., 2013), and beta-adrenergic receptor is composed of three subtypes, β1, β2 and β3 (Yamazaki et

Criteria for inclusion in this review
The following inclusion criteria should be met in these candidate studies: (1) the study design was interventional; (2) the breast cancer patients should be confirmed the pathological type; (3) the usage of Beta-adrenoceptor blockers were evaluated; (4) clinical studies used a control group excluding animal and cell line studies; (5) clinical outcomes should be provided, such as survival, diseasefree survival (DFS), tumor recurrence and metastasis.Divergences of the reviewers' inclusions were settled by discussion.Additional studies were identified by a hand search of the references cited in the original studies.

Search methods for identification of studies
Related literatures are searched from the Pub-Med, EMBASE and Web of nature databases through using terms for breast carcinoma/cancer/tumor and beta-adrenoceptor blockers/beta blockers/beta-adrenoceptor antagonists.The overall search was based on humans and clinic, without restriction on language or region.Furthermore, to extend the search, we also used the "related articles" section.Data retrieval included all eligible studies and their references were thoroughly investigated.These literatures which printed before October 1st, 2014 were in the scope of our screening.

Data extraction
As listed below, these data was extracted for each study: first author's name, publication year, patients' original country, number of patients investigated including comparison group and experimental group, exposure ascertainment, category of drug use (never/ever use), outcome confirmation, overall risk measurement, adjustments of confounders.The potential biases of all included articles were evaluated.Information was extracted from all eligible studies by two of the authors (Xuesong Chen, Ting Wang).Discrepancies between the authors were settled by consultation to reach a consensus.

Eligible studies
There were 2119 potentially relevant studies through electronic search.After checking the title and abstract and screening full text articles when needed, a total of 10 articles were eligible for inclusion criteria as showed in the Figure 1.The main characteristics of these eligible articles are outlined in Table 1.All of the articles were retrospective cohort studies built on the hospital.Five of the studies were located in Europe (Powe et al., 2010;Barron et al., 2011;Shah et al., 2011;Botteri et al., 2013;Cardwell et al., 2013), four in North America (Ganz et al., 2011;Melhem et al., 2011;Holmes et al., 2013;2013), and one in Asia (Turkey) (Sendur et al., 2012).A total of 19, 999 patients were included in the eligible studies, with study sizes ranging from 466 to 9817.It was variable in terms of beta-adrenoceptor blockers type and the average length of follow up.There were selective and no-selective selective and no-selective beta-adrenoceptor blockers.The average length of follow up ranged from 1.3 years to 10.5 years (Table 1).

Survival
It's presented in Table 2 of the risk estimates for survival.Barron et al. (2011) found women taking propranolol at the time of diagnosis (n=70) had an 81% lower risk of breast cancer-specific mortality (HR=0.19;95% CI=0.06-0.60).However, they observed no association with breast cancer-specific mortality between atenolol and matched nonuser, 26.8%v26.0%(HR=1.08;95% CI=0.84-1.40).After excluding patients with stage IV breast tumors, Propranolol users continued to enjoy a significantly lower risk of breast cancer-specific mortality, compared with matched nonusers (HR=0.20;95% CI: 0.04 to 0.94).But atenolol users did not (HR=1.16;95% CI=0.84 to 1.61).Powe et al. (2010) observed that the risk of breast cancer-specific mortality and metastasis reduced 71% (HR=0.291;95% CI=0.119-0.715;p=0.007) and 57% (HR=0.430;95% CI=0.200-0.926;p=0.031), respectively, after 10 years.Botteri et al. (2013) discussed the association BBS in triple-negative breast cancer (TNBC) patients.The population of breast cancer related death was 6 (8.1%) and 141 (19.4%), individually in betablocker users and non-users, with a corresponding adjusted HR=0.42 (95% CI=0.18-0.97;p=0.042).At univariate analysis, Botteri et al. (2013) observed a suggestion of increased risk of death from causes other than BC in betablocker users compared to non-users, but there was no significant difference.Cardwell et al. (2013) investigated little evidence of an association between beta-blocker use and breast cancer-specific mortality (odds ratio=0.97;95% CI=0.83, 1.13).Ganz et al. (2011) reported that betablocker users.ACEI users and beta-blocker combined with ACEI users had no statistically significant associated with cause-specific mortality.There was no reduction in overall mortality (HR= 1.04; 95% CI=0.72-1.51) in eta-blocker users and (HR= 1.94; 95% CI=1.22,3.10; p=0.01) in ACEI users.However, beta blocker combined with ACEI had a higher risk of overall mortality.Powe et al. (2010) showed that beta-blocker treated patients' breast cancer had longer disease free interval (LR=6.658.P=0.011) and longer breast cancer specific survival (LR=6.479;p=0.011) compared to non treated breast cancer patients in Kaplan-Meier modelling with log rank testing.Modeled simultaneously or individually, the association between the risk of breast cancer death and beta-blocker users was non-significant.Melhem et al. (2011) reported that β-Blocker use had no significant association with OS among women with ER-positive breast cancer, TNBC, and all breast cancer.Kaplan-Meier estimates of OS showed that the risk of beta-blocker users was significantly improved (p=0.03) in patients with TNBC on beta blockers when compared to TNBC not taking beta blockers.Betablocker users with ER-positive breast cancer had no significant effects on OS (P=0.65).Sendur et al. (2012) observed no statistical significance in 5-year OS rates between metoprolol users and nonusers (metoprolol 96.8%, nonusers 92.9%; p=0.28).Holmes et al. (2013) BBS had no effect on survival for breast cancers (HR= 1.10; 95% CI=0.92-1.32; p=.305).In a population-based retrospective cohort study, Shah et al. (2011) didn't found significant difference in OS (HR=1.09;95% CI=0.80-1.49) between patients with β-blocker (n=434) and patients with other antihypertensive medications (n=554).Holmes et al. (2013) observed no significant association with beta blockers and survival.

Disease Progression
Results for BBS use and disease progression are outlined in Table 2. Botteri et al. (2013) reported that the 5-year cumulative incidence of breast cancer related events (local recurrence, regional recurrence, distant metastases, death from breast cancer) for beta-blocker users and for non-users was 13.6 % and 27.9 % (Gray test P=0.015),individually.The risk of breast cancer related events was statistically significant for multivariable analysis (HR=0.52;95% CI=0.28-0.97;p=0.041) between beta-blocker users and non-users.The incidence of distant metastases was statistically significant decline (HR=0.32;95% CI=0.12-0.90;p=0.031) in favor of BBS.In the study by Powe et al. (2010), the authors reported a significant reduction in metastasis development (χ 2 =4.986; p=0.026).In addition, when analyzing the risk of distant metastases, they observed a significant difference between beta-blocker drugs users and other anti-hypertensive when compare metoprolol users to nonusers.In the study of Powe et al. (2010), the authors reported a significant reduction in tumor recurrence between BBS users and nonhypertensive breast cancer patients (χ 2 =13.091; p=0.001), and between other anti-hypertensive medications patients and BBS users (χ 2 =7.264; p=0.026).Ganz et al. (2011) reported patients with β-blockers showed a non-significant 14% reduction (HR=0.86;95% CI=0.57-1.32) in the risk of breast cancer recurrence (distant, loco-regional, or contralateral) compared to unexposed women (no BBS and ACEI).Melhem et al. (2011) found no significant 48%and 70% reduction in risk of breast cancer recurrence in beta users of TNBC and breast cancer, respectively.Botteri et al. (2013) also observed that the local and regional recurrence was no significant change between BBS users and non-users.

Discussion
Although the relationship between beta-adrenoceptor blockers and breast-carcinoma events has been observed in previous studies, the conclusions were inconsistent and some were even controversial.So a systematic review was needed in order to investigate the further association.To the best of our knowledge, this is the first systematic review to investigate the association between Betaadrenoceptor blockers and breast-carcinoma events.Ten retrospective cohort studies were identified.The majority of the eligible studies were from hospital.Most studies were in small size and had relatively short follow-up periods.
Three studies reported a significant reduction in the risk of breast cancer-specific mortality in beta-blocker users (Powe et al., 2010;Barron et al., 2011;Botteri et al., 2013).Furthermore, one of them observed a no significant improvement of the mortality from causes other than breast cancer in beta-blocker users (Botteri et al., 2013).Three studies demonstrated a suggestion of a reduced risk of breast cancer death associated with beta-blocker drugs, but not reached statistical significance (Ganz et al., 2011;Cardwell et al., 2013;Holmes et al., 2013).In these researchers, Ganz et al. (2011), Cardwell et al. (2013) and Holmes et al. (2013) adjusted most of the adjustments.Thomas I. Barron, Powe et al. (2010) and Botteri et al. (2013) only adjusted others, age, stage, and adjustment treatment.Powe et al. (2010) observed a significant association between breast cancer special survival and beta-adrenoceptor blockers.And only age and other confounding factors were adjusted in this literature.One study found no significant 36% and 65% reduction in risk of OS in beta blocker users with TNBC and breast cancer, respectively.However, the OS (P=0.03) of patients with TNBC on beta blockers were significantly improved in the Kaplan-Meier estimates (Melhem et al., 2011).The different statistical methods maybe affect the results.Three studies found no significant association between OS and beta-adrenoceptor blockers, and they also only adjusted age, stage, and other confounding factors (Shah et al., 2011;Sendur et al., 2012;Holmes et al., 2013).The risk of distant metastases was assessed in two studies.And both of them demonstrated a significant reduction in the risk of distant metastases in beta-blocker treated patients compared to non-treated patients (Powe et al., 2010;Botteri et al., 2013).One study demonstrated a significant reduction in the risk of breast cancer recurrence (Powe et al., 2010), and three studies observed no significant reduction (Ganz et al., 2011;Melhem et al., 2011;Botteri et al., 2013).Ganz et al. (2011) observed no significant 14% reduction.Powe et al. (2010), Melhem et al. (2011) and Botteri et al. (2013) adjusted the multiple confounding factors.Powe et al. (2010) adjusted two confounding factors.Hormone receptor status, age, stage, hypertension, menopausal status, adjuvant treatment, diabetes and BMI were important prognostic indicators.Recently, it's demonstrated that diabetes was an adverse factor for breast cancer (Liao et al., 2011;Melhem et al., 2011;De et al., 2013;Xiao et al., 2014), and so did BMI (Ortiz-Mendoza et al., 2014).A diagnosis of diabetes was associated with a worse OS (P=0.002) but not a worse RFS (P=0.42)(Melhem et al., 2011).Information about performance status (Huber et al., 2002;Van et al., 2011;Werner and Bruchim, 2012), physical activities (Akechi et al., 2011;Ying et al., 2013) and hereditary factors were not adjusted in the majority of studies, which were reported as important factors for cancer prognosis.Adjustment factors of the eligible studies were inconsistent, which maybe have an effect on the risk of breast cancer-specific mortality.There were only five articles referring to selective and non-selective beta blockers (Powe et al., 2010;Barron et al., 2011;Shah et al., 2011;Sendur et al., 2012;Cardwell et al., 2013).The consequences, however, were inconsistent.Only one of these studies reported that the different strategies of beta-adrenoceptor blockers showed a significantly different effect on breast cancer prognosis (Barron et al., 2011).
Potential biases or confounding.First, although we try our best to search all possible relevant data, it was unavoidable to miss data.Second, a part of the eligible studies was observational studies whose observations may have potential bias.Third, patients' information DOI:http://dx.doi.org/10.7314/APJCP.2015.16.18.8031 β-adrenergic Receptors : New Target Against Breast Cancer was obtained from hospital medical records in the cohort studies, which may appear incomplete information for patients due to differences in hospital classification of drugs and other ways to obtain drugs.Four, there are unavoidable differences in the definitions of methods, measurements, and outcomes in the eligible studies.Despite these potential biases or confounding, this systematic review had several noteworthy advantages.First, this is the first systematic review to investigate the association between BBS use and breast cancer progression and survival.Second, due to a considerable number of subjects and cases from different studies, the statistical power of the analysis was significantly increased.Third, all the eligible studies were searched from aforementioned databases, and when there were discrepancies about candidate articles, the articles were discussed and independently screened for inclusion criteria.
Because of the small number of selected articles and the heterogeneity of articles, a meta-analysis was not undertaken.In this systematic review, it's demonstrated that the risk of breast cancer-specific mortality, the risk of DM and the risk of breast cancer recurrence were decreased for BBS users when compared to non-users, despite the fact that some of the data was without statistical significance.Compared with non-users, the OS of breast cancer patients with beta blockers and different type of beta blockers was inconsistent.And the possible influencing factors could be the following.Firstly, the size of some studies' samples are not enough large; secondly, the discrepancy of the data analysis methods may influence the result; thirdly, other inconsistent confounders of the patients perhaps have some effect on the OS; fourthly, compared with non-users, BBS users were more likely to combine with other diseases which may have a influence on breast cancer prognosis and cancer therapy.

Conclusions
From this system review, it's suggested that betaadrenoceptor blocking therapy improve breast cancer prognosis.However, it's not fit to reach a definitive conclusion on the effect of beta-adrenoceptor blocking therapy on the breast cancer prognosis.More and more large preclinical studies were needed in order to further investigate the association between beta-adrenoceptor blockers and breast cancer.Meanwhile, more clinical studies on the association between breast cancer progression or survival and the dosage, frequency and duration of use of beta blockers were also needed to be further carried out.DOI:http://dx.doi.org/10.7314/APJCP.2015.16.18.8031 β-adrenergic Receptors : New Target Against Breast Cancer pathways in familial cancer. Lancet Oncol, 13, 537-44. Xiao Y, Zhang S, Hou G, et al (2014)

Figure 1 .
Figure 1.The Flow Chart of Study Selection and Exclusion10 articles include in review