Prognostic and Predictive Impact of Beta-2 Adrenergic Receptor Expression in HER2-Positive Breast Cancer

Caparica, Rafael; Richard, François; Brandão, Mariana; Awada, Ahmad; Sotiriou, Christos; Azambuja, Evandro de

doi:10.1016/j.clbc.2020.01.007

Cited by 15 publications

(19 citation statements)

References 41 publications

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“…As an example, our group previously demonstrated that a high expression of the ß2-adrenergic receptor gene (ADRB2)d which might occur as a result of beta-blocker usedmay be associated with a favorable prognosis and also predict trastuzumab benefit in patients with HER2-positive earlystage breast cancer. 11,56 Some limitations need to be considered when interpreting our findings. This meta-analysis was not based on individual patient data, and all studies included were retrospective or exploratory analyses, increasing the chances of bias and/or missing data.…”

Section: Esmo Openmentioning

confidence: 98%

“…7,8 Beta-blockers can also stimulate the production of inflammatory cytokines, induce lymphocyte infiltration and inhibit angiogenesis in the tumoral stroma, effects that may enhance the activity of anticancer treatments. [9][10][11] The evidence of preclinical activity against breast cancer, combined with the low cost and the manageable safety profile of beta-blockers generate interest in the repurposing of these drugs as an attempt to optimize the treatment of patients with breast cancer. 12 Some retrospective studies suggest that the use of betablockers is associated with a favorable prognosis in patients with breast cancer.…”

Section: Introductionmentioning

confidence: 99%

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Beta-blockers in early-stage breast cancer: a systematic review and meta-analysis

et al. 2021

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Background: Preclinical and retrospective studies suggest that beta-blockers are active against breast cancer. We carried out a systematic review and meta-analysis to assess the impact of beta-blockers on the outcomes of patients with earlystage breast cancer. Methods: A systematic literature search was performed to identify studies comparing outcomes of patients with earlystage breast cancer according to beta-blocker use (yes versus no). The primary endpoint was recurrence-free survival (RFS), defined as the occurrence of breast cancer recurrence or death. Secondary objectives were pathologic complete response (pCR), breast cancer recurrence, breast cancer-specific mortality and overall survival (OS). Hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were extracted from each study and a pooled analysis with the random-effect model was conducted. The Higgins' I-squared test was used to quantify heterogeneity. Egger's test was applied to assess publication bias. All P values were two-sided and considered significant if 0.05. Results: Overall, 13 studies were included as follows: RFS (6), pCR (2), breast cancer recurrence (6), breast cancerspecific mortality (7) and OS (5). The use of beta-blockers was associated with a significant RFS improvement in the overall population (N ¼ 21 570; HR 0.73; 95% CI, 0.56-0.96; P ¼ 0.025) and in patients with triple-negative disease (N ¼ 1212; HR 0.53; 95% CI, 0.35-0.81; P ¼ 0.003). No significant differences in terms of pCR (N ¼ 1554; OR 0.77; 95% CI, 0.44-1.36; P ¼ 0.371), breast cancer recurrence (N ¼ 37 957; OR 0.66; 95% CI, 0.42-1.03; P ¼ 0.065), breast cancer-specific mortality (N ¼ 64 830; HR 0.77; 95% CI, 0.56-1.08; P ¼ 0.130) or OS (N ¼ 103 065; HR 1.03; 95% CI, 0.87-1.23; P ¼ 0.692) were observed according to beta-blocker use. Discussion: In this meta-analysis, beta-blocker use was associated with a longer RFS in patients with early-stage breast cancer, with a more pronounced effect observed in those with triple-negative disease. Beta-blockers arise as an interesting option to be explored in prospective studies for patients with early-stage breast cancer.

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Section: Esmo Openmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Beta-blockers in early-stage breast cancer: a systematic review and meta-analysis

et al. 2021

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“…Clinical studies have suggested that chronic stress or depression and active exercise might influence cancer progression while β-adrenoceptors (β-ARs) could be involved as a major link (11)(12)(13)(14). Cells throughout the body express β-ARs, so as cancer cells, from which the β2adrenergic receptor (β2-AR) take a large part (11,15,16). The gene ADRB2 encodes β2-AR, which is a member of the G protein-coupled receptor superfamily (11,17).…”

Section: Introductionmentioning

confidence: 99%

“…Zahalka et al showed that the loss of endothelial ADRB2 weaken angiogenesis in prostate cancer (20). However, other reports also indicated that β2-AR activation significantly suppressed tumor growth (15,(21)(22)(23)(24). Sakakitani et al (24) demonstrated that β2-AR agonist inhibited cell motility and induced mesenchymal-epithelial transition in oral cancer.…”

Section: Introductionmentioning

confidence: 99%

ADRB2 is a potential protective gene in breast cancer by regulating tumor immune microenvironment

Wei¹,

Chen²,

Yang³

et al. 2021

Transl Cancer Res TCR

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Background: Breast cancer (BRCA) is the leading cause of cancer death among females. Studies suggested that β-adrenoceptors involved in tumor progression by regulating immune system. However, how ADRB2 affects the immune infiltration in BRCA is still being unraveled.Methods: Expressions of ADRB2 in multiple tissues, cancers and blood cells were analyzed by using the Human Protein Atlas and UALCAN database. Expression differentiation of ADRB2 in tumor microenvironment (TME) of BRCA was detected in TISCH database. Correlations between ADRB2 and immune cell infiltration were analyzed by TIMER 2.0, and co-expression genes of ADRB2 were obtained from the cBioPortal website. Functional enrichment analyses and protein-protein interactions were constructed as well. Finally, the potential mechanisms of ADRB2 and candidate drugs targeting BRCA were discussed by using the Metascape, STITCH and Cmap tools.Results: ADRB2 was significantly down-regulated in BRCA, and lower ADRB2 expression often resulted in worse prognosis in BRCA patients. ADRB2 was mainly expressed in breast tissue and blood. Among blood cell subtypes and TME of BRCA, ADRB2 was specifically expressed in T cell subtypes. Also, ADRB2 expression level was positively correlated with the infiltration levels of immune cells such as CD4+ T cell, CD8+ T cell, Tγδ and myeloid DC while negatively correlated with Treg, Tfh and myeloid-derived suppressor cell. Furthermore, functional enrichment analyses revealed that most enriched pathways were immune-related, especially in T cell-related pathways. Also, transcription factors (TFs) analyses showed that most downstream TFs regulated by ADRB2 were immune-related, and most candidate drugs had promising anti-tumor effects.Conclusions: In conclusion, ADRB2 was a potential protective gene in BRCA, and it might play a vital role in regulating immune responses. The expression level of ADRB2 was positively correlated with immune cells infiltration in BRCA, especially for T cells. Therefore, ADRB2 would be a target for boosting immunotherapy effects in BRCA.

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“…β2AR expression was found to correlate with poor prognosis of ER − breast cancer patients [123]. In another study, β2AR expression was associated with lower disease-free survival and higher lymph node metastasis rates in a small cohort of HER2 + breast cancer patients [121], but opposing results were obtained in another small cohort of HER2 + patients where it was associated with improved disease-free survival [124]. Inconsistencies regarding the type or level of expression of adrenergic receptors and the effect of their agonists in breast cancer cells thus limit confidence that modulation of βAR signaling in cancer cells may be of any solid predictive and therapeutic value, although this needs to be further examined.…”

Section: Sympathetic Innervation Of the Skeleton And Evidence For An Interplay With The Process Of Bone Metastasismentioning

confidence: 96%

Mechanisms Supporting the Use of Beta-Blockers for the Management of Breast Cancer Bone Metastasis

Madel

Elefteriou

2021

Cancers

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The skeleton is heavily innervated by sympathetic nerves and represents a common site for breast cancer metastases, the latter being the main cause of morbidity and mortality in breast cancer patients. Progression and recurrence of breast cancer, as well as decreased overall survival in breast cancer patients, are associated with chronic stress, a condition known to stimulate sympathetic nerve outflow. Preclinical studies have demonstrated that sympathetic stimulation of β-adrenergic receptors in osteoblasts increases bone vascular density, adhesion of metastatic cancer cells to blood vessels, and their colonization of the bone microenvironment, whereas β-blockade prevented these events in mice with high endogenous sympathetic activity. These findings in preclinical models, along with clinical data from breast cancer patients receiving β-blockers, support the pathophysiological role of excess sympathetic nervous system activity in the formation of bone metastases, and the potential of commonly used, safe, and low-cost β-blockers as adjuvant therapy to improve the prognosis of bone metastases.

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Prognostic and Predictive Impact of Beta-2 Adrenergic Receptor Expression in HER2-Positive Breast Cancer

Cited by 15 publications

References 41 publications

Beta-blockers in early-stage breast cancer: a systematic review and meta-analysis

Beta-blockers in early-stage breast cancer: a systematic review and meta-analysis

ADRB2 is a potential protective gene in breast cancer by regulating tumor immune microenvironment

Mechanisms Supporting the Use of Beta-Blockers for the Management of Breast Cancer Bone Metastasis

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