This meta-analysis showed that beta-blocker use could be related to the prolonged survival of patients with HCC. To our knowledge, this is the first meta-analysis to the association between beta-blockers and OS in patients with HCC.
The effect of beta-blockers on the incidence and prognosis has been extensively reported in several cancers, including lung, breast, ovary and prostate cancers [16–20]. A retrospective study of non-small-cell lung cancer patients who received definitive radiotherapy showed that beta-blocker use was associated with improved distant metastasis-free survival (HR = 0.67), disease-free survival (HR = 0.74), and OS (HR = 0.78) . The meta-analysis of breast cancer suggested that the use of beta-blockers significantly reduced the risk of cancer death among women with breast cancer (HR = 0.50) . A cohort study of ovarian cancer reported that a long duration of beta-blocker use was associated with better OS (HR = 0.26) and disease-specific survival (HR = 0.25) . Lu et al. suggested that beta-blocker use was an independent favorable prognostic factor for CSS in a meta-analysis of prostate cancer (HR = 0.85) .
Pre-clinical studies have suggested that beta-adrenergic signaling plays a role in cancer development, including that of HCC. Wu et al. reported that beta 2-adrenergic receptor (ADR) signaling sustained HCC cell proliferation and survival through the negative regulation of autophagy . Norepinephrine/epinephrine promotes HCC cell invasion via alpha 1A- and beta 2-ADRs and prevents anoikis via beta 2-ADR . Beta 2-ADR-mediated activation of YB-1 stimulates epithelial-to-mesenchymal transition and HCC metastasis . An in vitro study including HCC cells showed that beta-ADR blockers inhibited cancer cell proliferation, invasion, and migration .
In a clinical trial of breast cancer patients, preoperative beta-blockers reduced intratumoral mesenchymal polarization and stimulated immune cell infiltration in cancer . This provided the evidence that beta-blockers could enhance the anti-tumor immune response. In addition, beta-blockers reduced the risk of HCC development in patient with cirrhosis, which is a well-known risk factor for HCC [6, 26, 27].
These preclinical and clinical findings suggest that beta-blockers have anti-tumor effects by inhibiting tumor progression and metastasis . Therefore, the better OS of beta-blocker use patients in our analysis could be related to the reduction of cancer progression linked to inhibition of beta-ADR signaling in HCC pathology.
Previous studies have suggested that beta-blockers could enhance the effect of HCC treatment (e.g., tyrosine kinase inhibitor and embolization) Boas et al. reported that beta-blockers are responsible for improving survival in HCC patients who were treated with embolization . Chang et al. suggested that the beta-blocker propranolol may have a synergistic effect with sorafenib, radiotherapy and embolization . The xenograft model with HCC cells showed that inhibition of beta 2-ADR signaling by beta-blockers led to increased autophagy, HIF1α destabilization, tumor growth suppression, and enhanced anti-tumor activity of sorafenib . Beta-blockers suppress endothelial cell proliferation and arrest tumor angiogenesis, which is one of the resistance mechanisms of chemoembolization in HCC [29–31]. In addition, VEGF-induced Src-ERK pathways in HUVECs were inhibited by beta-blockers . Therefore, beta-blocker use in HCC patients may improve the efficacy of anti-tumor treatment, potentially resulting in better survival.
This study has several limitations. First, this meta-analysis was based on retrospective studies, which could increase the risk of bias. Further, the enrolled HCC patients were not uniform between the studies in clinical situations. In addition, each study had its specific definition of ‘beta-blocker exposure’, and thus the duration and the timing of beta-blocker use were not homogeneous. However, it should be noted that the between-study heterogeneity was acceptable in this analysis (I2 < 50%). Second, beta-blockers are a wide and heterogeneous group of molecules that act as competitive and reversible antagonists of beta 2-ADRs . The class effect of beta-blockers can cause different anti-cancer effects . However, we could not analyze the effect of the type of beta-blocker because two of the three studies in this analysis investigated propranolol. Third, a dose-response meta-analysis was not performed because of the lack of relevant data. Lastly, CSS data was available in one published article and the meta-analysis for CSS was not conducted. Future studies are warranted to evaluate CSS and beta-blockers in patients with HCC.