Beta Blockers – Ovarian Cancer
At a recent meeting of the American Society of Gynecologic Oncology in Los Angeles, CA., Anil Sood, MD, and colleagues from the MD Anderson Cancer Center in Houston, reported that patients with advanced ovarian cancer had significantly better survival if they took beta blockers.
In the past few years, more than a dozen studies have suggested that beta blockers hold substantial potential for therapeutical interventions in cancer.
Another recent study also indicates that a combination of beta-adrenergic antagonist and cyclooxygenase-2 inhibitor improves survival rates in murine models of postoperative metastasis. All these studies are based on the concept that catecholamines (CAs) through stimulation of beta-adrenoreceptors (ADRs) are involved in tumor development and/or tumor-related immunosuppression.
Catecholamines, the end products of the sympathetic nervous system, are major components of the autonomic nervous system and the peripheral stress system. It appears that CAs are able to affect tumor cells directly – through effects on tumor growth, angiogenesis, and migration or invasion, or alternatively, they may affect tumor growth, indirectly – through effects on the immune system (for example, through a multi-level immunosuppression).
The studies mentioned above indicate that the beta-ADRs antagonists, also known as beta blockers might exert beneficial effects by blocking beta-ADR-mediated signaling pathways involved in these processes.
Interestingly, and along these lines, new research indicates that high tumor norepinephrine (noradrenaline) levels correlate with the tumor grade and stage, and that low social support and depression are associated with elevated intratumoral CAs in ovarian cancer patients (Lutgendorf SK et al., Brain Behav Immun, 2009, 2011). Also, CAs increase the expression of the potent pro-angiogenic cytokine interleukin 6 in ovarian carcinoma cells (Nilsson MB et al., J Biol Chem, 2007). Moreover, human ovarian cancer cells exposed to CAs exhibit lower levels of anoikis, the process by which cells enter apoptosis (Sood AK et al., J Clin Invest, 2010).
In the American Society of Gynecologic Oncology meeting’s report by Anil Sood et al., the multicenter retrospective study identified patients with stage III or IV ovarian cancer and compared records of patients who had been treated or not with beta blockers.
The analysis involved 1,425 patients, including 269 patients whose records documented the use of beta blockers. Of note, the survival difference more than doubled in the subgroup of patients treated with nonselective beta blockers (see below – Updates – for the results of this multicenter study, published in Cancer in 2015).
Updates
A 2015 multicenter study published in Cancer was based on a multi-institution retrospective chart review on epithelial ovarian, primary peritoneal or fallopian tube cancers (collectively, EOC) patients. These patients were diagnosed and treated with at least one cycle of platinum based doublet chemotherapy, at the University of Texas MD Anderson Cancer Center, Washington University School of Medicine, Mayo Clinic, and Mercy Medical Center.
According to this study, patients with epithelial ovarian cancer who took non-selective beta blockers (NSBBs) during chemotherapy had significantly improved overall survival (OS) than those who did not.
The ability to show improved survival using nonselective agents, which inhibit a specific stress pathway, is the culmination of years of research into ovarian cancer biology and pathogenesis said senior author Anil Sood, MD. Sood is a professor in gynecologic medical oncology and cancer biology at University of Texas MD Anderson Cancer Center in Houston.
According to Sood, most of the patients in this retrospective study were taking the NSBBs for hypertension or other cardiac conditions. Ongoing research will clarify whether NSBBs can improve outcomes of ovarian cancer in patients without cardiac abnormalities and identify the group of patients that would benefit from such therapies based on biomarker analysis.
A 2016 systematic review identified six clinical studies showing inconsistent results with respect to the administration of beta blockers and disease course. The 13 preclinical studies identified showed almost without exception both that catecholamines had detrimental effects on tumour progression.
Overall the available evidence does not justify the use of beta blockers in clinical practice for ovarian carcinoma at the present time. Preclinical research findings are however very impressive. They not only form an important basis for the development of future clinical studies but also, through revealing new pathomechanisms.
A 2016 a multi-center retrospective study in women who underwent primary cytoreductive surgery for ovarian cancer, showed an association between perioperative β blocker use and longer overall survival in patients undergoing primary ovarian cancer cytoreductive surgery. Out of 185 eligible patients, 70 received β blockers and 115 underwent cytoreductive surgery without perioperative β blockers.
A 2018 nationwide population-based cohort study, beta blockers (BBs) use was associated with better survival outcomes in ovarian cancer in cases of long term duration of use, in older patients, and in cardiovascular and/or other underlying disease. Among 866 eligible patients, 206 (23.8%) were BB users and 660 (76.2%) were non-users. Among the 206 BB users, 151 (73.3%) were non-selective beta blocker (NSBB) users.
Of note, longer duration of BB medication (≥1 year) was associated with better survival outcome in patients with ovarian cancer regardless of BB type. The authors also discussed that small cohorts in single retrospective center studies with different approaches, patient characteristics, and confounders between the series may have been obstacles to elucidation of the clinical impact of BBs in ovarian cancer.
A 2019 population-based study found a significant increase in mortality associated with post-diagnostic β-blocker use. This association remained similar in dose–response analyses, in subgroup analyses and in sensitivity analyses. Thus, β-blocker use was associated with decreased overall- and ovarian cancer-specific survival. This decreased in survival was observed for selective and non-selective β-blocker users.
A 2020 a retrospective cohort study reviewing charts of women who underwent primary or interval cytoreduction for stage IIIC and IV epithelial ovarian cancer. Of note, in this study 105 women (19.7%) on a beta-blocker of whom 94 (90%) were on a cardioselective beta-blocker. In this retrospective study, the authors report that patients identified as being on a beta-blocker at the time of surgery had worse overall survival and greater risk of death when compared to those patients not on beta-blockers.
A large 2023 population-based study assessed whether beta-blocker (BB) use at the time of primary ovarian cancer surgery was associated with improved survival. In this study a population-based cohort of 3,844 Australian women age 50 years or older with a history of cardiovascular conditions who underwent surgery for EOC was followed for survival outcomes.
Women with cardiovascular conditions (CVCs) and ovarian cancer had better 2-year survival if they received a nonselective beta blocker (NSBB) at or around the time of cancer surgery. Two-year postoperative survival was 80% in the patients who received NSBBs versus 69% for those who did not receive NSBBs. The difference represented a 53% reduction in the hazard ratio for all-cause mortality. The NSBB subgroup also had better cancer-specific survival (CSS). The survival benefit was no longer apparent at 8 years.
The beneficial effects on overall survival (OS) and CSS did not apply to women who received cardioselective beta blockers (SBB), reported Susan J. Jordan, PhD, of the University of Queensland School of Public Health in Herston, Australia, and colleagues. The findings add to a growing body of evidence that NSBBs may improve outcomes in ovarian cancer, said Anil Sood, MD, of the MD Anderson Cancer Center in Houston. Sood, who was not involved in the current study. “We proposed a while back that it’s important to look at the subtypes of beta blockers that are used, selective versus nonselective,” Sood told MedPage Today.
A 2023 study, published in the May issue of Brain, Behavior, and Immunity indicates that the combined therapy of propranolol (PRO, nonselective beta blocker) and programmed death-ligand 1 (PD-L1) inhibitor decreased metastasis and improved anti-tumour immunity in both in vitro and in vivo epithelial ovarian cancer (EOC) models.
Of note, the Programmed death-1 (PD-1) is a cell surface receptor which is involved in regulating T cell exhaustion. PD-1 binds to its ligand, programmed death-ligand 1 (PD-L1), activating downstream signalling pathways and inhibiting T cell activation. In this study PRO showed a modulation of the cancer immune response by decreasing IFN-γ production and, in turn, IFN-γ-mediated PD-L1 overexpression. The combined therapy of PRO and PD-(L)1 inhibitor decreased metastasis and improved anti-tumour immunity offering a promising new therapy.
