Clinical impact of selective and nonselective beta‐blockers on survival in patients with ovarian cancer

Abstract

BACKGROUND Preclinical evidence suggests that sustained adrenergic activation can promote ovarian cancer growth and metastasis. We examined the impact of beta-adrenergic blockade on clinical outcome of women with epithelial ovarian, primary peritoneal or fallopian tube cancers (collectively, EOC). METHODS A multicenter review of 1,425 women with histopathologically confirmed EOC was performed. Comparisons were made between patients with documented beta blocker use during chemotherapy and those without beta blocker use. RESULTS The median age of patients in this study was 63 years (range, 21–93 years). The sample included 269 patients who received beta blockers. Of those, 193 (71.7%) were receiving beta-1 adrenergic receptor (ADRB1) selective agents, and the remaining patients were receiving non-selective beta antagonists. The primary indication for beta blocker use was hypertension but also included arrhythmia and post-myocardial infarction management. For patients receiving any beta blocker, the median overall survival (OS) was 47.8 months versus42 months (P = 0.04) for non-users. The median OS based on beta blocker receptor selectivity was 94.9 months for those receiving non-selective beta blockers versus 38 months for those receiving ADRB1 selective agents (P < 0.001). Hypertension was associated with decreased OS compared to no hypertension across all groups. However, even in patients with hypertension, users of a non-selective beta blocker had a longer median OS than non-users observed (38.2 vs 90 months, P < 0.001). CONCLUSION Use of non-selective beta blockers in epithelial ovarian cancer patients was associated with longer OS. These findings may have implications for new therapeutic approaches.

Sympathetic nervous system regulation of the tumour microenvironment

“…Consistent with that concept, several observational epidemiologic studies have documented associations between β-blocker exposure and reduced progression of prostate 47,48,104 , breast 39–41,45 , lung 44,105 , and ovarian cancer 106,107 , as well as malignant melanoma 42,43,46 . However, the epidemiological literature is also inconsistent, and some studies fail to find any evidence of a protective effect (likely due to methodological variations considered below).…”

“…These issues include the selection of optimal pharmacologic agents (for example, non-selective antagonists that block β 2 receptors — such as propranolol — are likely to be more effective than the β 1 -selective agents more commonly used in cardiology) 14,35,40,53,54,107,111 ; optimal disease settings (e.g., for reasons that are not yet understood mechanistically, some pharmaco-epidemiologic studies have found that β-antagonists are associated with greater protective effects on triple negative breast tumours than on tumours that express oestrogen receptor (ER), progesterone receptor (PR), or HER2 41,45 ), and optimal intervention timing and duration. For example, experimental models suggest that initiating β-antagonists prior to surgery may reduce SNS-mediated promotion of peri-surgical metastasis 112,113 .…”

β-Adrenoceptor Blockade for Infantile Hemangioma Therapy: Do β₃-Adrenoceptors Play a Role?

“…Notably, Watkins et al [99] showed that nonselective β-adrenoceptor antagonist therapies seemed to be associated with a longer overall survival in patients with ovarian cancer compared to those receiving selective β 1 -adrenoceptor antagonist therapies. Similarly, Montoya et al [100] demonstrated that selective β 1 -adrenoceptor antagonist therapies were less effective against proliferation of tumors than nonselective ones.…”

Beta‐blockers in epithelial ovarian cancer

“…1 The authors and the editorialists 2 have proposed multiple mechanisms such as antiapoptotic, antimetastatic, antiangiogenic, antistress, and proimmunity mechanisms. Increased drug exposure by suppression of the drug efflux pump P-glycoprotein (MDR1/ABCB1), a known property of propranolol, 3 is another possibility.…”

“…However, it is not possible to narrow down the principal mechanism(s) due to the lack of details in the article. 1 For example, an improved response rate in those patients administered neoadjuvant chemotherapy would suggest an effect on drug efficacy (increased exposure, antiangiogenic), whereas an improved disease-free survival rate would be more in favor of an effect (possibly immunological) on quiescent cancer stem cells.…”