Beta-blockers – safe and inexpensive drugs used for 4 decades in the management of cardiovascular disease – have shown surprising promise in inhibiting breast cancer progression and metastasis.
Two retrospective observational studies, published May 31 in Journal of Clinical Oncology, offer the latest evidence that the drugs, which have a role in neuroendocrine signaling pathways, lower the risk of recurrence, metastasis, and cancer-specific mortality.
In an editorial comment (doi:10.1200/JCO.2011.35.8820) accompanying the articles, Dr. Patricia A. Ganz and Steven W. Cole, Ph.D., both of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, wrote that the findings raised "the intriguing possibility" that these and other agents targeted to other diseases might provide "previously unappreciated opportunities for therapeutic control of disease progression, metastasis, and disease recurrence."
Because of this, they argued, future clinical treatment trials should "endeavor to collect prospective data on relevant medication exposures, weight and weight gain, comorbid conditions, and behaviors that have the potential to influence the microenvironment of the tumor, as these may be potent mediators of prognosis and survival, and may or may not be effectively accounted for in randomization."
In both studies, women with breast cancer prescribed beta-blockers for hypertension and other cardiovascular conditions were compared with women not taking the drugs.
For the first study (doi:10.1200/JCO.2010.33.5422), Thomas I. Barron, Ph.D., of Trinity College Dublin and his colleagues used linked data from an Irish national tumor registry and a pharmacy database to set up a case-control comparison of women prescribed the beta-blockers propranolol (n = 70) or atenolol (n = 525) in the year before and after their breast cancer diagnoses. These women were matched 1:2 to 4,738 women not prescribed beta-blockers, with matching inclusive of age, socioeconomic status, tumor grade and stage, and comorbidities.
After a median follow-up period of 3.5 years for the propranolol group and controls and slightly less than 3 years for the atenolol group and controls, the investigators found significant reductions in tumor size and nodal or metastatic distribution for the propranolol users, but not for the atenolol users. The cumulative probability of breast cancer–specific mortality was significantly lower among propranolol users (HR, 0.19). Propranolol users were also significantly less likely to present with a T4 (OR, 0.24) or N2/N3/M1 (OR, 0.20) tumor compared with matched controls. However, the atenolol group saw neither a significant reduction in breast-cancer specific mortality nor a difference in T4 or N2/N3/M1 tumor incidence from the matched controls.
In the second study (doi:10.1200/JCO.2010.33.4441), Dr. Amal Melhem-Bertrandt of the M.D. Anderson Cancer Center at the University of Texas, Houston, and colleagues identified 1,413 patients treated for breast cancer in a 12-year period, comparing those with (n = 102) and without (n = 1,311) concurrent beta-blocker exposure for a pathologic complete response, relapse-free survival, and overall survival. Mean follow-up was 55 months in the beta-blocker group and 63 months in the nonuser group.
The investigators saw no difference in pathologic response for those taking beta-blockers; however, after adjustment for variables including age, race, and tumor grade, women on beta-blockers showed significantly greater relapse-free survival (HR, 0.52; P = .015) and a trend toward greater overall survival that did not reach statistical significance (HR, 0.64; P = .09).
In a triple-negative subgroup (n = 377), the investigators found significant effects for beta-blocker use on relapse-free (HR, 0.30; P = .03) but not overall survival (HR, 0.35; P = .05) after adjustment.
In their editorial, Dr. Ganz and Dr. Cole noted that the findings from the second study, in which most of the beta-blockers were the beta-1–selective agents metoprolol (42% of patients) followed by atenolol (37%), would seem to contradict Dr. Barron and his colleagues’ findings, in which only propranolol, which inhibits both beta 1 and beta 2, had a significant effect. However, they wrote, "Neither metoprolol or atenolol is totally beta-1 specific; both partially inhibit beta-2–adrenergic receptors as well."
The editorialists noted that the new findings build on recent animal work indicating that beta-adrenergic receptors affect breast tumor growth and metastasis, and also on a 2010 U.K. retrospective study (n = 466) that was the first to look at a variety of antihypertensive agents in women with breast cancer. It found that women treated simultaneously with beta-blockers had a 57% reduced risk of metastasis compared with breast cancer patients receiving either other types of antihypertensive drugs or no antihypertensive drugs. Women on beta-blockers also saw 71% less cancer-specific mortality after 10 years (Oncotarget 2010; 1: 628-38).
"Beta-adrenergic signaling appears to have little effect on the biologic processes involved in breast cancer initiation, but more strongly affects the biologic processes involved in the subsequent progression and metastasis of incipient tumors. Given these results from the laboratory, and the clinical results from three recent retrospective reports suggesting the potential to limit recurrence of incident tumors, perhaps it is time to consider proof-of-concept trials testing the value of [beta-blockers] in the setting of breast cancer," Dr. Ganz and Dr. Cole wrote.