I read with interest the article by Zheng and colleagues (1) showing that some beta-blockers increase the risk of breast cancer and that this effect depends on the dosage as well as the affinity of the beta-blockers for beta-adrenergic receptor subtypes. While the authors found no effect of propranolol treatment on breast cancer incidence, accumulated data suggest that propranolol may not increase, but instead decrease cancer risk (2). It has been shown that this cancer risk-reducing effect of propranolol is mediated via a blockade of beta2-adrenergic signaling (3). However, it cannot be excluded that a reduction of cancer incidence in patients treated by propranolol reflects a suppressive effect of this beta-blocker on already present dormant cancer resulting from propranolol-mediated inhibition of angiogenesis and other cancer progression–related processes.
The reason why Zheng and colleagues (1) did not find reduced cancer incidence in patients treated with propranolol may be multifactorial. The available data indicate that the inhibitory effect of propranolol on cancer induction depends on the dosage, duration of treatment, cancer type and subtype, psychosocial characteristics of the patient, and other factors. In support of this, the findings of Zheng and colleagues (1) indicate a U-shaped effect of propranolol on cancer incidence, as the HR was lowest in patients treated with 25 to 50 mg of propranolol per day compared with patients treated with lower or higher doses. Interestingly, a similar U-shaped inhibitory effect of propranolol on tumor growth was observed in a mouse model of melanoma (4). These findings, together with published data, indicate that propranolol-related reduction of cancer incidence is a complex phenomenon that could reflect its effects on cancer micro- and macroenvironment, including a steal effect on tumor perfusion.
One factor that has potentially influenced interpretation of the authors' data on propranolol's effect on breast cancer incidence might be the control group of probands used. It is known that hypertension itself can increase the risk of breast cancer (5) and, therefore, the control group used, which included normotensive individuals, may impair interpretation of propranolol's effect on cancer risk.
Further studies are needed to determine whether propranolol reduces the risk of breast cancer and risk of other types of cancers. If propranolol's suppressive effect on cancer induction is confirmed, it will then be necessary to consider whether or not it is more appropriate to treat hypertensive patients with an increased cancer risk, preferentially with propranolol, if possible.
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