Because β-adrenergic signaling modulates tumor progression via multiple downstream molecular pathways, β antagonists may provide a highly-leveraged adjuvant therapy strategy with pleiotropic impacts on the primary tumor, its surrounding microenvironment, and metastatic target sites. The biological appeal of this concept is enhanced by the widespread availability of safe, inexpensive, and well-understood β antagonists (4
). However, several issues need to be resolved in order to establish the translational potential of β-blockers as adjuvant therapy for cancer.
The most pressing need involves direct assessment of β antagonists’ clinical efficacy in randomized Phase II trials. Conflicting results from currently available non-randomized observational studies (11
) suggest that further observational studies are not likely to definitively establish β-blockers’ clinical utility in cancer due to methodologic difficulties such as, 1.) confounding by indication (e.g., the primary historical indication for β-blockade, cardiovascular disease, shares common pathophysiologic drivers with cancer progression such as smoking, adiposity, and systemic inflammation), 2.) confounding with other pharmacologic exposures that may affect cancer progression (e.g., ACE inhibitors), 3.) absence of information on influential risk factors and treatment parameters (e.g., cardiovascular datasets provide limited information on cancer progression/mortality risk factors, and cancer-related datasets provide limited measures of β-blocker agents/utilization), and, 4.) time- and practice pattern-related confounding of cancer survival trends with β-blocker utilization trends (particularly for non-selective β-antagonists which are most likely to be efficacious as outlined below). Randomized controlled trials provide the only certain way to overcome such biases and definitively assess β-antagonists’ protective effects on clinical cancer progression. The availability of pre-clinical data and approved, safe, and inexpensive β-antagonists with well-understood pharmacology and minimal side-effects provide a favorable risk/benefit profile for initial Phase II proof-of-concept trials in clinical oncology.
Clinical trial initiation will require selection of optimal disease settings and treatment regimens for assessing clinical impact. Preclinical laboratory models and human pharmaco-epidemiologic studies both suggest that β-antagonists are likely to be most effective in inhibiting the micro-metastatic spread of early-stage tumors, as opposed to chemoprevention of new tumors or reduction of advanced tumor burdens. As such, it makes sense to target tumor types such as breast or prostate cancer that are routinely detected at early stage, metastasize via inflammatory and circulatory mechanisms already linked to β-adrenergic signaling, and are sufficiently prevalent to provide high-power detection of group differences amidst the low progression/recurrence rates characteristic of early stage disease. In the context of breast cancer, some epidemiologic data suggest that β-antagonists may be particularly valuable in the context of ER-/PR-/Her2- “triple negative breast cancer” (TNBC) (13
). Initial trials should also target disease settings such as ovarian carcinoma and malignant melanoma for which extensive pre-clinical or pharmaco-epidemiologic data already exist and suggest a significant therapeutic potential.
Optimal β-antagonist regimens also need to be defined, including the specific agent, the timing of its initiation, and the duration of treatment. Pharmacologic dissection of pre-clinical models of ovarian, breast, and prostate cancer find SNS effects to be mediated predominately byβ2
- or β3
-adrenergic receptors (16
). Non-selective β-antagonists such as Propranolol and Nadolol have been highly active in these model systems, but the more commonly prescribed β1
-selective agents such as Atenolol generally failed to inhibit SNS effects on tumor progression. Similar effects have been observed in pharmaco-epidemiologic analyses of breast cancer, with non-selective β-antagonists showing comparable (13
) or greater protective effects than β1
-selective agents (12
). Given these observations, the use of non-selective antagonists such as Propranolol would provide the broadest biological leverage and minimize the risk of missing an active β-receptor target. CNS adrenergic receptors appear to play a role in some protective effects of β-antagonists, suggesting that CNS-penetrant agents such as Propranolol may be preferred over agents that do not cross the blood-brain-barrier such as Nadolol. Experimental data showing that β-antagonist inhibition of surgery-induced metastasis (24
) suggest initiation prior to surgery (i.e., neo-adjuvant) and perhaps in combination with an NSAID. The duration of β-blockade required to reduce tumor progression/recurrence rates has not been determined, but long-term β-blockade has routinely been used in cardiology and would seem to provide an appropriate starting point in oncology.
β-blocker treatment could potentially be targeted based on tumor characteristics such as the expression of β-receptors (57
) or their downstream target genes (48
), or based on patient characteristics such as stress or anxiety levels (9
). However, there is currently no evidence that any patient- or tumor-level characteristics affect β-blocker efficacy in clinical oncology. As such, initial RCTs should target the general disease settings in which β-blockade is likely to be most effective (as outlined above) and collect additional patient- and tumor-specific data to support responder analyses identifying predictive biomarkers of treatment efficacy. There are several reasons why tumor β-receptor expression might not provide an accurate predictive biomarker, including the fact that receptor expression does not assess the amount of SNS NE/E ligand impinging upon the receptor and potential adrenergic effects at extra-tumoral sites such as metastatic target tissues or the bone marrow hematopoietic generation of subsequently infiltrating macrophages and lymphocytes (22
Although a variety of translational parameters remain to be optimized, a growing body of pre-clinical and pharmaco-epidemiologic data suggest that β-adrenergic antagonists hold considerable promise for inhibiting the pleiotropic effects of SNS activation on tumor progression and metastasis. Over the next few years, we can expect further data expanding the range of tumor types examined, identifying additional mechanisms of β-adrenergic effects on tumor progression, and initial RCTs assessing the efficacy of β-blockade as an adjuvant therapy in clinical oncology.