The objective of this retrospective study was to describe the effect of beta-blocker intake on pCR rates and subsequent survival outcomes in patients with breast cancer treated with anthracycline- and taxane-based neoadjuvant chemotherapy. We found that pCR rates were not associated with beta-blocker intake. Interestingly, despite a lack of effect on pCR, RFS was longer in patients who took beta blockers. The two groups were well balanced with regard to the amount of chemotherapy delivered. The improvement in OS approached significance in the TNBC subgroup.
Beta blockers have been shown previously to improve OS, likely related to their cardioprotective effects; however, the improvement in RFS suggests a cancer-specific effect.37
Our findings are concordant with a study by Powe et al19
where 43 patients with breast cancer taking beta blockers were found to have significant reduction in breast cancer recurrence compared to a similar cohort not on beta blockers. Interestingly, although beta-blocker intake in our study was associated with better RFS when all patients were analyzed, subset analysis also showed a highly significant association between beta-blocker use and improved RFS in the TNBC subgroup, while no significant RFS differences were noted for patients with ER-positive breast cancer (C, D). This could be due to the relatively short follow-up time in this study; median follow-up was 55 months for patients on beta blockers. While this may be sufficient to detect an improvement in RFS for patients with TNBC due to shorter relapse times, this may not be sufficient for patients with ER-positive breast cancer. Another possible explanation may be related to tumor biology, whereby the presence of the ER may modulate the response to beta blockers. Furthermore, one can speculate that the lack of association between beta-blocker intake and pCR suggests an effect on the tumor metastases cascade rather than a primary effect on increasing cytotoxic sensitivity to systemic chemotherapy. It is important to point out that only pCR was analyzed in this retrospective study as a surrogate for response to therapy. Arguably, if beta blockers have cytostatic rather than cytotoxic properties, looking at pCR alone may not suffice to detect an effect on primary tumor.
These findings may also be explained in part by a recent study by Sloan et al38
linking breast cancer metastatic potential to activation of neuroendocrine pathways. Specifically, in an orthotopic mouse model of breast cancer, mice subjected to chronic stress had minimal growth of their primary breast tumor, but a significant increase in metastasis to distant tissues. These effects required β-adrenergic signaling, which increased the infiltration of macrophages into primary tumor and correlated with a pro-metastatic gene expression signature. Treatment with the β-antagonist propranolol reversed the macrophage infiltration and inhibited metastatic tumor spread. The effects of stress on distant metastasis were also inhibited by in vivo macrophage suppression using the CSF-1 receptor kinase inhibitor GW2580. CSF-1 receptor kinase is also known to be upregulated by glucocorticoids the other major effectors of the stress response.39
Interestingly, our study is consistent with previous observations that patients with TNBC have higher rates of obesity20–22
; this in turn has been linked to increased activation of the stress response pathway and disruption of the SNS and HPA axis.40
A positive correlation between stress reduction and reduction of breast cancer recurrence has also been observed in a randomized biobehavoral intervention trial of 277 patients with early-stage breast cancer.41,42
This study may be limited by its retrospective nature and subset analyses for patients with TNBC. Information regarding beta-blocker use during neoadjuvant chemotherapy was obtained by medical record review and compliance could not be assessed. Furthermore, duration of beta-blocker intake after completion of neoadjuvant therapy could not be accurately determined for all patients, in view of the variability in follow-up care. It is also possible that not all the patients receiving beta blockers were correctly identified, likely diluting any possible association. However, it is important to note that the database used for this study is prospectively maintained and survival information is updated yearly. All the patients were treated at a single institution with fairly homogenous chemotherapeutic regimens and definitive surgical and radiation treatment. Other factors that could affect breast cancer relapse may also be confounding this study. These include aspirin use, alcohol intake, dietary factors, and lack of exercise. As this is a retrospective study not all factors could be controlled for.
To our knowledge, our study provides the first clinical evidence linking the use of beta blockers to TNBC relapse. In a population with limited targeted options and early relapse risk, this potentially beneficial intervention should be studied further.43
Future trials that prospectively examine the effects of low-dose beta blockade on breast cancer recurrence with a focus on patients with TNBC are needed. The future challenges in designing such trials will mainly involve appropriate patient selection. Specifically, should trials target patients with evidence of a hyperactive SNS, such as patients with the metabolic syndrome, or should all TNBC patients be included? Appropriate beta-blocker selection will also be important.44
In our study, most of the patients were on a selective β1-ADRB, the study by Sloane et al used a nonselective beta blocker. These have the potential to efficiently inhibit all ADRBs, such as the β2 and β3 ADRBs, which are involved in adipocyte lipolysis and thermogenic activity.45,46
However, it is important to note that although beta blockers are labeled as selective or nonselective, they still have affinity for both the β1 and β-2 ADRB. The β1 and β2 receptors are very similar and absolute selectivity has not been achieved.47
Conceivably, the benefits of more broad beta blockers may be even greater than the more selective ones. Optimal dose titration in the absence of a surrogate marker (eg, blood pressure) for activity must also be addressed. As both the adrenergic and the glucocorticoid-mediated HPA axis potentiate the stress response, and both are implicated in breast cancer progression, correlative studies examining the receptors for cortisol and epinephrine in primary tumors and stromal tissue should be performed. We predict that a subset of patients with TNBC may eventually be identified that are likely to benefit most from concomitant blockade of stress physiology and more traditional antitumor therapy.