Use of beta-blockers in patients with ductal carcinoma in situ and risk of invasive breast cancer recurrence: a Swedish retrospective cohort study

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of precancerous lesions. The incidence of DCIS has dramatically increased due to screening mammography; however, it varies between countries. In Sweden, DCIS comprises approximately 15 percent of all newly screening detected breast cancers [1]. The goal of therapy for DCIS is to prevent the development of invasive breast cancer. The majority of DCIS patients never progress to invasive breast cancer [2, 3]. Nevertheless, due to the uncertainty over which DCIS patients will progress, almost all patients are currently treated by surgery with or without adjuvant radiotherapy, whereas the use of endocrine treatment is still controversial. The consequence is a considerable overtreatment, while at the same time, it is noteworthy that regardless of treatment modalities, a small subgroup of patients will still experience invasive recurrent disease [4]. All treatment modalities are associated with a non-negligible risk of overtreatment and exposure to adverse long-lasting side-effects affecting the patient’s quality of life [5]. Therefore, more effective and less toxic treatment options are highly warranted. The repurposing of drugs, which have proven low toxicity and well tolerability in other medical indications, emerges as an attractive option particularly for this patient group.

Beta-adrenergic receptor antagonists, commonly known as “beta-blockers”, are widely used to treat cardiac and respiratory ailments. Beta-blockers represent a potentially promising group of drugs with a distinctive mode of action, affecting multiple aspects of tumor progression [6]. Moreover, beta-adrenergic receptors are expressed by tumor cells as well as cells of the tumor microenvironment [7], albeit with high intra- and intertumoral heterogeneity [8]. Beta-adrenergic receptors are G-protein coupled receptors and mediate the signaling cascade of catecholamine hormones, which are produced in the context of stress responses. In preclinical models, beta-adrenergic signaling is described to induce the upregulated expression of metastasis-associated genes and downregulate expression of genes facilitating anti-tumor immune responses. These processes could be successfully blocked through administration of non-selective beta-blockers, suggesting a potential pharmacological strategy for prevention of cancer metastases [9‐11]. Moreover, some of these studies provided evidence of preclinical activity of beta-blockers in breast cancer models specifically [12‐14].

To date, several retrospective studies as well as two meta-analyses concerning the impact of beta-blocker exposure in breast cancer patients have revealed conflicting [9, 15‐23] findings. Of note, the majority of these studies included patients with both advanced and early disease stages without specific stratification. However, one recent meta-analysis focusing on early-stage invasive breast cancer noted a potential protective effect of beta-blockers specifically in this patient group [24]. These observations suggest that the efficacy of beta-blockers in preventing breast cancer progression is likely dependent on disease stage and might be most pronounced at early stages. Nevertheless, there is only one randomized clinical trial (phase II) that has investigated the effect of beta blocker usage in breast cancer patients. Results from this study suggest indeed that the use of preoperative propranolol reduced biomarkers of metastatic potential and improved biomarkers of cellular immune response [25]. According to clinicaltrials.gov there are currently two phase II studies in preparation, where propranolol is combined with immunotherapy in advanced or metastatic triple negative breast cancer, but not yet recruiting.

In the light of current evidence, suggesting potential anti-tumor effects of beta-blockers particularly at early breast cancer stages, we hypothesize that exposure to beta-blockers in patients with DCIS is associated with clinical benefits. Hence, the aim of our study was to investigate the potential impact of beta-blocker exposure on risk for invasive breast cancer recurrence in women diagnosed with pure DCIS.

This large population-based observational study suggests a potential clinical benefit of beta-blocker exposure on invasive progression in DCIS. The dose-dependent tendency emphasizes the importance of considering the duration and intensity of beta-blocker exposure. Our data align with prior experimental and clinical evidence highlighting the anti-tumor effects of beta-blockers, but now for the first time provide support that already the progression of DCIS to invasive breast might be inhibited by beta-blocker usage.

One of our main findings was that the cumulative exposure to beta-blockers did appear to reduce the risk of invasive breast cancer in a dose-dependent manner, though the associations did not reach statistical significance. Further studies are clearly warranted. While the strengths of our study are the large number of included patients and reliable data including detailed prescription information, several limitations should be acknowledged.

First, the low number of events of invasive progression necessarily limits the power of the applied statistical models. The low number of events of invasive progression is intrinsic for DCIS with its generally very favorable prognosis; however, it might also partly be explained by underreporting of recurrences in two of the three healthcare regions with data included in BCBaSe 2.0 [30]. Wadsten et al. reported a 10% 10-year general recurrence rate (invasive and in situ) after DCIS diagnosis in Uppsala-Örebro 1992–2012, and a validation revealed that only 65% had been registered [31]. Thus, an approximately 13% 10-year recurrence rate for DCIS would probably be more accurate, which is in line with previous randomized trials [1]. Because half of recurrences of DCIS are invasive, the estimated number of invasive events in the present study would be 5–6% opposed to the 1.9% that we report. Invasive recurrences after surgery for pure DCIS occur over a longer time period of up to 20 years post diagnosis and treatment, thus the median follow-up of 8.7 years in our study is still relatively short [32]. Of note, while BCBaSe 2.0 covers three regions representing 60% of Sweden, it doesn't include the entire country. However, 60% has a similar distribution of urban and rural areas and similar socioeconomic status compared to rest 40% (https://​www.​scb.​se/​en/​), implying minimal negative impact on our results with access to data from all Swedish regions.

Second, in consequence of the low number of invasive events, only a small number of adjustment covariates were selected, those deemed to be the most important confounders using subject matter expertise, in order to avoid over-fitting of the statistical model, thereby compromising its generalizability. Some patient- and tumor-related characteristics differed between patients who were exposed to beta-blockers and those who were not. On average, patients exposed to beta-blockers were older with a lower proportion of grade III DCIS. Although we used multivariable adjustment, it is difficult to rule out confounder imbalances or omitted variable bias. Furthermore, our study focused on beta-blocker exposure post DCIS diagnosis without accounting for exposure to beta-blockers prior to DCIS diagnosis. This pre-diagnostic beta-blocker usage might have impacted the general tumor characteristics and aggressiveness. This question would be of interest to address in future follow-up studies. Finally, we were unable to investigate the potential impact per category and type of beta-blockers due to the limited number of events.

Despite these limitations, it should be highlighted that, to the best of our knowledge, this is the first study to investigate beta-blockers usage in DCIS. Our study is hypothesis-generating and the results are in support of clinical evidence on the potential impact of beta-blockers on disease progression in patients with early breast cancer [24], considering that DCIS is classified as stage 0 breast cancer, namely the earliest stage of breast cancer.

In the era of precision medicine, future in depth tissue analyses are necessary to identify the cellular presence of the drug target as a prerequisite of successful pharmacological intervention. To date, tissue-based analyses of beta-adrenergic receptors in breast cancer only analyzed few patient samples, predominantly of triple negative cases, showing that actually only a small subset of tumor cells is positive for beta-adrenergic expression [33]. This observation indicates that the anti-cancer effects of beta-blocker are likely not due to direct blockage of adrenergic receptors on tumor cells but rather to an inhibition of adrenergic signaling within the tumor microenvironment. Furthermore, these controversies highlight the importance of spatial tissue-based analyses as complement to functional preclinical studies using cancer models. In the optimal scenario, a comparison of histopathological features of diagnostic DCIS tissue samples from patients who were taking beta-blockers at time of diagnosis with those who did not, are strongly motivated. Such data could provide tissue-based evidence on the direct impact of beta-blocker on the underlying biology of breast cancer progression. Interestingly, propranolol may have the ability to revert adrenergic stress mediated immunosuppression [34]. Thus, it may be possible that beta-blocker exposure can enhance the abscopal response following radiation. Given the described effects of adrenergic stress on immune response, future efforts should also aim to investigate potential interactions between beta-blocker exposure and adjuvant radiotherapy. We therefore suggest follow-up studies on DCIS, investigating specifically the efficiency of radiotherapy in the context of beta-blocker exposure.

In conclusion, we present the first study to investigate the potential association of exposure to beta-blockers in patients with pure DCIS and risk of progression to invasive breast cancer. Despite the inherent limitations associated with the observational nature of the study, our findings offer actually new insights of potential clinical importance for DCIS with a beta-blocker dose–response relationship concerning risk for invasive breast cancer recurrence. We hope this work motivates follow-up studies in carefully selected DCIS cohorts with long clinical follow-up. Ideally, such studies should be designed to allow the investigation of specific DCIS subgroups such as high-risk DCIS of different molecular subtypes [35] or DCIS with high tumor infiltrating lymphocytes counts [36] as well as the effect of beta-blocker on radiotherapy efficacy [37].