BERKELEY, CA (UroToday.com) - In a Norwegian cohort, we found that β-blocker use was associated with prostate cancer survival. A five-fold reduction in prostate cancer specific mortality was observed for β-blocker users on androgen deprivation therapy (ADT). This study was recently was recently published in The Prostate.[1]
Why did we perform this study?
In recent years, β-blockers have been gaining momentum as possible treatment agents in cancer. For instance, use of β–blockers has earlier been reported to be associated with reduced disease progression and mortality in breast cancer and malignant melanoma. Specifically, β-blockers were shown to be associated with less aggressive disease at time of diagnosis, longer relapse-free survival and to prevent tumor recurrence, and distant metastasis and cancer-specific mortality in breast cancer patients.[2, 3, 4] As for malignant melanoma, reduced risk of disease progression and improved survival was observed in patients with thick malignant melanoma and malignant melanoma, respectively.[5, 6] Much research is conducted aiming at overcoming the clinical issue of castration- independent prostate cancer. Besides new ways of targeting the androgen receptor, focus is on alternative pathways contributing to both prostate cancer progression and treatment resistance. In different cancer cell-line studies, β–adrenergic signaling has been shown to be involved in several important processes such as proliferation and apoptosis resistance, cell motility, and angiogenesis.[7] In prostate cancer cell-line and xenograft models, the beta adrenergic receptor signaling pathway has been shown to contribute to important processes such as activation of the androgen receptor[8] and development of stress-induced metastasis.[9]
What did we do, and how?
We had access to information on the participants from the Oslo II cohort, a cohort of Norwegian men originally followed to study prognostic factors for heart disease. Patient characteristics, including use of beta blocker from this cohort study, were coupled with information from the Norwegian Cancer Registry, to identify prostate cancer cases and prognostic information from time of prostate cancer diagnosis. Mortality data was obtained from Statistics Norway.
Besides estimating the possible effect of β-blocker use on prostate cancer risk, we compared β–blocker users and non-users with regard to clinical prognostic markers at diagnosis. Finally, we analyzed the association between β–blocker use and prostate cancer specific and all-cause mortality. Prostate cancer risk and all-cause mortality were analyzed with Cox proportional hazards modeling, while prostate cancer specific mortality was assessed by competing risk-regression modeling. Final survival analyzes were adjusted for age at diagnosis, level of education, and metastasis status at diagnosis. Clinical prognostic markers at diagnosis were compared using Student t test, the Wilcoxon-Mann-Whitney U test, and the Pearson’s chi-square test, where applicable.
Main findings
We found no effect of β–blocker use on prostate cancer risk or the proportion of patients presenting with aggressive disease (high Gleason score, PSA levels, or clinical T-stage, and/or metastasis at diagnosis).
When looking into prostate cancer specific survival, we saw no effect in the patient group as a whole (sub-hazard ratio, SHR = 0.55; 95% confidence interval (CI) 0.24-1.26, p-value 0.16). However, when stratifying patients according to treatment plan at diagnosis, there was a statistically significant reduction in prostate cancer specific mortality among β-blocker users when planned to receive ADT (SHR= 0.14, 95% CI = 0.02-0.85, p= 0.032). The rationale for this stratification was an aim to stratify patients according to disease aggressiveness; given the lack of complete information regarding prognostic markers, the planned use of ADT was considered a potential substitute.
Given the low rate of prostate cancer mortality during follow-up for patients not planned to receive ADT (10.4%), there is a possibility that these patients also would benefit from β–blocker use, if length of follow-up is increased.
Limitations and future investigations
The main limitations in this study were small cohort size and the lack of ability to adjust for important clinical markers in the survival analyses. Also, given the observational nature of this study, we cannot make any statements as to whether the association between β-blocker use and prostate cancer specific mortality in the ADT group is causal. It is likely that there are several fundamental differences between the groups compared in this study, and we have not been able to control for potentially important confounders.
After performing this study, it became clear that larger epidemiological studies were needed to look into the use of β–blockers in high-risk patients -- both treated and not treated with ADT -- to establish whether the potential effects of β–blockers are dependent on concurrent ADT. Also, the potential confounding from important prognostic markers such as Gleason, PSA, and T-stage needed to be assessed.
On this notion, we will take the opportunity to mention a recent publication by our group where the main limitations mentioned have been addressed. In the recent study “Association between use of β-blockers and prostate cancer-specific survival: A cohort study of 3561 prostate cancer patients with high-risk or metastatic disease,”[10] we again found that β-blocker use among men with high-risk or metastatic disease was associated with a lower prostate cancer specific mortality. After adjusting for prognostic information recorded at the Cancer Registry of Norway, we found a SHR of 0.79 (95% CI 0.68-0.91; p-value 0.001). ADT proved not to be a prerequisite for the observed association.
Potential implications for patients, clinicians and scientists
Given that the findings of the current study are reproducible, and further research establishes a causal relationship between the use of β–blockers and prostate cancer progression and survival, β–blockers could be a valuable tool for urologists and patients as an adjuvant to ADT for high-risk patients. β– blockers may also have a potential as a low-threshold treatment option for patients presenting with moderate aggressive disease.
References:
- Grytli HH, Fagerland MW, Fossa SD, Tasken KA, Haheim LL. Use of beta-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy. Prostate 2012.
- Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta blockers and breast cancer mortality: a population- based study. J Clin Oncol 2011; 29:2635-2644.
- Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F, Sood AK, Conzen SD, Hortobagyi GN, Gonzalez-Angulo AM. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol 2011; 29:2645-2652.
- Powe DG, Voss MJ, Zanker KS, Habashy HO, Green AR, Ellis IO, Entschladen F. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget 2010; 1:628-638.
- De Giorgi V, Grazzini M, Gandini S, Benemei S, Lotti T, Marchionni N, Geppetti P. Treatment with beta-blockers and reduced disease progression in patients with thick melanoma. Arch Intern Med 2011; 171:779-781.
- Lemeshow S, Sorensen HT, Phillips G, Yang EV, Antonsen S, Riis AH, Lesinski GB, Jackson R, Glaser R. beta-Blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol Biomarkers Prev 2011; 20:2273-2279.
- Cole SW, Sood AK. Molecular pathways: beta-adrenergic signaling in cancer. Clin Cancer Res 2012; 18:1201-1206.
- Kasbohm EA, Guo R, Yowell CW, Bagchi G, Kelly P, Arora P, Casey PJ, Daaka Y. Androgen receptor activation by G(s) signaling in prostate cancer cells. J Biol Chem 2005; 280:11583-11589.
- Palm D, Lang K, Niggemann B, Drell TL, Masur K, Zaenker KS, Entschladen F. The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers. Int J Cancer 2006; 118:2744-2749.
- Grytli HH, Fagerland MW, Fossa SD, Tasken KA. Association Between Use of beta-Blockers and Prostate Cancer-Specific Survival: A Cohort Study of 3561 Prostate Cancer Patients with High-Risk or Metastatic Disease. Eur Urol 2013.
Written by:
Helene Hartvedt Grytli and Kristin Austlid Taskén as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Institute of Cancer Reseach, The Radium Hospital, Oslo University Hospital, Norway
More Information about Beyond the Abstract