Beta Blockers Associated With Longer Survival in Ovarian Cancer

Anil Sood, MD

Anil Sood, MD

According to a recent multi-institutional retrospective study inCancer,¹patients with epithelial ovarian cancer who took non-selective beta blockers (NSBBs) during chemotherapy had significantly improved overall survival (OS) than those who did not. These findings provide clinical support for the role of sustained adrenergic activation in ovarian cancer and introduce implications for future therapeutic approaches.

“The ability to show improved survival using nonselective agents, which inhibit a specific stress pathway, is the culmination of years of research into ovarian cancer biology and pathogenesis,” said senior author Anil Sood, MD, in a recent press release.²Sood is a professor in gynecologic medical oncology and cancer biology at University of Texas MD Anderson Cancer Center in Houston.

Preclinical data shows that exposure to high levels of the stress-related hormones norepinephrine and epinephrine increases invasiveness of ovarian cancer cells, and the beta-adrenergic antagonist propanolol blocks norepinephrine-induced increase of tumor invasiveness in mice.³To clinically investigate the possible relationship between adrenergic inhibition and improved outcomes in ovarian cancer, Sood et al analyzed outcomes in 1425 women with histologically confirmed epithelial ovarian cancers (which included epithelial ovarian, primary peritoneal, and fallopian tube cancers) treated between 2000 and 2010. They compared the 269 patients who had used beta blockers during chemotherapy with the rest of the patients who had not and stratified outcomes according to beta blocker selectivity (beta-1 adrenergic receptor selective beta blocker [SBB] vs NSBB).

Patients who took any type of beta blocker had a significantly longer median OS than did nonusers (47.8 vs 42 months). Patients taking NSBBs (n = 76) had a median OS of 94.9 months. According to the researchers, this survival improvement was particularly remarkable, because the patients taking NSBBs presented with more advanced cancer, had a higher body mass index (BMI), and were more likely to be hypertensive. Hypertension and elevated BMI were associated with decreased survival in the nonusers, but the patients taking NSBBs had comparable or improved OS regardless of prognostic factors or other comorbidities.

These improvements in survival were not observed in the patients with comorbidities and taking SBBs, and the median OS among all patients taking SBBs was 38 months. According to Sood, these findings provided clinical support for previous research indicating the beta adrenergic receptor-beta-2 and 3 (ADRB2 and ADRB3, respectively) pathways targeted by the NSBBs play a greater role in the development and progression of cancer than the ADRB1 pathway targeted by the SBB.

“A substantial proportion of ovarian cancers have these adrenergic receptors, especially the beta-2 and beta-3 receptors,” said Sood. “[Future research will identify] more specific subgroups of patients that would benefit the most from beta blockers.”

Nonselective beta blockers are commonly used to treat conditions, such as heart disease, hypertension, and glaucoma, characterized by excessive activation of the sympathetic nervous system in response to stress. Sood also indicated the role of these stress-activated pathways in promoting inflammation, which contributes to tumor growth and metastasis. Therefore, he stated a multitherapeutic approach that includes NSBBs and other classes of drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), may be an effective treatment approach.

According to Sood, most of the patients in this retrospective study were taking the NSBBs for hypertension or other cardiac conditions. Ongoing research will clarify whether NSBBs can improve outcomes of ovarian cancer in patients without cardiac abnormalities and identify the group of patients that would benefit from such therapies based on biomarker analysis. According to the study authors, therapeutic potential of NSBBs include improvement of wound healing during recovery from surgery and decrease of tumor growth and metastasis when used in adjunct with chemotherapy.

“[Nonselective beta blockers] could be used as adjunctive therapies to our current standard of care therapies,” said Sood.

However, Sood indicates that understanding the role of NSBBs in ovarian cancer outcomes and possibly developing agents that specifically target the ADRB2 pathway in tumors will require a stepwise progression of feasibility studies and prospective, randomized clinical trials. Currently, MD Anderson is conducting a clinical trial to evaluate the combination of chemotherapy and propanolol on cancer biology and stress modulators in patients with recently diagnosed epithelial ovarian cancer.

Nevertheless, the authors indicate that the results of the current study provide an important foundation of clinical knowledge for the next step of clinical research.

“The stratification of patients by beta-blocker use and selectivity in this study makes it unique among all other studies examining the impact of these drugs on cancer,” said Sood.²“It also builds on the mounting evidence that beta-blockers may become a key treatment component for many patients in the future.”

References:

1. Watkins JL, Thaker PH, Nick AM, et al. Clinical impact of selective and nonselective beta-blockers on survival in patients with ovarian cancer.Cancer. 2015 Aug 24. doi: 10.1002/cncr.29392.

2. MD Anderson Cancer Center press release. Generic heart medication shown to prolong ovarian cancer patients’ survival.http://www.mdanderson.org/newsroom/news-releases/2015/beta-blocker-ovarian-cancer.html. Accessed August 28, 2015.

3. Sood AK, Bhatty R, Kamat AA, et al. Stress hormone-mediated invasion of ovarian cancer cells.Clin Cancer Res. 2006;12(2):369-375.