Nonselective β-adrenergic blockade impacts pancreatic cancer tumor biology, decreases perineural invasion and improves patient survival
Year: 2020
Type: article
Study design: Observational Study
Abstract: Background: Beta (β) adrenergic signaling mediates progression and invasion in many cancer subtypes. β-blockade, often prescribed for a chronic medical illness such as hypertension, is associated with improved outcomes in breast and prostate cancer. While hypertension is a frequent comorbid condition found in patients diagnosed with pancreatic ductal adenocarcinoma (PDAC), the impact of β-blockade in this disease remains unknown. Methods: Clinical data were prospectively collected for 1,933 patients undergoing pancreatectomy between 2000 and 2016 at a high-volume pancreatic surgery center of excellence. β-blocker use was utilized to stratify patients into independent cohorts and histopathologic and oncologic outcomes data were investigated. Differences between these two cohorts prompted investigations in patient-derived models of PDAC. A proposed mechanism of action of β-blockade on tumor biology is explored. Results: In total, 457 of 1,933 patients taken to the operating room for a diagnosis of PDAC were prescribed β-blockade by their primary care physician or cardiologist. Three-hundred and ninety-seven patients were taking β1-selective-blockers and 60 received non-selective β-blockers. When stratified by selectivity, non-selective β-blockade is associated with decreased perineural invasion (PNI) compared to β1-selective or no β-blockade (Noβ) (non-selective 68.3%, β1-selective 84.9%, Noβ 85.9%, P<0.001). Non-selective β-blockade is also associated with longer overall survival (OS) (median: non-selective 26.1 months, β1 18.5 months, Noβ 18.8 months, P<0.01). With these data associating β-blockade and PNI, a direct local mechanism involving noradrenergic hormones was hypothesized. In vitro human derived PDAC cell line demonstrated increased cell growth and migration with norepinephrine administration; however, co-administration of propranolol successfully abrogated norepinephrine-induced growth and migration. Conclusions: Non-selective blockade is independently associated with decreased PNI and improved OS in resected PDAC. In vitro , norepinephrine stimulates cell growth and migration. While propranolol does not impact cell growth in isolation, co-administration with norepinephrine abrogates the increased growth and migration seen with norepinephrine administration alone. This work highlights the impact of commonly used antihypertensive medications on tumor biology and may elucidate a rationale for the use of common antihypertensive medications as therapeutic adjuncts in PDAC.
Source: Annals of Pancreatic Cancer
DOI: 10.21037/apc-19-45
Institutions: Johns Hopkins University, Johns Hopkins Medicine
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W3044579423