Nonselective β-adrenergic blockade impacts pancreatic cancer tumor biology, decreases perineural invasion and improves patient survival

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.