NON-SELECTIVE β-ADRENERGIC BLOCKADE IMPACTS PANCREATIC CANCER TUMOR BIOLOGY, DECREASES PERINEURAL INVASION AND IMPROVES PATIENT SURVIVAL
Alex Blair*1, Noelle Jurcak2, Ammar A. Javed1, Jonathan Teinor1, Noah Rozich1, Vincent P. Groot1, John Cameron1, Matthew J. Weiss1, Jin He1, Christopher L. Wolfgang1, Lei Zheng2, Richard Burkhart1
1Surgery, Johns Hopkins Hospital, Baltimore, MD; 2Oncology, Cellular Molecular Medicine, Johns Hopkins Hospital, Baltimore, MD
Background: β-adrenergic signaling mediates progression and invasion in many cancer subtypes. β-blockade is associated with improved outcomes in breast and prostate cancer. The impact of β-blockade in pancreatic adenocarcinoma (PDAC) is not established.
Methods: Clinical data were abstracted from a prospectively collected database of resected PDAC at a single high-volume institution. β-blocker use was noted, and histopathologic and oncologic outcomes data were investigated. A proposed mechanism of tumor biology is explored in a human-derived model of PDAC.
Results: Pancreatectomy was performed in 1,933 patients for PDAC. 397 patients were taking β1-selective-blockers, and 60 received non-selective β-blockers. Non-selective β-blockade is associated with decreased perineural invasion 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 associated with longer overall survival (median: non-selective=26.1 months, β1=18.5m, Noβ=18.8m, p<0.01). With these data associating β-blockade and perineural invasion, a paracrine mechanism involving noradrenergic hormones was hypothesized. Recapitulating this in-vitro using a human PDAC cell line, norepinephrine administration demonstrated increased cell growth and migration. Co-administration of propranolol successfully abrogated norepinephrine-induced growth and migration.
Conclusions: Non-selective β-blockade is independently associated with decreased perineural invasion and improved overall survival 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.
Figure 1. Overall survival comparison of resected PDAC patients taking non-selective β-blockers, β1-selective blockers, or no β-blockade.
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