Abstract 957: Use of angiotensin system inhibitors is associated with longer overall survival in pancreatic ductal adenocarcinoma patients who underwent pancreatectomy
Authors: Liu Hao , Pinter Matthias , Incio Joao , Lee Hang , Ho William , Crain Jonathan , Naxerova Kamila , Di Mengyang , Jacobson Alex , Santos Daniella Dias , Zanconato Andrea , Deshpande Vikram , Lillemoe Keith , Castillos Carlos Fernandez del , Downes Michael , Evans Ronald , Michaelson James , Ferrone Cristina , Boucher Yves , Rakesh Jain K. 
Published: July 2017

Abstract
Introduction: Angiotensin system inhibitors (ASI) are widely used to manage hypertension. Laboratory and retrospective clinical data suggests that ASIs can improve cancer prognosis. The aim of this study is to investigate the effect of ASIs on overall survival in pancreatic ductal adenocarcinoma (PDAC) patients.
Methods: We performed a retrospective review of the clinicopathologic records of patients with PDAC seen at the Massachusetts General Hospital (MGH) between 1/2006 - 12/2010. Patients on angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) were included as ASI users. We performed RNAseq and Gene Set Enrichment Analysis (GSEA) of primary tumor samples from patients with or without chronic ASI use. We also identified a surrogate signature of differentially expressed genes and we measured the extent of angiotensin inhibition in GEO and TCGA datasets. The extent of inhibition was used to correlate with survival. Statistical analysis was performed using Kaplan-Meier estimator and Cox proportional hazards ratio model.
Results: A total of 794 consecutive PDAC patients were included, of whom 297 (37.4%) were on ASIs and 183 (23.0%) were on non-ASI antihypertensive drug therapy. In resected patients, ASI users had a significantly longer overall survival on univariate (median OS: 36.3 vs. 19.3 months, p=0.011) and multivariate analysis (HR, 0.49; 95%CI, 0.333-0.734; p&lt;0.001). In our sub-group analysis of resected hypertensive patients treated with chemotherapy, chronic ASI users had a significantly longer overall survival than ASI-naïve patients (p=0.048) (28.7 vs 12.3 months, p&lt; 0.05). Gene Set Enrichment Analysis revealed that the ASI lisinopril down-regulated genes which stimulate the mitotic cell cycle, WNT and Notch signaling and the interaction between integrins and the extracellular matrix. Lisinopril also enhanced gene sets linked with oxidative phosphorylation, antigen processing and presentation and the cytotoxic activity of T cells. In unresected patients, the effect of ASI was only significant in patients with locally advanced disease in multivariate analysis (HR, 0.572; 95%CI, 0.386-0.847; p=0.005), but not in metastatic patients. The low expression of genes down-regulated by ACEi was also significantly associated with longer survival in the TCGA and GSE71729 datasets.
Conclusion: In patients with PDAC, ASI use is associated with longer overall survival in resected patients and may benefit patients with locally advanced disease. These findings suggest the need for a prospective study to determine the efficacy of ASI in PDAC patients.
Citation Format: Hao Liu, Matthias Pinter, Joao Incio, Hang Lee, William Ho, Jonathan Crain, Kamila Naxerova, Mengyang Di, Alex Jacobson, Daniella Dias Santos, Andrea Zanconato, Vikram Deshpande, Keith Lillemoe, Carlos Fernandez del Castillos, Michael Downes, Ronald Evans, James Michaelson, Cristina Ferrone, Yves Boucher, Jain K. Rakesh. Use of angiotensin system inhibitors is associated with longer overall survival in pancreatic ductal adenocarcinoma patients who underwent pancreatectomy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 957. doi:10.1158/1538-7445.AM2017-957