Abstract A115: Use of angiotensin system inhibitors is associated with immune activation and longer survival in pancreatic ductal adenocarcinoma patients
Authors: Talele Nilesh P. , Liu Hao , Naxerova Kamila , Pinter Matthias , Incio Joao , Lee Hang , Shigeta Kohei , Ho William W. , Michelakos Theodoros , Hong Theodore S. , Clark Jeffrey W. , Murphy Janet E. , Ryan David P. , Deshpande Vikram , Lillemoe Kieth D. , Castillo Carlos Fernandez-del , Downes Michael , Evans Ronald M. , Michaelson James , Duda Dan G. , Ferrone Cristina R. , Bouches Yves , Jain Rakesh 
Published: February 2019

Abstract
Purpose: Angiotensin system inhibitors (ASIs) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients. Experimental Design: We performed an analysis of the records of ASI users and non-user patients with PDAC seen at Massachusetts General Hospital between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA-Seq of resected primary lesions. In a prospective trial (NCT01821729), we investigated circulating biomarkers of losartan activity. Results: 794 consecutive patients were included. In 299 resected patients, ASI-users experienced longer overall survival (OS) in both univariate (median OS: 36.3 vs. 19.3 months, p=0.011) and adjusted multivariate (HR, 0.505; 95%CI, 0.339 - 0.750; p=0.001) analyses. Propensity score adjusted analysis also showed a longer median OS for chronic ASI users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI-users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g., WNT and Notch signaling) and an increased expression of genes linked with the activity of T-cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature that is predictive of survival in independent validation cohorts. Circulating biomarker data will be presented at the meeting. Conclusions: In patients with non-metastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASI reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC.
Citation Format: Nilesh P. Talele, Hao Liu, Kamila Naxerova, Matthias Pinter, Joao Incio, Hang Lee, Kohei Shigeta, William W. Ho, Theodoros Michelakos, Theodore S. Hong, Jeffrey W. Clark, Janet E. Murphy, David P. Ryan, Vikram Deshpande, Kieth D. Lillemoe, Carlos Fernandez-del Castillo, Michael Downes, Ronald M. Evans, James Michaelson, Dan G. Duda, Cristina R. Ferrone, Yves Bouches, Rakesh Jain. Use of angiotensin system inhibitors is associated with immune activation and longer survival in pancreatic ductal adenocarcinoma patients [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A115.