Expression status of folate receptor alpha is a predictor of survival in pancreatic ductal adenocarcinoma

// Lei Cai 1, 2, * , Theodoros Michelakos 1, * , Cristina R. Ferrone 1 , Liyuan Zhang 1 , Vikram Deshpande 3 , Qi Shen 3 , Albert DeLeo 4 , Teppei Yamada 1 , Gong Zhang 1 , Soldano Ferrone 1, 5 and Xinhui Wang 1 1 Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 2 Department of Hepatobiliary, Southwest Hospital, Third Military Medical University, Chongqing, China 3 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 4 University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA 5 Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA * Lei Cai and Theodoros Michelakos contributed equally to this paper Correspondence to: Xinhui Wang, email: XWANG30@mgh.harvard.edu Keywords: folate receptor alpha, pancreatic ductal adenocarcinoma, predictor of survival, smoking, alcohol consumption Received: January 28, 2017      Accepted: March 01, 2017      Published: April 05, 2017 ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognosis among malignancies. Thus, the identification of markers useful in developing innovative diagnostic and therapeutic methods is an imperative need. Folate receptor alpha (FRα) has been associated with prognosis in several cancers and has served as a target of novel anti-tumor therapies. However, FRα expression in PDAC and its correlation with the clinical course of the disease has not been thoroughly investigated. In this study, we analyzed FRα expression in 140 PDAC specimens and 7 PDAC cell lines in order to define the significance of FRα expression in PDAC and its potential role as a target for immunotherapy. Immunohistochemical analysis demonstrated that FRα expression intensity was low, intermediate and high in 22(16%), 73(52%) and 45(32%) PDACs, respectively. The staining was located in both membrane and cytoplasm in most cases (123, 88%). Lower FRα expression was associated with cigarette smoking (p<0.001), alcohol consumption (p<0.001), and lymphovascular invasion (p=0.002). Additionally, lower FRα expression was associated with poor overall survival (5-year overall survival: low 13%, intermediate 31%, high 33%; p=0.006). FRα expression (HR=0.61; p=0.03) and Charlson Comorbidity Index (HR=1.16; p=0.01) emerged as independent predictors of survival. The analysis by flow cytometry of 7 PDAC cell lines (AsPC-1, Capan-2, MIA PaCa-2, PANC-1, PDAC2, PDAC3, and PDAC5) demonstrated the highest expression of FRα on the PDAC3 cell line (45%). Therefore, a higher FRα expression is predictive of a favorable prognosis in PDAC and FRα may represent a promising target for novel treatments, including immunotherapy.