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.
Highlights
Pancreatic Ductal Adenocarcinoma (PDAC) continues to have one of the worst outcomes of any malignancy
In this study, which to our knowledge is the first of its kind to evaluate the prognostic value of Folate receptor alpha (FRα) expression in Pancreatic ductal adenocarcinoma (PDAC), high FRα expression intensity in surgically removed PDAC specimens was found to be significantly associated with favorable prognosis
High FRα expression in lung adenocarcinoma was found to be associated with early stage disease and favorable prognosis [20, 27]; in contrast, high FRα expression was shown to be associated with poor prognosis in breast cancer [28, 29] [21], and with poor disease-free and overall survival, as well as chemoresistance in ovarian cancer [30,31,32]
Summary
Pancreatic Ductal Adenocarcinoma (PDAC) continues to have one of the worst outcomes of any malignancy. It is the fourth most common cause of cancer death in the United States [1, 2]. Major risk factors for PDAC, namely, smoking [4, 5], excessive alcohol consumption [6], meat-rich diet and diabetes [7], have been identified, diagnostic methods using specific markers to predict the occurrence of PDAC are lacking. Efforts are being made to identify relevant factors and/or markers that predict a high risk of recurrence and poor prognosis, which may help to optimize perioperative therapeutic approaches for those patients with resectable PDAC [8, 9]. It is urgent to understand the pathogenesis of PDAC to aid in the identification of markers useful in developing innovative diagnostic and therapeutic methods for this disease
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