Cytokines as Biomarkers of Pancreatic Ductal Adenocarcinoma: A Systematic Review

RESEARCH ARTICLE Cytokines as Biomarkers of Pancreatic Ductal Adenocarcinoma: A Systematic Review Yandiswa Yolanda Yako, Deirdré Kruger*, Martin Smith, Martin Brand Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Parktown, Gauteng, South Africa * Abstract Objectives a11111 A systematic review of the role of cytokines in clinical medicine as diagnostic, prognostic, or predictive biomarkers in pancreatic ductal adenocarcinoma was undertaken. Materials and Methods OPEN ACCESS Citation: Yako YY, Kruger D, Smith M, Brand M (2016) Cytokines as Biomarkers of Pancreatic Ductal Adenocarcinoma: A Systematic Review. PLoS ONE 11(5): e0154016. doi:10.1371/journal.pone.0154016 Editor: Francisco X. Real, Centro Nacional de Investigaciones Oncológicas (CNIO), SPAIN Received: September 4, 2015 Accepted: April 7, 2016 Published: May 12, 2016 Copyright: © 2016 Yako et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The authors would like to acknowledge the National Research Foundation (NRF) in South Africa for financial assistance. Competing Interests: The authors have declared that no competing interests exist. A systematic review was conducted according to the 2009 PRISMA guidelines. PubMed database was searched for all original articles on the topic of interest published until June 2015, and this was supplemented with references cited in relevant articles. Studies were evaluated for risk of bias using the Quality in Prognosis Studies tools. Results Forty one cytokines were investigated with relation to pancreatic ductal adenocarcinoma (PDAC) in 65 studies, ten of which were analyzed by more than three studies. Six cytokines (interleukin[IL]-1β, -6, -8, -10, vascular endothelial growth factor, and transforming growth factor) were consistently reported to be increased in PDAC by more than four studies; irrespective of sample type; method of measurement; or statistical analysis model used. When evaluated as part of distinct panels that included CA19-9, IL-1β, -6 and -8 improved the performance of CA19-9 alone in differentiating PDAC from healthy controls. For example, a panel comprising IL-1β, IL-8, and CA 19–9 had a sensitivity of 94.1% vs 85.9%, specificity of 100% vs 96.3%, and area under the curve of 0.984 vs 0.925. The above-mentioned cytokines were associated with the severity of PDAC. IL-2, -6, -10, VEGF, and TGF levels were reported to be altered after patients received therapy or surgery. However, studies did not show any evidence of their ability to predict treatment response. Conclusion Our review demonstrates that there is insufficient evidence to support the role of individual cytokines as diagnostic, predictive or prognostic biomarkers for PDAC. However, emerging evidence indicates that a panel of cytokines may be a better tool for discriminating PDAC from other non-malignant pancreatic diseases or healthy individuals. PLOS ONE | DOI:10.1371/journal.pone.0154016 May 12, 2016 1 / 33 Cytokines and Pancreatic Ductal Adenocarcinoma Introduction Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer, accounting for more than 80% of all pancreatic neoplasms diagnosed [1, 2]. It is the fourth leading cause of cancer-related mortality worldwide, accounting for 6% of cancer deaths annually. Various treatment strategies have been introduced over the years, however, with little impact on the 5-year survival rate of 3–5% [3, 4]. Biomarkers for diagnosis, prognosis and predictive response to treatment are necessary to guide patient management and treatment decisions. Specifically, the use of biomarkers to guide therapeutic decisions in non-pancreatic cancers such as colorectal, breast, lung, and prostate cancer is well established. For example, in patients with metastatic colorectal cancer the genetic analysis of the KRAS mutation and microsatellite instability is routinely performed to select those that may benefit from therapy with biological agents targeting these mutations [5]. Tumour hormone receptor and human epidermal growth factor receptor-2 (HER2) have been identified as biomarkers for predicting therapeutic response in breast [6] and gastric cancers [7]. With regard to PDAC, serum carbohydrate antigen 19–9 (CA19-9) remains the only routinely used diagnostic and prognostic biomarker. However it has a low sensitivity as approximately 5–10% of the general population do not genetically express the antigenic determinant of CA 19–9 [8], nor is it increased in the early stages of the disease. Furthermore, it exhibits poor prognostic value in patients with localized disease undergoing resection due to falsely elevated levels in the presence of biliary obstruction, and in those receiving chemotherapy [9]. Novel therapeutic targets, therefore, have been investigated and introduced in an attempt to improve survival outcomes. PDAC is characterized by the presence of dense stromal tissue within the tumour which primarily consists of various inflammatory cell types [10, 11]. Inflammatory cells produce and secrete cytokines, some of which have an immunosuppressive effect, and these include interleukin (IL)-6, IL-10, IL-13, vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-β). It is hypothesized that these immunosuppressive cytokines support a favorable environment for the development and progression of PDAC [12, 13]. This review was undertaken to collate the available evidence on alterations of cytokine levels found in PDAC and their implications in diagnosis, prognosis, and prediction of treatment response. Materials and Methods Data source and Study selection The review was conducted according to the 2009 PRISMA guidelines [14]. A PubMed search, limited to human clinical studies published in English, was conducted to identify all original articles on the topic of interest published until June 2015, using a combination of search terms as shown in S1 Table. The reference lists of relevant published articles were scanned to supplement the electronic search. Two investigators (YYY and DK) independently screened retrieved citations by title and abstracts for inclusion into the review. After selecting relevant citations from reviews and meta-analyses, duplicates were removed. Full-text and, where necessary, supplemental materials of publications without abstracts or insufficient information in the abstract were reviewed. Disagreements were solved by consensus or reviewed by a third investigator (MB). Studies were considered eligible if they i) were retrospective or prospective case-control and/or cohort, and ii) investigated the correlation of cytokines with primary PDAC (...truncated)