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Prognostic Impact of Carboxylesterase 2 in Cholangiocarcinoma.

ABSTRACT: Carboxylesterase 2 (CES2) is instrumental for conversion of ester-containing prodrugs in cancer treatment. Novel treatment strategies are exceedingly needed for cholangiocarcinoma (CCA) patients. Here, we assessed CES2 expression by immunohistochemistry in a CCA cohort comprising 171 non-liver fluke associated, intrahepatic (n?=?72) and extrahepatic (perihilar: n?=?56; distal: n?=?43) CCAs. Additionally, 80 samples of high-grade biliary intraepithelial neoplastic tissues and 158 corresponding samples of histological normal, non-neoplastic biliary tract tissues were included. CES2 expression was highest in non-neoplastic biliary tissue and significantly decreased in CCA. Patients showing any CES2 expression in tumor cells had a significantly better overall survival compared to negative cases (p?=?0.008). This survival benefit was also maintained after stratification of CES2-positive cases, by comparing low, medium and high CES2 expression levels (p-trend?=?0.0006). Evaluation of CCA subtypes showed the survival difference to be restricted to extrahepatic tumors. Correlation of CES2 expression with data of tumor-infiltrating immune cells showed that particularly CD8+ T cells were more frequently detected in CES2-positive CCAs. Furthermore, treatment of CCA cell lines with the prodrug Irinotecan reduced cell viability, increased cytotoxicity and modulated inflammatory gene expression. In conclusion, reduced CES2 expression is associated with poor outcome and low CD8+ T cell infiltration in CCA patients. Further clinical studies could show, whether CES2 expression may serve as a predictive marker in patients treated with prodrugs converted by CES2.

SUBMITTER: Goeppert B

PROVIDER: S-EPMC6416336 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Prognostic Impact of Carboxylesterase 2 in Cholangiocarcinoma.

Goeppert Benjamin B Renner Marcus M Singer Stephan S Albrecht Thomas T Zhang Qiangnu Q Mehrabi Arianeb A Pathil Anita A Springfeld Christoph C Köhler Bruno B Rupp Christian C Weiss Karl Heinz KH Kühl Anja A AA Arsenic Ruza R Pape Ulrich Frank UF Vogel Arndt A Schirmacher Peter P Roessler Stephanie S Utku Nalân N

Scientific reports 20190313 1

Carboxylesterase 2 (CES2) is instrumental for conversion of ester-containing prodrugs in cancer treatment. Novel treatment strategies are exceedingly needed for cholangiocarcinoma (CCA) patients. Here, we assessed CES2 expression by immunohistochemistry in a CCA cohort comprising 171 non-liver fluke associated, intrahepatic (n = 72) and extrahepatic (perihilar: n = 56; distal: n = 43) CCAs. Additionally, 80 samples of high-grade biliary intraepithelial neoplastic tissues and 158 corresponding sa ...[more]

PMID: 30867471

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Project description:BACKGROUND:Pancreaticoduodenectomy is the only definitively curative therapy for the long-term survival of distal cholangiocarcinoma patients. Lymph node metastasis is widely accepted as an important prognostic factor for distal cholangiocarcinoma. The latest American Joint Committee on Cancer (AJCC) TNM classification system for distal cholangiocarcinoma has divided the lymph node metastasis patients into N1 and N2 by lymph node metastasis number. However, some studies suggested that the lymph node metastasis ratio may be better than the lymph node metastasis number. Therefore, we develop a program to analyze the correlation between lymph node parameters (lymph node dissection number, lymph node metastasis number, and lymph node metastasis rate) and long-term prognosis. METHODS:We retrospectively reviewed 123 distal cholangiocarcinoma patients after pancreatoduodenectomy from January 2011 to December 2019. The patients were grouped according to lymph node metastases and tumor-free and overall survival rates which were investigated with the Kaplan-Meier analysis. The logistic regression models were used for multivariate analysis to determine the risk factors for lymph node metastases. And the X-tile program was used to calculate the cutoff values for the lymph node parameters that discriminated survival. RESULTS:The 1-year, 3-year, and 5-year overall survival rates of patients with distal cholangiocarcinoma after pancreatoduodenectomy were 75.2%, 37.1%, and 31.5%, respectively. And the 1-year, 3-year, and 5-year overall survival rates of patients without and with lymph node metastasis were 83.0%, 50.7%, and 42.5% and 63.5%, 19.0%, and 19.0% (p = 0.000), respectively. Logistic regression showed CA19-9 and portal vein system invasion as independent risk factors for lymph node metastases. The receiver operating characteristic curve showed the optimal cutoff value of CA19-9 to predict the lymph node metastases was 75.5?U/mL. Determined by the X-tile software, the optimal cutoff values of the lymph node dissection number were 24 (p = 0.021), the lymph node metastasis number were 1 and 7 (p = 0.504), and the lymph node metastasis rate were 0.13 (p = 0.002). CONCLUSION:Lymph node metastasis is an important factor affecting the long-term survival of distal cholangiocarcinoma patients.CA19-9 and portal vein system invasion are independent risk factors for lymph node metastasis. Besides, the lymph node dissection number and lymph node metastasis rate can predict the long-term survival better than lymph node metastasis number.

Project description:BackgroundCholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics.MethodsWe describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials.ResultsThere were significant differences between intrahepatic (n = 55) and extrahepatic CCA (n = 20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n = 20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors.ConclusionThere are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.

Dataset Information

Prognostic Impact of Carboxylesterase 2 in Cholangiocarcinoma.

Publications

Prognostic Impact of Carboxylesterase 2 in Cholangiocarcinoma.

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