Abstract
e16172 Background: Despite recent advancements in the understanding of the molecular biology of biliary tract cancer (BTC), target therapy and immunotherapy have demonstrated only limited efficacy, with cytotoxic systemic therapy still being the most effective treatment in BTC, except for surgery. Thus, this study aimed to analyze the role of DKK1 or β-catenin as a prognostic factor in BTC and determine the clinical association of ß-catenin and DKK1 with CD8+ tumor-infiltrating lymphocyte (TIL). Methods: We used data in The Cancer Genome Atlas (TCGA) Research Network and the clinicopathological data of 145 patients with BTC who had undergone primary radical resection between 2006 and 2016. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections, and whole tissue sections of representative tumor samples were used for antigen retrieval. Results: CD8+TIL expression was a significant predictor of favorable overall survival (OS) and recurrence-free survival (RFS) (median OS, 34.9months in TIL-high, 16.7months in TIL-low, P < 0.0001 respectively; median RFS, 27.1months in TIL-high, 10months in TIL-low, P < 0.0001 respectively). Positive ß-catenin expression and high DKK1 expression was also associated with a shorter OS (median OS, 23.95months in positive ß-catenin, 26.1months in negative ß-catenin, P = 0.1009 respectively; median OS, 19.4months in high DKK1, 31.65months in Low DKK1, P = 0.0093 respectively), but not RFS (p = 0.1466, at ß-catenin respectively; p = 0.2924, in DKK1 respectively). In the CD8+TIL-high BTC group, the tumor expression of β-catenin and DKK1 had a significant negative impact on either OS or RFS (p = 0.0146 and p = 0.0112, at ß-catenin respectively; p = 0.0950 and p = 0.3904, in DKK1 respectively). However, in the TIL-low BTC group, there were no differences in OS or RFS according to ß-catenin and DKK1 expression (p = 0.5108 and p = 0.8431, at ß-catenin respectively; p = 0.1127 and p = 0.1095, in DKK1 respectively). Cox regression multivariate analysis demonstrated that CD8+ TIL (hazard ratio [HR], 0.490; 95% confidence interval (CI), 0.303-0.791; p = 0.004) and β-catenin (HR, 1.652; 95% CI, 1.035-2.639; p = 0.036) retained significant association with OS after adjustment for all variables. Conclusions: Among patients with resected BTC, β-catenin and DKK1 protein levels are associated with poor clinical outcomes, whereas high CD8+ TIL levels are associated with good clinical outcomes. This confirms the differential clinical role of Wnt/β-catenin and DKK1 proteins according to TIL expression in BTC.
Highlights
Biliary tract cancer (BTC) accounts for approximately 3% of all gastrointestinal malignancies and is the most common hepatobiliary cancer after hepatocellular carcinoma[1]
This retrospective study analyzed data from The Cancer Genome Atlas (TCGA) Research Network to identify the associations of Wnt/β-catenin gene expression in CD8 cells and clinical outcomes in BTC. mRNA expression data and clinical data were downloaded from the TCGA data portal
We found no significant differences in overall survival (OS) and relapse-free survival (RFS) between patients with high β-catenin/DKK1 and high tumor-infiltrating lymphocytes (TIL) expression and those with low TIL expression. These results suggest that despite high CD8 TIL levels in tumor tissues, a favorable clinical effect of CD8 T cells could be expected from low Wnt/βcatenin signaling activation
Summary
Biliary tract cancer (BTC) accounts for approximately 3% of all gastrointestinal malignancies and is the most common hepatobiliary cancer after hepatocellular carcinoma[1]. BTC is a fatal and rare adenocarcinoma that arises in the biliary tree, including the intrahepatic (ICC) and extrahepatic (ECC) bile duct and gallbladder (GBC)[2,3]. Surgical resection is the primary treatment modality for early-stage BTC, but the majority of patients still develop a recurrence[4]. The mortality rate is high primarily because patients are diagnosed at a late stage[5]. Despite recent advancements in our understanding of the molecular biology of BTC, limited progress has been made in cytotoxic systemic therapy for this disease.
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