Immuno-histochemical assessment of hENT1 biomarker as a prognostic biomarker for patients undergoing gemcitabine-based chemotherapy for resected biliary tract cancers: A systematic review and meta-analysis

Background

Human Equilibriative Nucleoside Transporters (hENT) are trans-membranous ubiquitous proteins which facilitate the uptake of nucleosides and nucleoside analogues, such as gemcitabine, in to the cell. Research has tentatively inferred that the expression of hENT1 transporters in resected biliary tract cancer is a prognostic biomarker for gemcitabine-based chemotherapy. The aim of this meta-analysis and systematic review is to assess if hENT1 expression, as determined by immuno-histochemistry, is a prognostic biomarker for subsequent treatment with gemcitabine-based chemotherapy.

Methods

The authors systematically identified articles pertaining to hENT1 immuno-histochemical analysis in resected biliary tract cancer specimens from patients who subsequently underwent gemcitabine-based chemotherapy. Eligible studies had to contain survival analysis statistics, reporting specifically Overall Survival (OS), Disease Free Survival (DFS) and Progression Free Survival (PFS) with associated Hazard Ratios (HR's) stratified by hENT1 status. Potential sources of inter-study heterogeneity were identified and accounted for in the statistical meta-analysis by use of a Random-Effects model to produce Forest Plots.

Results

Of 105 received articles, 6 were deemed suitable for review, with a total population of 283 patients underwent statistical meta-analysis. Immuno-histochemically detected hENT1 expression is found to be significantly associated with both univariate PFS (0.43[95% CI 0.31-0.69]; I² 0%; Z Score= 5.16; p= 0.00001) and univariate OS (0.50[95%CI 0.38-0.67]; I² 0%; Z score= 4.75; p= 0.00001).

Conclusions

This meta-analysis demonstrates empirical evidence that hENT1 expression is a valid predictor of survival for patients undergoing gemcitabine-based chemotherapy. The hENT1 biomarker should be used to stratify patients into appropriate adjuvant chemotherapeutic regimens to improve outcomes and reduce un-necessary exposure to inefficacious treatments for patients determined to be hENT1-ve.

Clinical trial identification

Not Applicable

Legal entity responsible for the study

Liverpool University and University Hospital Aintree

Funding

Liverpool University Translational Medicine Department

Disclosure

All authors have declared no conflicts of interest.