Antibodies matter: A meta-analysis of the prognostic value of human equilibrative nucleoside transporter 1 (hENT1) antibodies in pancreatobiliary cancer
Authors: D. Yusuf, L. Vos, A. Lui, Z. Abdelaziz, S. Ghosh, J. Spratlin, J. Mackey
Journal: Annals of Oncology (2018)

Introduction: Gemcitabine, the primary drug for the treatment of pancreatobiliary cancer (PC), requires human equilibrative nucleoside transporter 1 (hENT1) to enter cells. High tumoral hENT1 expression has been linked to improved survival among PC patients treated with gemcitabine, however this finding has been inconsistent and studies used different anti-hENT1 immunohistochemistry (IHC) antibody assays. Methods: We reviewed the literature for studies that examined hENT1 and clinical outcome in PC. Of the 138 publications, we identified 45 studies, 36 of which used immunohistochemistry (IHC) with one of eight anti-hENT1 protein antibody assays, while 9 used polymerase chain reaction for hENT1 RNA expression. In order to assess the contribution of antibody choice on outcomes and the prognostic value for gemcitabine benefit in PC we only examined the studies that utilized IHC. Three of the studies were excluded because they were ampullary or gallbladder cancer treated with surgery only and an additional 4 studies were removed from the analysis for population redundancy. Twenty-nine studies underwent detailed review. Results: Among the 29 studies that underwent detailed review, 22 were in the adjuvant or neoadjuvant setting and 7 were of patients with locally advanced, metastatic, or recurrent disease. Of the 29 studies, 27 reported median overall survival (OS) values with p-values in 26, 22 reported progression-free survival (PFS). disease-free survival (DFS), or time to treatment failure (TTF) (21 of which reported p-values), and 19 reported p-values for both. High hENT1 expression was found in an average of 52% (range 24-92%) of tumor samples examined. Among studies that examined hENT1 expression and OS, 58% (15/26) showed an association between high tumoral hENT1 and improved OS for gemcitabine-treated patients. Among 10D7G2 antibody studies, 88% (7/8) demonstrated an association. Studies with other antibodies – in particular SP120 (2/9) – were less consistent. The ability to detect an association between high hENT1, with the 3 most commonly used antibodies (10D7G2, SP120, and PAB2255), and improved survival was antibody-dependent (Chi-square p = 0.0237). The progression-free survival (DFS) and recurrence-free survival (RFS) results were similar with 71% (15/21) of studies demonstrating an association between high tumoral hENT1 expression and improved survival. Among 10D7G2 antibody studies, 100% (6/6) demonstrated an association while only 43% (3/7) of studies that used SP120 demonstrated an association between high hENT1 and improved PFS/DFS. Pooled hazard ratio (HR) analyses of all antibody studies still demonstrate a link between high hENT1 tumor expression and improved OS (HR for death 0.754, 95% CI 0.665-0.854) and DFS (HR for relapse 0.832, 95% CI 0.709-0.976). Conclusion: High tumoral hENT1 expression on IHC with 10D7G2 is a strong and reproducible prognostic marker for improved OS among gemcitabine-treated patients with PC. The use of other antibodies should be discouraged.