Influence of MRP4 levels on clinical outcomes in biliary tract cancer.

624 Background: Biliary tract cancer (BTC) are rare tumors with a poor prognosis.Multidrug resistance protein 4 (MRP4) is a transmembrane efflux transporter that influences on cellular growth and differentiation. Recent studies have linked high MRP4 levels to increased aggressiveness in pancreatic cancer and other tumor types. This study aimed to evaluate the role of MRP4 in BTC and its association with clinical outcomes in a real-world cohort from endemic areas in Argentina. Methods: We conducted a retrospective analysis of clinical outcomes and MRP4 expression in paraffin-embedded tissue samples from 78 patients with BTC. Immunohistochemistry staining was performed, and MRP4 expression was scored based on staining intensity and the percentage of positive cells. A score exceeding 100 was classified as high MRP4 levels. Statistical analyses included Chi-square, Kaplan-Meier survival curves, and log-rank tests, with significance set as p <0.05 (two-tailed). Results: High MRP4 levels were observed in 46 out of the 78 samples (59%). Patients with gallbladder cancer (n=64) and elevated MRP4 levels had significantly poorer overall survival (OS) compared to those with low MRP4 levels (median 11.3 and 14.5 months, high and low, p =0.038). In the broader BTC cohort evaluable for survival (n=73; 64 gallbladder, 7 cholangiocarcinoma, 1 ampulla of Vater, and 1 biliary undefined) patients with elevated MRP4 levels had non-significant shorter OS (median 12.4 and 13.5 months, high and low, p =0.17). Poorly differentiated tumors were more likely to express high MRP4 levels ( p =0.06). High MRP4 expression was found in 59% of localized stages (0-II) and in 57% of advanced stages (III, IV and relapsed). Conclusions: High MRP4 expression is common in BTC, particularly gallbladder cancer, and could be a marker of poor prognosis. MRP4 levels appear more elevated in poorly differentiated tumors, and are similar in both, early and advanced stages, suggesting its involvement in early tumor progression. Further prospective studies are needed to confirm MRP4 as a biomarker. If MRP4 is a driver gene, targeting with inhibitors could represent a promising therapeutic strategy for these challenging tumors.