Pharmacogenomics of Sorafenib in Hepatocellular Carcinoma (HCC): A LncRNA-Expression Guided Approach Using UCA1 and MALAT1 for Personalizing Therapy in a 154-Patient Cohort.

: Hepatocellular carcinoma (HCC) presents limited therapeutic options for advanced disease, and sorafenib therapy is hampered by significant interpatient heterogeneity in response. This necessitates biomarker-guided strategies to personalize treatment. This study investigated the long noncoding RNAs UCA1 and MALAT1 as pharmacogenomic biomarkers for personalizing sorafenib therapy in advanced HCC. : In a prospective cohort of 154 HCC patients receiving first-line sorafenib (400 mg twice daily), serum lncRNA levels were quantified by RT-qPCR at baseline, Week 4, and Week 12. Expression levels were correlated with treatment response (mRECIST), time-to-progression (TTP), and overall survival (OS). Statistical analyses included Kaplan-Meier estimates, Cox proportional hazards models, and ROC curve analysis. : High baseline expression of UCA1 (77.9% of patients) and MALAT1 (73.4%) was associated with aggressive disease. High UCA1 correlated with reduced 12-month survival (60.8% vs. 73.5%, = 0.026) and shorter median Time-to-Progression (TTP) (18.0 vs. 21.9 weeks, = 0.002). High MALAT1 was associated with significantly shorter median TTP (18.0 vs. 25.2 weeks, = 0.003). In multivariable analysis, both lncRNAs were independent prognostic factors for shorter TTP (UCA1: HR = 1.52, = 0.014; MALAT1: HR = 1.61, = 0.006). Serial monitoring revealed that a ≥10% rise in either lncRNA by Week 4 predicted a five-fold higher progression risk by Week 12 (52% vs. 10%, < 0.001), providing a median lead time of 7.0 weeks before radiological confirmation of progression. These findings demonstrate that UCA1 and MALAT1 enable early identification of sorafenib resistance. Baseline stratification and serial monitoring can provide early detection of treatment resistance, informing clinical decision-making and supporting their potential utility for personalizing therapy in advanced HCC.