B-catenin pathway mutations predict favorable outcomes after transarterial chemoembolization in unresectable hepatocellular carcinoma

Background Transarterial chemoembolization (TACE) is the most common treatment in unresectable hepatocellular carcinoma (HCC); however, response rates and durability vary widely, and patients frequently require repeat treatments. With the development of alternative locoregional and systemic therapies for patients with HCC, identifying predictors of response to TACE has become increasingly important for a patient population with minimal hepatic reserve. Preliminary data suggests β-catenin pathway mutations may predict favorable response to liver tumors following bland embolization. We hypothesized that activating β-catenin pathway mutations would lead to improved outcomes following TACE in patients with unresectable HCC. Material and Methods Patients with a clinical diagnosis of HCC planned for TACE were enrolled in a prospective cohort study at two academic medical centers from April 2016 to October 2021. Liver biopsies were taken at time of TACE and mutational profiles determined using a custom next generation sequence panel. Patients with at least one follow-up MRI were included. Primary outcome was objective response rate (ORR) of the targeted tumor at first imaging follow-up. Objective response was defined as complete (CR) or partial response (PR) by mRECIST criteria. Secondary outcomes were CR of targeted tumor at first imaging and at best response, time to target tumor progression (TTP), and overall survival (OS). Results 53 HCC tumors from 50 patients were included in the analysis. Most patients had BCLC stage B disease (28/53, 52.8%) with underlying cirrhosis (42/53, 84.0%) that was well compensated (45/53 Child-Pugh A, 84.9%). Median size of targeted tumor was 4.0 cm (IQR 2.5-6.3 cm). First follow-up imaging was done at a median of 37 days after TACE (IQR 32-63 days) with ORR of 46/53 (86.8%), including 15 tumors with CR (28.3%). At best response, ORR was 49/53 (92.5%), including 19 tumors with CR (35.9%). 19/53 lesions (35.9%) had progression during the study period with a median TTP of 13.7 months and median OS of 23.4 months. Despite similar ORRs (20/22, 90.2% vs 26/31, 83.8%, p=0.46), tumors with activating β-catenin pathway mutations had increased rates of CR at first imaging (9/22, 40.9% vs 6/31, 19.4%, p=0.09) and at best response (12/22, 54.5% vs 7/31, 22.6%, p=0.02) when compared to tumors without these mutations, as well as longer TTP (median not yet reached vs 8.3 months, p=0.02). Conclusions In patients with unresectable HCC, activating mutations in β-catenin pathway have better and more durable response to TACE – a finding that may help guide therapeutic decision making in this heterogeneous population. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Research reported in this publication was supported by Penn Center for Precision Medicine Accelerator Grant and VA CSR&D I01 CX-001933. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by Institutional Review Boards (IRB) at both institutions (University of Pennsylvania IRB #823696 and Corporal Michael J Crescenz VA Medical Center IRB #01779) and all research was performed in accordance with their guidelines/regulations, including obtaining informed consent from all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. * AFP : alpha-fetoprotein BCLC stage : Barcelona clinic liver cancer stage CT : computed topography CCA : cholangiocarcinoma HCC : hepatocellular carcinoma cHCC-CCA : combined hepatocellular and cholangiocarcinoma FDG PET : fluorodeoxyglucose positron emission tomography HCV : hepatitis C virus HBV : hepatitis B virus IRB : institutional review board IQR : interquartile range LIRADS score : liver reporting and data system score LRT : locoregional therapy MELD : model for end-stage liver disease MRI : magnetic resonance imaging NAFLD : non-alcoholic fatty liver disease PDX : patient-derived xenografts SD : standard deviation TERT : telomerase reverse transcriptase US : ultrasound