Molecular profiling and potential therapeutic implications of molecular testing utilizing a large database of hepatocellular carcinoma patients.

594 Background: The incidence of hepatocellular carcinoma (HCC) diagnoses is increasing worldwide with an estimated 1 million new cases of liver cancer in the year 2025. HCC is commonly diagnosed through imaging and clinical evaluation alone. Many patients with HCC never undergo biopsy or complete molecular testing. As a result, molecular profiling of large numbers of HCC patients has not been reported. This impairs our ability to identify mutations that may be treated with approved targeted therapies or could be targeted in future clinical trials. Methods: Utilizing the Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB), we collected tissue and circulating tumor DNA-derived somatic testing results from 447 patients with HCC. We evaluated the frequency at which alterations were discovered, excluding alterations present in less than 1% of patients. Univariate analysis using Fischer’s exact testing was then undertaken to evaluate if alterations were present in different proportions of patients with distinct HCC risk factors. The number of alterations associated with an FDA approved targeted therapy in another cancer type was determined. Alterations currently being investigated with therapeutic agents in clinical trials enrolling HCC patients was also determined using clinicaltrials.gov as a reference. Results: Molecular data from 447 HCC patients was analyzed. Fifty six alterations were present in over 1% of individuals. Genes altered in at least 3% of patients included TERT (26.5%), CTNNB1 (19.7%), TP53 (18.8%), MYC (13%), ARID1A (5.6%), CDKN2A (5.4%), RB1 (5.1%), CCND1 (4.9%), RAD21 (4.9%), LYN(4.5%), DNMT3A (4%), FGF19 (4%), PTEN (4%), FGF3 (3.6%), MLL2 (3.4%), TSC2 (3.4%), FGF4 (3.1%), and NTRK1 (3.1%). A higher proportion of patients with hepatitis C were found to have alterations in TERT (p = 0.019) but less likely to have an RB1 alteration (p = .003). Patients with obesity had a higher proportion of CCND1 mutations than non-obese patients (p= .035). FDA approved targeted therapies in other cancer types are available for 10 of the 56 alterations present in over 1% of patients and there are clinical trials evaluating targeted therapies that are actively recruiting patients with HCC for 5 of the alterations including CTNNB1, FGF19, VEGFA, ERBB2, and APC. Conclusions: There are a significant number of genetic alterations present in hepatocellular carcinoma patients that may be targetable with approved therapies available in other tumor types or clinical trial treatments. Additional research assessing the efficacy of existing targeted treatments and trial therapies in HCC patients is greatly needed.