Reference Detail

Ref Type Journal Article
PMID (30373752)
Authors Harding JJ, Nandakumar S, Armenia J, Khalil DN, Albano M, Ly M, Shia J, Hechtman JF, Kundra R, El Dika I, Do RK, Sun Y, Kingham TP, D'Angelica MI, Berger MF, Hyman DM, Jarnagin W, Klimstra DS, Janjigian YY, Solit DB, Schultz N, Abou-Alfa GK
Title Prospective Genotyping of Hepatocellular Carcinoma: Clinical Implications of Next-Generation Sequencing for Matching Patients to Targeted and Immune Therapies.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol
Issue
Date 2018 Oct 29
URL
Abstract Text Purpose: Prior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies.Experimental Design: Matched tumor/normal DNA from patients with HCC (N = 127) were analyzed using a hybridization capture-based NGS assay designed to target 341 or more cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles.Results: WNT/β-catenin pathway (45%) and TP53 (33%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib-treated patients (n = 81), oncogenic PI3K-mTOR pathway alterations were associated with lower disease control rates (DCR, 8.3% vs. 40.2%), shorter median progression-free survival (PFS; 1.9 vs. 5.3 months), and shorter median overall survival (OS; 10.4 vs. 17.9 months). For patients treated with immune checkpoint inhibitors (n = 31), activating alteration WNT/β-catenin signaling were associated with lower DCR (0% vs. 53%), shorter median PFS (2.0 vs. 7.4 months), and shorter median OS (9.1 vs. 15.2 months). Twenty-four percent of patients harbored potentially actionable alterations including TSC1/2 (8.5%) inactivating/truncating mutations, FGF19 (6.3%) and MET (1.5%) amplifications, and IDH1 missense mutations (<1%). Six percent of patients treated with systemic therapy were matched to targeted therapeutics.Conclusions: Linking NGS to routine clinical care has the potential to identify those patients with HCC likely to benefit from standard systemic therapies and can be used in an investigational context to match patients to genome-directed targeted therapies.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CTNNB1 act mut hepatocellular carcinoma decreased response unspecified CTLA4 antibody + unspecified PD-1 antibody Clinical Study - Cohort Actionable In a clinical study, treatment with immune checkpoint antibodies, including anti-PD-1, anti-PD-L1, or anti-CTLA-4 monotherapy or combinations of anti-PD-1 with anti-CTLA-4, anti-LAG3, or anti-KIR, was less effective in patients with Wnt pathway mutations in CTNNB1 or AXIN1 compared to patients without mutations in this pathway, with 0% (0/10) vs. 53% (9/17) achieving disease control, respectively, and shorter progression-free survival (2.0 months vs. 7.4 months) (PMID: 30373752; NCT01775072). 30373752
PTEN mutant hepatocellular carcinoma decreased response Sorafenib Clinical Study - Cohort Actionable In a clinical case study, Nexavar (sorafenib) treatment of patients with hepatocellular carcinoma harboring Mtor pathway mutations in PIK3CA, PTEN, TSC2, or TSC1 (n=12), resulted in a lower disease control rate (8.3% vs. 40.2%), shorter progression-free survival (1.9 months vs. 5.3 months) and shorter overall survival (10.4 months vs. 17.9 months) compared to patients without mutations in this pathway (n=67) (PMID: 30373752; NCT01775072). 30373752
CTNNB1 act mut hepatocellular carcinoma decreased response unspecified PD-L1 antibody Clinical Study - Cohort Actionable In a clinical study, treatment with immune checkpoint antibodies, including anti-PD-1, anti-PD-L1, or anti-CTLA-4 monotherapy or combinations of anti-PD-1 with anti-CTLA-4, anti-LAG3, or anti-KIR, was less effective in patients with Wnt pathway mutations in CTNNB1 or AXIN1 compared to patients without mutations in this pathway, with 0% (0/10) vs. 53% (9/17) achieving disease control, respectively, and shorter progression-free survival (2.0 months vs. 7.4 months) (PMID: 30373752; NCT01775072). 30373752
CTNNB1 act mut hepatocellular carcinoma decreased response unspecified CTLA4 antibody Clinical Study - Cohort Actionable In a clinical study, treatment with immune checkpoint antibodies, including anti-PD-1, anti-PD-L1, or anti-CTLA-4 monotherapy or combinations of anti-PD-1 with anti-CTLA-4, anti-LAG3, or anti-KIR, was less effective in patients with Wnt pathway mutations in CTNNB1 or AXIN1 compared to patients without mutations in this pathway, with 0% (0/10) vs. 53% (9/17) achieving disease control, respectively, and shorter progression-free survival (2.0 months vs. 7.4 months) (PMID: 30373752; NCT01775072). 30373752
CTNNB1 act mut hepatocellular carcinoma decreased response unspecified PD-1 antibody Clinical Study - Cohort Actionable In a clinical study, treatment with immune checkpoint antibodies, including anti-PD-1, anti-PD-L1, or anti-CTLA-4 monotherapy or combinations of anti-PD-1 with anti-CTLA-4, anti-LAG3, or anti-KIR, was less effective in patients with Wnt pathway mutations in CTNNB1 or AXIN1 compared to patients without mutations in this pathway, with 0% (0/10) vs. 53% (9/17) achieving disease control, respectively, and shorter progression-free survival (2.0 months vs. 7.4 months) (PMID: 30373752; NCT01775072). 30373752