Prospective Genotyping of Hepatocellular Carcinoma: Clinical Implications of Next-Generation Sequencing for Matching Patients to Targeted and Immune Therapies

Abstract

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 ¼ 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/b-catenin pathway (45%) and TP53 (33%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib-treated patients (n ¼ 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 ¼ 31), activating alteration WNT/b-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. See related commentary by Pinyol et al., p. 2021

Integrative analysis of highly mutated genes in hepatitis B virus‐related hepatic carcinoma

“…Among these identified highly mutated genes, TP53, TERT, PEEX2, CTNNB1, and AXIN1 in HCC, especially in HBV‐related HCC, have been investigated, and the published studies showed that these mutated genes played very important roles in the development of HCC . In addition, consistent with the published studies, we found that COL11A1, RB1, MUC16, and PCLO, which have been detected by next‐generation sequencing technology, including whole genome sequencing and whole‐exome sequencing by different groups, are also found to be associated with HCC in our research. However, the role of other mutated genes, including ABCA13, COL11A1, and COL12A1 as shown in Figure A, in HBV‐related HCC, has not been well clarified and needs to be investigated in future studies.…”

“…Accumulation of genetic alterations is a hallmark of HCC, and a great number of mutated genes, including CTNNB1, TSC1/2, PREX2, TP53, TERT, AXIN1, ARID1A, RET, and ARID2, have been identified in HCC, especially, in HBV‐related HCC . Current studies suggest that the mutations of CTNNB1 are associated with low stage HCC .…”

“…With the developing of sequencing technology, the mutations of several new genes, including APC, MYC, JAK1, COL11A1, LRP1B, FGF19, RB1, MUC16, and PCLO, in HCC tissues, especially in HBV‐related HCC tissues, have been discovered recently . However, to date, a comprehensive understanding of the highly mutated genes, which are responsible for the development of HBV‐related HCC, is lacking.…”

“…Accumulation of genetic alterations is a hallmark of HCC, 8 and a great number of mutated genes, including CTNNB1, TSC1/2, PREX2, TP53, TERT, AXIN1, ARID1A, RET, and ARID2, have been identified in HCC, especially, in HBVrelated HCC. 3,[9][10][11][12][13][14][15] Current studies suggest that the mutations of CTNNB1 are associated with low stage HCC. 16 TERT promoter mutations are more frequently observed in HCC patients with low α-fetoprotein (AFP) levels and advanced ages.…”

Optimizing curative management of hepatocellular carcinoma

“…This subclass has not been found to influence prognosis. However, molecular profiling of tumour biopsies from advanced HCC has suggested an altered response to immune checkpoint inhibitors . This could be important for future adjuvant/neoadjuvant strategies (see below).…”