Elsevier

Seminars in Oncology

Volume 45, Issue 3, June 2018, Pages 116-123
Seminars in Oncology

Biomarker-Driven and Molecular Targeted Therapies for Hepatobiliary Cancers

https://doi.org/10.1053/j.seminoncol.2018.03.002Get rights and content

ABSTRACT

The recent accumulation of molecular profiling data for primary hepatobiliary malignancies, including hepatocellular carcinoma and biliary tract cancers, has led to a proliferation of promising therapeutic investigations in recent years. Treatment with pathway-specific targeted inhibitors and immunotherapeutic agents have demonstrated promising early clinical results. Key molecular alterations in common hepatobiliary cancers and ongoing interventional clinical trials of molecularly targeted systemic agents focusing on hepatocellular carcinoma and biliary tract cancer are reviewed.

Introduction

Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) represent the first and second most common hepatobiliary tumors. To date, development of successful systemic therapeutics has been hampered by an incomplete understanding of tumor biology and by comorbidities associated with a patient population typically affected by underlying hepatic dysfunction, symptoms secondary to presentation at a late clinical stage, or both. Recent efforts that have focused on deciphering the molecular alterations for each disease can increasingly be leveraged for patient benefit, especially in the context of a rapidly expanding armamentarium of molecularly targeted therapeutics. Recent and ongoing efforts to identify targeted therapeutics for HCC and BTC, with a focus on the rapidly developing treatment of intrahepatic cholangiocarcinoma (ICC), are reviewed here.

Section snippets

Current systemic therapy in advanced HCC

HCC is the second-leading cause of global cancer-related mortality with rising incidence in the United States population [1], [2]. Despite current therapeutic options, patients in the US with locally advanced or metastatic disease achieve 5-year survival rates of 11% and 3% from time of presentation, respectively [2]. Standard cytotoxic chemotherapy has failed to demonstrate significant benefit in advanced disease, while clinical benefits were shown in the positive randomized phase 3 trials of

Systemic therapy and molecular targets for advanced BTCs

BTCs, encompassing intrahepatic (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder carcinoma, represent a group of clinically aggressive and molecularly heterogeneous diseases. Commonly accepted systemic options include fluoropyrimidine-based adjuvant therapy after surgical resection based on the recent randomized phase 3 BILCAP trial of adjuvant capecitabine versus placebo (median OS, 51 v 36 months) [57]. Additionally, platinum-based doublets in advanced/metastatic disease

Conclusions

Armed with both an increased understanding of the molecular drivers of advanced-stage HCC and BTCs and novel targeted therapeutics, researchers in hepatobiliary oncology are poised to introduce several molecularly targeted systemic therapeutics in the coming years. Pathway-specific targeted therapy will require further refinement in HCC. Several pathways, including cMET and FGF, hold promise for future gains and potential identification of biomarker-selected populations. The relatively high

References (99)

  • El-KhoueiryAB et al.

    Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial

    Lancet

    (2017)
  • B Sangro et al.

    A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C

    J Hepatol

    (2013)
  • A Oba et al.

    ARID2 modulates DNA damage response in human hepatocellular carcinoma cells

    J Hepatol

    (2017)
  • TS Gujral et al.

    A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis

    Cell

    (2014)
  • F Farshidfar et al.

    Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles

    Cell Rep

    (2017)
  • RP Graham et al.

    Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma

    Hum Pathol

    (2014)
  • PP Provenzano et al.

    Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma

    Cancer Cell

    (2012)
  • JW Valle et al.

    Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial

    Lancet Oncol

    (2015)
  • D Malka et al.

    Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial

    Lancet Oncol

    (2014)
  • HB El-Serag

    Hepatocellular carcinoma

    N Engl J Med

    (2011)
  • RL Siegel et al.

    Cancer statistics, 2017

    CA Cancer J Clin

    (2017)
  • JM Llovet et al.

    Sorafenib in advanced hepatocellular carcinoma

    N Engl J Med

    (2008)
  • K Schulze et al.

    Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

    Nat Genet

    (2015)
  • N Nishida et al.

    Recent advancements in comprehensive genetic analyses for human hepatocellular carcinoma

    Oncology

    (2013)
  • Comprehensive and integrative genomic characterization of hepatocellular carcinoma

    Cell

    (2017)
  • Y Hirotsu et al.

    Targeted and exome sequencing identified somatic mutations in hepatocellular carcinoma

    Hepatol Res

    (2016)
  • J Zucman-Rossi et al.

    Genetic landscape and biomarkers of hepatocellular carcinoma

    Gastroenterology

    (2015)
  • C Guichard et al.

    Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma

    Nat Genet

    (2012)
  • K Schulze et al.

    Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

    Nat Genet

    (2015)
  • C Ang et al.

    Comprehensive multiplatform biomarker analysis of 350 hepatocellular carcinomas identifies potential novel therapeutic options

    J Surg Oncol

    (2016)
  • G Amaddeo et al.

    Integration of tumour and viral genomic characterizations in HBV-related hepatocellular carcinomas

    Gut

    (2015)
  • SM Wilhelm et al.

    BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis

    Cancer Res

    (2004)
  • S Giambartolomei et al.

    Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein

    Oncogene

    (2001)
  • K Ikeda et al.

    Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma

    J Gastroenterol

    (2017)
  • SM Wilhelm et al.

    Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity

    Int J Cancer

    (2011)
  • L Abou-Elkacem et al.

    Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model

    Mol Cancer Ther

    (2013)
  • CG Huh et al.

    Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair

    Proc Natl Acad Sci U S A

    (2004)
  • G Forte et al.

    Hepatocyte growth factor effects on mesenchymal stem cells: proliferation, migration, and differentiation

    Stem Cells

    (2006)
  • PC Ma et al.

    c-Met: structure, functions and potential for therapeutic inhibition

    Cancer Metastasis Rev

    (2003)
  • T Takami et al.

    Loss of hepatocyte growth factor/c-Met signaling pathway accelerates early stages of N-nitrosodiethylamine induced hepatocarcinogenesis

    Cancer Res

    (2007)
  • YW Zhang et al.

    Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation

    Proc Natl Acad Sci U S A

    (2003)
  • NK Venepalli et al.

    Targeting the HGF-cMET axis in hepatocellular carcinoma

    Int J Hepatol

    (2013)
  • L Rimassa et al.

    Second-line tivantinib versus placebo in patients with MET-high hepatocellular carcinoma: results of the METIV-HCC phase III trial

    J Clin Oncol

    (2017)
  • T Ueki et al.

    Expression of hepatocyte growth factor and its receptor c-met proto-oncogene in hepatocellular carcinoma

    Hepatology

    (1997)
  • L Rimassa et al.

    Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib

    Oncotarget

    (2016)
  • R Katayama et al.

    Cytotoxic activity of tivantinib (ARQ 197) is not due solely to c-MET inhibition

    Cancer Res

    (2013)
  • Abou-AlfaG et al.

    Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma

    N Engl J Med

    (2018)
  • KelleyR et al.

    Outcomes in patients who had received sorafenib as the only prior systemic therapy in the phase 3 CELESTIAL trial of cabozantinib versus placebo in advanced hepatocellular carcinoma

    J Clin Oncol

    (2018)
  • TC Yau et al.

    A phase I/II multicenter study of single-agent foretinib as first-line therapy in patients with advanced hepatocellular carcinoma

    Clin Cancer Res

    (2017)
  • Disclosures: Dr. Harris has received grants from Halozyme, Eisai, Arqule, BMS, Agio, other from Bayer, Eisai outside the submitted work. Dr. Abou-Alfa has received grants from Agios, Array, Astra Zeneca, Bayer, BMS, Casi, Celgene, Exelixis, Genentech, Incyte, Lilly, Mabvax, Medimmune, Momenta, OncoMed Pharmaceuticals, Roche, other from Agios, Amgen, Aptus, Aslan, Astellas, Astra Zeneca, Bayer, BMS, Boston Scientific, Carsgen, Celgene, Casi, CytomX, Daiichi, Debio, Delcath, Gilead, Halozyme, Inovio, Ipsen, Merck, Medimmune, Onxeo, PCI Biotech, Roche, Sanofi, Servier, Silenseed, Sillajen, Sirtex, YakultÐ during the conduct of the study. Drs. Wong, Saha, and El Dika have nothing to disclose.

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