Biomarker-Driven and Molecular Targeted Therapies for Hepatobiliary Cancers
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
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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.