New Horizons for Precision Medicine in Biliary Tract Cancers

Abstract

Biliary tract cancers (BTC), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients present with resectable disease but relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been demonstrated. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g., radioembolization or external beam radiation), pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next-generation sequencing analyses have identified actionable mutations (e.g., FGFR fusion rearrangements and IDH1 and IDH2 mutations), with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC, is rapidly evolving and is the subject of this review.Significance: The authors address genetic drivers and molecular biology from a translational perspective, in an intent to offer a clear view of the recent past, present, and future of BTC. The review describes a state-of-the-art update of the current status and future directions of research and therapy in advanced BTC. Cancer Discov; 7(9); 943-62. ©2017 AACR.

Figure 1

BTC, are a group of different diseases, which includes ICC, ECC and gallbladder cancer. They differ in many aspects, such as anatomical location, demographics, clinical presentations and treatment options. BTC: biliary tract cancer; ICC: intrahepatic cholangiocarcinoma; ECC: extrahepatic cholangiocarcinoma; PEI: pancreatic exocrine insufficiency.

Figure 2

IDH1 and IDH2 are metabolic enzymes found in the cytoplasm and mitochondria respectively, and catalyze the decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), resulting in the reduction of NADP+ to NADPH. The oncometabolite2-hydroxyglutarate (2-HG) can competitively inhibit one or more members of the family of over 60 dioxygenases which require α-KG as a cofactor. The dioxygenases include the JmjC family of histone demethylases and the Ten-eleven translocation (TET) family of methylcytosine dioxygenase enzymes that catalyze the demethylation of DNA. IDH and Kras mutations can cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic ICC. Agents targeting IDH1 and IDH2 are under development.

Figure 3

Chromatin remodeling complex: DNA is packaged in chromatin to allow 1.8 meter-long human genome to fit in a single cell of the body. SWI/SNF (SWItch/Sucrose Non-Fermentable) complexes are evolutionary conserved, ATP-dependant, molecular machines that alter local chromatin structure. ARID1A encodes an accessory subunit of the SWI/SNF chromatin remodeling complex. ARID1A: AT-rich interactive domain-containing protein 1A. BAF: BRG1 associated factor. BRD: Bromo domain containing protein. SMARC: SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, also known as BRG: Brahma related gene. BAP1: BRCA1 associated protein-1 ASXL: additional sex combs-like. OGT:UDP-glucose-dependent O-glucosyltransferase. HCF1:host cell factor 1. YY1: Ying Yang 1. FOXK: Forkhead box protein K.

Figure 4

Genetic landscape on BTC. Most frequent genetic aberrations in targetable pathways of interest in BTC. The mutation is quoted as the highest to lowest with range from different reports on each mutation. Those without range come from single reports. Extracted from: Desphande et al BMC Cancer 2011(105), Borger et al The Oncologist 2012(104), Voss et al Human Pathology 2013(208), Ross et al The Oncologist 2014(52), Ong et al Nature Genetics 2012(45), Graham et al Human Pathology 2014(126), Arai et al Hepatology 2014(81), Sia et al Nature Communications 2015(82), Javle et al Cancer 2016(53), Zou et al Nature Communications 2014(62), Li et al Nat Genet 2014(103), Zhu et al Ann Surg Oncol 2014(118), Sia Gastroenterology 2013(54), Jiao et al Nature Genetics 2013(119), Chan-on et al Nature Genetics 2013(46), Wang et al Oncogene 2013(117), Wu et al Cancer Discovery 2013(79), Ross et al Journal of Clinical Oncology 2015(51), Nakamura et al Nature Genetics 2015(89), Borad et al PLoS Genetics 2014(48), Randall et al Journal of Clinical Oncology 2015(50), Galdy et al Cancer and Metastases Reviews 2016(165), Churi et al PlosOne 2014(83), Turner et al Nature Reviews in Cancer 2010(127), Pai et al European Journal of Cancer Prevention 2011(203), Riener et al Genes Chromosomes and Cancer 2008(212). ICC: intrahepatic cholangiocarcinoma, ECC: extrahepatic cholangiocarcinoma, GBCA gallbladder cancer.

Figure 5

Summary of the relevant pathways for biliary tract cancers. Activation links are described with black arrows. Negative links are described as red lines. Red asterix identifies the mutated variant of the protein. TGFB: Transforming Growth Factor Beta. VEGFA: Vascular Endothelial growth factor A. VEGFR2: Vascular Endothelial Growth Factor Receptor 2. FGF: Fibroblast Growth Factor. FGFR2: Fibroblast Growth Factor Receptor 2. ERBB: Avian Erithroblastic Leukemia Oncogene Homologue protein, previous name for EGFR: Epidermal Growth Factor Receptor. EGF: Epidermal Growth Factor. HER: Human Epidermal growth factor Receptor. SOS: Son Of Sevenless, Ras/Rac Guanine Nucleotide Exchange Factor. HRAS: Harvey Rat Sarcoma Viral Oncogene Homolog protein. KRAS: Kirsten Rat Sarcoma Viral Oncogene Homolog protein. NRAS: Neuroblastoma Rat Sarcoma Viral Oncogene Homolog protein. BRAF: v-Raf murine sarcoma viral oncogene homolog B. SMAD:Mothers against decapentaplegic homolog 1 (Drosophila) protein also know as Transforming Growth Factor-Beta Signaling Protein. MEK:Mitogen-Activated Protein Kinase Kinase. ERK: Mitogen-activated protein kinase. FAK: Focal Adhesion Kinase. PIK3CA: Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha. PIP2: Phosphatidylinositol 4,5-bisphosphate. PIP3:Phosphatidylinositol (3,4,5)-trisphosphate. SRC:Avian Sarcoma (Schmidt-Ruppin A-2) Viral Oncogene Homolog protein. PDK1: Pyruvate Dehydrogenase Kinase 1. PTEN: Phosphatase And Tensin Homolog. AKT: V-Akt Murine Thymoma Viral Oncogene-Like Protein. TSC: Tuberous sclerosis protein. RHEB: Ras Homolog Enriched In Brain protein. mTOR: Mechanistic or Mammalian Target Of Rapamycin. P70S6K: Ribosomal Protein S6 Kinase B1. MDM2: Human Homolog Of Mouse Double Minute 2, P53-Binding Protein. P53: Mutant Tumor Protein 53. IL6: Interleukin 6. IL6RA: IL-6 Receptor Subunit Alpha. JAK: Janus Kinase. STAT: Signal Transducer And Activator Of Transcription. WNT: Wingless-Type MMTV Integration Site Family proteins. AXIN: Axis Inhibition Protein. DSH: Dishevelled family of proteins. GBP: Guanylate Binding Protein. GSK3: Glycogen Synthase Kinase 3. APC: Adenomatous Polyposis Coli BCAT: Beta-catenin. MLL3: Mixed-Lineage Leukemia 3 protein. TET2: Tet Methylcytosine Dioxygenase 2. KDM: Histone lysine demethylase. ARID1A: AT Rich Interactive Domain 1A. PBRM: Polybromo 1 protein. IDH: Isocitrate Dehydrogenase