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Mishra S, Kumari S, Husain N. Liquid biopsy in gallbladder carcinoma: Current evidence and future prospective. THE JOURNAL OF LIQUID BIOPSY 2024; 6:100280. [PMID: 40027313 PMCID: PMC11863890 DOI: 10.1016/j.jlb.2024.100280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 03/05/2025]
Abstract
Although there have been significant advances in the early detection and treatment of gallbladder cancer (GBC), it is still considered a leading cause of morbidity and mortality. Molecular profiling of tumors is generally performed using samples obtained during surgery or biopsy. However, tissue genotyping has its limitations as it only provides a single snapshot and is susceptible to spatial selection bias due to the tumor heterogeneity. Over the past decade, there has been a remarkable transition from invasive diagnostic methods to non-invasive alternatives, including liquid biopsy, for cancer diagnosis and monitoring. Liquid biopsies have ushered in a new era in clinical oncology, enabling convenient tumor sampling, continuous monitoring through repeated analysis, development of personalized treatment regimens, and assessment of therapy resistance. While peripheral blood is the primary medium for these biopsies, other biological fluids, including urine, saliva, and bile, also serve as valuable sources of information. Currently, the focus of blood-based biopsy analyses is on four main sources of biomarkers for cancer detection and stratification: circulating tumor DNA (ctDNA) or circulating free DNA (cfDNA), circulating tumor cells (CTCs), and extracellular vesicle (EVs). There are over 300 clinical trials either ongoing or actively recruiting participants to investigate the diagnostic and prognostic applications of ctDNA/cfDNA in the context of cancer. This review outlines the current standard of care for individuals with GBC, anticipates future treatment developments, and evaluates the potential applications of liquid biopsies in various clinical contexts. The review addresses ctDNA/cfDNA, CTC, and circulating microRNA and highlights their prospective roles in management of GBC.
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Affiliation(s)
- Sridhar Mishra
- Department of Pathology, Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226010, India
- Department of Plastic and Reconstructive Surgery, King George Medical University, Lucknow, Uttar 1pradesh, 226003, India
| | - Swati Kumari
- Department of Pathology, Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226010, India
- Department of Pathology, King George Medical University, Lucknow, Uttar 1pradesh, 226003, India
| | - Nuzhat Husain
- Department of Pathology, Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226010, India
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Kehmann L, Jördens M, Loosen SH, Luedde T, Roderburg C, Leyh C. Evolving therapeutic landscape of advanced biliary tract cancer: from chemotherapy to molecular targets. ESMO Open 2024; 9:103706. [PMID: 39366294 PMCID: PMC11489061 DOI: 10.1016/j.esmoop.2024.103706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 08/07/2024] [Accepted: 08/12/2024] [Indexed: 10/06/2024] Open
Abstract
Biliary tract cancer, the second most common type of liver cancer, remains a therapeutic challenge due to its late diagnosis and poor prognosis. In recent years, it has become evident that classical chemotherapy might not be the optimal treatment for patients with biliary tract cancer, especially after failure of first-line therapy. Finding new treatment options and strategies to improve the survival of these patients is therefore crucial. With the rise and increasing availability of genetic testing in patients with tumor, novel treatment approaches targeting specific genetic alterations have recently been proposed and have demonstrated their safety and efficacy in numerous clinical trials. In this review, we will first consider chemotherapy options and the new possibility of combining chemotherapy with immune checkpoint inhibitors in first-line treatment. We will then provide an overview of genomic alterations and their potential for targeted therapy especially in second-line therapy. In addition to the most common alterations such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, fibroblast growth factor receptor 2 (FGFR2) fusions, and alterations, we will also discuss less frequently encountered alterations such as BRAF V600E mutation and neurotrophic tyrosine kinase receptor gene (NTRK) fusion. We highlight the importance of molecular profiling in guiding therapeutic decisions and emphasize the need for continued research to optimize and expand targeted treatment strategies for this aggressive malignancy.
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Affiliation(s)
- L Kehmann
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité University Medicine Berlin, Berlin, Germany; Servier Deutschland GmbH, München, Germany
| | - M Jördens
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - S H Loosen
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - T Luedde
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - C Roderburg
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - C Leyh
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany.
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Farha N, Dima D, Ullah F, Kamath S. Precision Oncology Targets in Biliary Tract Cancer. Cancers (Basel) 2023; 15:2105. [PMID: 37046766 PMCID: PMC10093316 DOI: 10.3390/cancers15072105] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/25/2023] [Accepted: 03/30/2023] [Indexed: 04/03/2023] Open
Abstract
Targeted therapies in biliary tract cancer (BTC) are emerging as options for patients not who do not respond to first-line treatment. Agents acting on tumor-specific oncogenes in BTC may target fibroblast growth factor receptor 2 (FGFR2), isocitrate dehydrogenase (IDH), B-raf kinase (BRAF), and human epidermal growth factor receptor 2 (HER-2). Additionally, given the heterogeneous genetic landscape of advanced BTCs, many harbor genetic aberrations that are common among solid tumors, including RET fusions, tropomyosin receptor kinase (TRK) fusions, and high tumor mutational burden (TMB). This review aims to provide updates on the evolving array of therapeutics available, and to summarize promising works on the horizon.
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Affiliation(s)
- Nicole Farha
- Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Danai Dima
- Department of Hematology/Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 44195, USA; (D.D.)
| | - Fauzia Ullah
- Department of Hematology/Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 44195, USA; (D.D.)
| | - Suneel Kamath
- Department of Hematology/Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 44195, USA; (D.D.)
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Carotenuto M, Sacco A, Forgione L, Normanno N. Genomic alterations in cholangiocarcinoma: clinical significance and relevance to therapy. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:200-223. [PMID: 36046845 PMCID: PMC9400790 DOI: 10.37349/etat.2022.00079] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 02/22/2022] [Indexed: 11/22/2022] Open
Abstract
Improving the survival of patients with cholangiocarcinoma (CCA) has long proved challenging, although the treatment of this disease nowadays is on advancement. The historical invariability of survival outcomes and the limited number of agents known to be effective in the treatment of this disease has increased the number of studies designed to identify genetic targetable hits that can be efficacious for novel therapies. In this respect, the increasing feasibility of molecular profiling starting either from tumor tissue or circulating cell-free DNA (cfDNA) has led to an increased understanding of CCA biology. Intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA) display different and typical patterns of actionable genomic alterations, which offer opportunity for therapeutic intervention. This review article will summarize the current knowledge on the genomic alterations of iCCA and eCCA, provide information on the main technologies for genomic profiling using either tumor tissue or cfDNA, and briefly discuss the main clinical trials with targeted agents in this disease.
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Affiliation(s)
- Marianeve Carotenuto
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Alessandra Sacco
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Laura Forgione
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Nicola Normanno
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
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Mishra S, Kumari S, Srivastava P, Pandey A, Shukla S, Husain N. Genomic profiling of gallbladder carcinoma: Targetable mutations and pathways involved. Pathol Res Pract 2022; 232:153806. [DOI: 10.1016/j.prp.2022.153806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 01/27/2022] [Accepted: 02/09/2022] [Indexed: 02/07/2023]
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Kuipers H, de Bitter TJJ, de Boer MT, van der Post RS, Nijkamp MW, de Reuver PR, Fehrmann RSN, Hoogwater FJH. Gallbladder Cancer: Current Insights in Genetic Alterations and Their Possible Therapeutic Implications. Cancers (Basel) 2021; 13:5257. [PMID: 34771420 PMCID: PMC8582530 DOI: 10.3390/cancers13215257] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/14/2021] [Accepted: 10/18/2021] [Indexed: 12/29/2022] Open
Abstract
Due to the fast progression in molecular technologies such as next-generation sequencing, knowledge of genetic alterations in gallbladder cancer (GBC) increases. This systematic review provides an overview of frequently occurring genetic alterations occurring in GBC and their possible therapeutic implications. A literature search was performed utilizing PubMed, EMBASE, Cochrane Library, and Web of Science. Only studies reporting genetic alterations in human GBC were included. In total, data were extracted from 62 articles, describing a total of 3893 GBC samples. Frequently detected genetic alterations (>5% in >5 samples across all studies) in GBC for which targeted therapies are available in other cancer types included mutations in ATM, ERBB2, and PIK3CA, and ERBB2 amplifications. High tumor mutational burden (TMB-H) and microsatellite instability (MSI-H) were infrequently observed in GBC (1.7% and 3.5%, respectively). For solid cancers with TMB-H or MSI-H pembrolizumab is FDA-approved and shows an objective response rates of 50% for TMB-H GBC and 41% for MSI-H biliary tract cancer. Only nine clinical trials evaluated targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM, and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials.
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Affiliation(s)
- Hendrien Kuipers
- Department of Surgery, Section Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (M.T.d.B.); (M.W.N.)
| | - Tessa J. J. de Bitter
- Department of Pathology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands; (T.J.J.d.B.); (R.S.v.d.P.)
| | - Marieke T. de Boer
- Department of Surgery, Section Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (M.T.d.B.); (M.W.N.)
| | - Rachel S. van der Post
- Department of Pathology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands; (T.J.J.d.B.); (R.S.v.d.P.)
| | - Maarten W. Nijkamp
- Department of Surgery, Section Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (M.T.d.B.); (M.W.N.)
| | - Philip R. de Reuver
- Department of Surgery, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands;
| | - Rudolf S. N. Fehrmann
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
| | - Frederik J. H. Hoogwater
- Department of Surgery, Section Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (M.T.d.B.); (M.W.N.)
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Intrahepatic Cholangiocarcinoma: A Summative Review of Biomarkers and Targeted Therapies. Cancers (Basel) 2021; 13:cancers13205169. [PMID: 34680318 PMCID: PMC8533913 DOI: 10.3390/cancers13205169] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/08/2021] [Accepted: 10/14/2021] [Indexed: 01/07/2023] Open
Abstract
Simple Summary Intrahepatic cholangiocarcinoma is the second most common primary liver malignancy. Among patients with operable disease, surgical resection is the cornerstone of therapy. Among the majority of patients who present with advanced disease treatment, systemic or targeted therapy is indicated. Recent advancements have provided more novel therapeutic approaches to a subset of patients with intrahepatic cholangiocarcinoma. Abstract Although rare, intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy and the incidence of ICC has increased 14% per year in recent decades. Treatment of ICC remains difficult as most people present with advanced disease not amenable to curative-intent surgical resection. Even among patients with operable disease, margin-negative surgical resection can be difficult to achieve and the incidence of recurrence remains high. As such, there has been considerable interest in systemic chemotherapy and targeted therapy for ICC. Over the last decade, the understanding of the molecular and genetic foundations of ICC has reshaped treatment approaches and strategies. Next-generation sequencing has revealed that most ICC tumors have at least one targetable mutation. These advancements have led to multiple clinical trials to examine the safety and efficacy of novel therapeutics that target tumor-specific molecular and genetic aberrations. While these advancements have demonstrated survival benefit in early phase clinical trials, continued investigation in randomized larger-scale trials is needed to further define the potential clinical impact of such therapy.
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De Lorenzo S, Garajova I, Stefanini B, Tovoli F. Targeted therapies for gallbladder cancer: an overview of agents in preclinical and clinical development. Expert Opin Investig Drugs 2021; 30:759-772. [PMID: 33966562 DOI: 10.1080/13543784.2021.1928636] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023]
Abstract
Introduction: Gallbladder cancer (GC) is a rare malignancy with a dismal prognosis. When diagnosed early enough, it can be cured by surgical removal. Unfortunately, only few GC patients can be amenable to surgery, though, with a high relapse rate. Conventional chemotherapy remains the golden standard for unresectable or metastatic GC, both in the first and second-line settings, even if leading to a fair outcome improvement.Areas covered: In recent years, according to the concept of 'precision medicine', new potential molecular targets have been examined. We provided a general outline of the current first- and second-line chemotherapies. New therapeutic possibilities are also reviewed, particularly HER2, EGFR, VEGF, TKI, MEK and BRAF inhibitors, and immunotherapy. Furthermore, published clinical trials are utilized to analyze the principal drug effectiveness in GC.Expert opinion: GC is characterized by vast cancer heterogeneity and individual's efficacy to different drugs. The ongoing trials have the potentiality of reshaping the landscape of systemic treatments for GC in the very next years. Nowadays, amongst therapeutic combinations, the addition of ICIs to chemotherapy has yielded encouraging results needing confirmation. In the next future, systematic implementation of gene profiling and further explorations of combination therapies will likely change the treatment scenario.
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Affiliation(s)
| | - Ingrid Garajova
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Bernardo Stefanini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
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Song X, Hu Y, Li Y, Shao R, Liu F, Liu Y. Overview of current targeted therapy in gallbladder cancer. Signal Transduct Target Ther 2020; 5:230. [PMID: 33028805 PMCID: PMC7542154 DOI: 10.1038/s41392-020-00324-2] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/08/2020] [Accepted: 09/10/2020] [Indexed: 02/08/2023] Open
Abstract
Gallbladder cancer (GBC) is rare, but is the most malignant type of biliary tract tumor. Unfortunately, only a small population of cancer patients is acceptable for the surgical resection, the current effective regimen; thus, the high mortality rate has been static for decades. To substantially circumvent the stagnant scenario, a number of therapeutic approaches owing to the creation of advanced technologic measures (e.g., next-generation sequencing, transcriptomics, proteomics) have been intensively innovated, which include targeted therapy, immunotherapy, and nanoparticle-based delivery systems. In the current review, we primarily focus on the targeted therapy capable of specifically inhibiting individual key molecules that govern aberrant signaling cascades in GBC. Global clinical trials of targeted therapy in GBC are updated and may offer great value for novel pathologic and therapeutic insights of this deadly disease, ultimately improving the efficacy of treatment.
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Affiliation(s)
- Xiaoling Song
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Yunping Hu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Yongsheng Li
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Rong Shao
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
- Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| | - Fatao Liu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China.
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
| | - Yingbin Liu
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
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Abou-Alfa GK, Jarnagin W, El Dika I, D'Angelica M, Lowery M, Brown K, Ludwig E, Kemeny N, Covey A, Crane CH, Harding J, Shia J, O'Reilly EM. Liver and Bile Duct Cancer. ABELOFF'S CLINICAL ONCOLOGY 2020:1314-1341.e11. [DOI: 10.1016/b978-0-323-47674-4.00077-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Xi SY, Fang D, Huo JG. Progress in molecular targeted therapy of intrahepatic cholangiocarcinoma. Shijie Huaren Xiaohua Zazhi 2018; 26:1707-1716. [DOI: 10.11569/wcjd.v26.i29.1707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Intrahepatic cholangiocarcinoma is an uncommon malignant tumor with a poor prognosis due to an incomplete understanding of its molecular pathogenesis and a lack of effective treatment. Precision medical planning and cancer genomics can help to understand the molecular pathogenesis of cancer and identify potential therapeutic targets. With the deepening of basic and clinical research, accurate targeted therapy will be able to improve the prognosis and overall survival of patients with intrahepatic cholangiocarcinoma.
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Affiliation(s)
- Song-Yang Xi
- Department of Oncology, Zhenjiang Hospital of Chinese Traditional and Western Medicine, Zhenjiang 212000, Jiangsu Province, China
| | - Dong Fang
- Department of Oncology, Zhenjiang Hospital of Chinese Traditional and Western Medicine, Zhenjiang 212000, Jiangsu Province, China
| | - Jie-Ge Huo
- Department of Oncology, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing 210028, Jiangsu Province, China
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Lombardi P, Marino D, Fenocchio E, Chilà G, Aglietta M, Leone F. Emerging molecular target antagonists for the treatment of biliary tract cancer. Expert Opin Emerg Drugs 2018; 23:63-75. [PMID: 29468924 DOI: 10.1080/14728214.2018.1444749] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Biliary tract cancers (BTCs) are a heterogeneous group of cancers, characterized by low incidence but poor prognosis. Even after complete surgical resection for early stage, relapse is frequent and the lack of effective treatments contributes to the dismal prognosis. To date, the only standard treatment in first-line is cisplatin/gemcitabine combination, whereas no standard in 2nd-line has been defined. Hence, the current goal is to better understand the biology of BTCs, discovering new treatment methods and improving clinical outcomes. Areas covered: The development of next-generation-sequencing has unveiled the picture of the molecular signatures characterizing BTCs, leading to the identification of actionable mutations in biomarker-driven clinical trials. In this review we will cover the genetic landscape of BTC, focusing on the efficacy of existing treatments. Furthermore, we will discuss emerging molecular targets and evaluate the findings of pre-clinical studies. Finally, the encouraging results of clinical trials involving targeted therapies or immunotherapy will be reviewed. Expert opinion: FGFR fusion rearrangements and IDH1 or IDH2 mutations are the most promising targeted treatments under evaluation. In addition, innovative trial design will allow to offer a chance for tailored medicine to infrequent subgroups of BTCs patients based on their molecular features rather than their histology.
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Affiliation(s)
- Pasquale Lombardi
- a Department of Oncology , University of Turin Medical School , Turin , Italy
| | - Donatella Marino
- b Medical Oncology , Candiolo Cancer Institute - FPO- IRCCS , Candiolo , Italy
| | | | - Giovanna Chilà
- a Department of Oncology , University of Turin Medical School , Turin , Italy
| | - Massimo Aglietta
- a Department of Oncology , University of Turin Medical School , Turin , Italy.,b Medical Oncology , Candiolo Cancer Institute - FPO- IRCCS , Candiolo , Italy
| | - Francesco Leone
- a Department of Oncology , University of Turin Medical School , Turin , Italy
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Kayhanian H, Smyth EC, Braconi C. Emerging molecular targets and therapy for cholangiocarcinoma. World J Gastrointest Oncol 2017; 9:268-280. [PMID: 28808500 PMCID: PMC5534395 DOI: 10.4251/wjgo.v9.i7.268] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 01/05/2017] [Accepted: 03/24/2017] [Indexed: 02/05/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a rare cancer arising from the biliary tree with a poor prognosis and limited therapeutic options. Recent large scale molecular characterisation studies have identified recurrent genetic alterations in CCA which may be amenable to therapeutic targeting. In this review we explore the genomic landscape of CCA and examine results from trials of molecularly targeted agents and immunotherapy in this disease. Challenges in CCA diagnosis, treatment and trial design are discussed and we reflect on future directions which may lead to improved outcomes for CCA patients.
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Sohal DP, Shrotriya S, Abazeed M, Cruise M, Khorana A. Molecular characteristics of biliary tract cancer. Crit Rev Oncol Hematol 2016; 107:111-118. [DOI: 10.1016/j.critrevonc.2016.08.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 08/09/2016] [Accepted: 08/31/2016] [Indexed: 12/30/2022] Open
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Huang WC, Tsai CC, Chan CC. Mutation analysis and copy number changes of KRAS and BRAF genes in Taiwanese cases of biliary tract cholangiocarcinoma. J Formos Med Assoc 2016; 116:464-468. [PMID: 27745798 DOI: 10.1016/j.jfma.2016.07.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Revised: 07/18/2016] [Accepted: 07/20/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/PURPOSE Cholangiocarcinoma (CC) is a fatal malignancy originating from biliary tracts and constitutes approximately 10-20% of hepatobiliary cancers. CC is characterized by a very poor prognosis. The definite molecular mechanisms leading to oncogenesis remain unclear. This study aimed to perform mutation analysis and copy number changes of KRAS and BRAF genes of CC in Taiwan. METHODS A total of 182 cases of biliary tact CC were studied for point mutation and quantitative real-time polymerase chain reaction analysis of KRAS and BRAF genes. The obtained data were analyzed with clinical and histopathological variables and survival. RESULTS KRAS point mutations were detected in intrahepatic CC (7.6%), common bile duct cancer (13.3%), and gallbladder carcinoma (3.3%). BRAF gene amplifications were demonstrated in intrahepatic CC (4.3%), common bile duct cancer (3.3%), and gallbladder cancer (5%). No association was observed between mutation patterns and histopathological features. The analyses of risk factors for overall survival in patients with CC revealed no significant association in age, tumor site, genetic mutation, or amplifications. The tumor stage was the significant prognostic factor. CONCLUSION Unlike other studies from American, European, or Japanese groups which showed certain levels of gene mutations in CC, our data revealed a rather low frequency of KRAS mutations and BRAF gene amplifications in CC in Taiwan. Tumor TNM stage was the only significant prognostic parameter in this analysis. It is crucial to gain more information of carcinogenesis, molecular mechanisms and therapeutic strategy in biliary tract cholangiocarcinoma.
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Affiliation(s)
- Wen-Chih Huang
- Department of Anatomic Pathology, Far Eastern Memorial Hospital, New Taipei, Taiwan; College of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.
| | - Chien-Chen Tsai
- Department of Anatomic Pathology, Far Eastern Memorial Hospital, New Taipei, Taiwan
| | - Chih-Chieh Chan
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
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16
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Tsukahara T, Shimoyama Y, Ebata T, Yokoyama Y, Igami T, Sugawara G, Mizuno T, Yamaguchi J, Nakamura S, Nagino M. Cholangiocarcinoma with intraductal tubular growth pattern versus intraductal papillary growth pattern. Mod Pathol 2016; 29:293-301. [PMID: 26769137 DOI: 10.1038/modpathol.2015.152] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 11/17/2015] [Accepted: 11/20/2015] [Indexed: 02/08/2023]
Abstract
Intraductal neoplasms of the bile duct are macroscopically characterized by exophytic or polypoid growth patterns and have a favorable prognosis. Although some tumors with a predominantly tubular microscopic pattern have been reported, they have not been well characterized clinicopathologically. The purpose of the present study was to compare the newly recognized cholangiocarcinoma with an intraductal tubular growth pattern and cholangiocarcinoma with an intraductal papillary growth pattern and to investigate the pathological and prognostic significance of the former. This study analyzed 161 patients with tumors with exophytic or polypoid growth patterns from a large series of 733 cholangiocarcinoma cases surgically resected from January 1998 to May 2013. The study patients were divided into two groups: those whose tumors showed a predominantly tubular growth pattern (n=52) and those whose tumors exhibited a predominantly papillary growth pattern (n=109). Tubular growth pattern was associated with combined vascular resection and the absence of macroscopic mucin. Several histological indexes were significantly higher for the tubular growth pattern than the papillary one, including tubular adenocarcinoma, depth of invasion, microscopic lymphatic invasion, venous invasion, perineural invasion, and necrosis. Although the survival curves overlapped (P=0.693), the rate of liver metastasis was significantly higher for the tubular growth pattern than for the papillary one (P=0.012). Genomic DNA analysis focusing on somatic mutations in codons 12 and 13 of KRAS and codon 600 of BRAF revealed only one (4%) KRAS and no BRAF mutation among the 25 tubular cases examined. In conclusion, the tubular growth pattern exhibited differences in some histologic indexes, in addition to a higher hepatic metastasis rate and a lower KRAS mutation frequency, compared with the papillary growth pattern, but no difference in prognosis was observed. The distinctiveness of this tubular neoplasm should be further examined in the future.
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Affiliation(s)
- Tetsuo Tsukahara
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshie Shimoyama
- Department of Pathology and Clinical Laboratories, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomoki Ebata
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukihiro Yokoyama
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tsuyoshi Igami
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Gen Sugawara
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Mizuno
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Junpei Yamaguchi
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shigeo Nakamura
- Department of Pathology and Clinical Laboratories, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masato Nagino
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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17
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Viterbo D, Gausman V, Gonda T. Diagnostic and therapeutic biomarkers in pancreaticobiliary malignancy. World J Gastrointest Endosc 2016; 8:128-142. [PMID: 26862363 PMCID: PMC4734972 DOI: 10.4253/wjge.v8.i3.128] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/17/2015] [Accepted: 12/08/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) are two malignancies that carry significant morbidity and mortality. The poor prognoses of these cancers are strongly related to lack of effective screening modalities as well as few therapeutic options. In this review, we highlight novel biomarkers that have the potential to be used as diagnostic, prognostic and predictive markers. The focus of this review is biomarkers that can be evaluated on endoscopically-obtained biopsies or brush specimens in the pre-operative setting. We also provide an overview of novel serum based markers in the early diagnosis of both PDAC and CCA. In pancreatic cancer, the emphasis is placed on prognostic and theranostic markers, whereas in CCA the utility of molecular markers in diagnosis and prognosis are highlighted.
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18
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Marks EI, Yee NS. Molecular genetics and targeted therapeutics in biliary tract carcinoma. World J Gastroenterol 2016; 22:1335-1347. [PMID: 26819503 PMCID: PMC4721969 DOI: 10.3748/wjg.v22.i4.1335] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 10/29/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.
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19
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Loaiza-Bonilla A, Furth EE, Morrissette JJD. Next-generation sequencing and personalized genomic medicine in hepatobiliary malignancies. Hepat Oncol 2015; 2:359-370. [PMID: 30191018 PMCID: PMC6095428 DOI: 10.2217/hep.15.20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Liver cancer is a heterogeneous group of tumors characterized by significant molecular and genomic heterogeneity. The advent of powerful genomic technologies has allowed detection of recurrent somatic alterations in liver cancer, including mutations, copy number alterations as well as changes in transcriptomes and epigenomes, with the potential to translate these data into clinically relevant predictive and prognostic factors. In this review, we discuss recent advances in the application of high-throughput genomic technologies in liver cancer and the integration of such cancer genome profiling data, highlighting specific relevant subgroups and explain how this knowledge can be used in translational clinical research, 'basket trials', molecular tumor boards, targeted therapy and for personalized genomic medicine applications.
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Affiliation(s)
- Arturo Loaiza-Bonilla
- Abramson Cancer Center, Perelman Center for Advanced Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Emma E Furth
- Department of Pathology & Laboratory Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Jennifer JD Morrissette
- Department of Pathology & Laboratory Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA
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20
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Ang C. Role of the fibroblast growth factor receptor axis in cholangiocarcinoma. J Gastroenterol Hepatol 2015; 30:1116-22. [PMID: 25678238 DOI: 10.1111/jgh.12916] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/22/2015] [Indexed: 02/06/2023]
Abstract
Advanced cholangiocarcinoma (CCA) is a highly lethal disease with limited therapeutic options beyond cytotoxic chemotherapy. Molecular profiling of CCA has provided insights into the pathogenesis of this disease and identified potential therapeutic targets. The fibroblast growth factor receptor (FGFR) axis is important for maintaining tissue homeostasis. Aberrations in FGFR activity have been implicated in the development and progression of CCA and other malignancies, which has generated significant interest in exploring FGFR's therapeutic potential. FGFR2 fusion events are present in up to 17% of intrahepatic CCAs and appear to predict sensitivity to FGFR inhibitors even after progression on chemotherapy. These observations have led to a clinical trial evaluating FGFR inhibition in patients with CCA enriched for FGFR alterations. This review summarizes current knowledge about the role of the FGFR pathway in cholangiocarcinogenesis and ongoing work in developing FGFR-directed therapies as an antineoplastic strategy for CCA.
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Affiliation(s)
- Celina Ang
- Division of Medicine, Hematology, and Medical Oncology, Mount Sinai School of Medicine, New York, New York, USA
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21
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Loaiza-Bonilla A, Clayton E, Furth E, O'Hara M, Morrissette J. Dramatic response to dabrafenib and trametinib combination in a BRAF V600E-mutated cholangiocarcinoma: implementation of a molecular tumour board and next-generation sequencing for personalized medicine. Ecancermedicalscience 2014; 8:479. [PMID: 25435907 PMCID: PMC4239128 DOI: 10.3332/ecancer.2014.479] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Indexed: 12/12/2022] Open
Abstract
This is the case of a 47-year-old woman diagnosed with chemotherapy and radiation-refractory BRAF V600E mutant, poorly differentiated intrahepatic cholangiocarcinoma (ICC), with multiple metastatic lesions within the liver, lungs, pleura, and bone, stage IV. Discussion of her malignancy's next-generation sequencing genomic information at a multidisciplinary molecular tumour board took place. The patient was considered a suitable candidate for dual BRAF and MEK inhibition, with the intent to prolong her survival and optimize the quality of life. We report her excellent tolerance and exceptional response to dual therapy with dabrafenib and trametinib, including symptomatic and sustained near-complete radiological improvement. We also briefly review the current knowledge of the genomics of cholangiocarcinoma with a focus on BRAF mutations, and make a point of the importance of the establishment of a molecular tumour board for personalized genomic medicine approaches. To our knowledge, this is the first reported case of the use of personalized genomic information for the successful management of a patient with ICC, and it is also the first description of dual BRAF and MEK targeted therapy in this malignancy, leading to what is considered an exceptional response.
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Affiliation(s)
- Arturo Loaiza-Bonilla
- Abramson Cancer Center of the University of Pennsylvania, Perelman Center for Advanced Medicine, Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Erica Clayton
- Abramson Cancer Center of the University of Pennsylvania, Perelman Center for Advanced Medicine, Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Emma Furth
- Abramson Cancer Center of the University of Pennsylvania, Perelman Center for Advanced Medicine, Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Mark O'Hara
- Abramson Cancer Center of the University of Pennsylvania, Perelman Center for Advanced Medicine, Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Jennifer Morrissette
- Abramson Cancer Center of the University of Pennsylvania, Perelman Center for Advanced Medicine, Civic Center Boulevard, Philadelphia, PA 19104, USA
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22
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Andersen JB. Molecular pathogenesis of intrahepatic cholangiocarcinoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2014; 22:101-13. [PMID: 25174625 DOI: 10.1002/jhbp.155] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cholangiocarcinoma (CCA) is an orphan cancer of the hepatobiliary tract, the incidence of which has increased in the past decade. The molecular pathogenesis of this treatment-refractory disease is poorly understood. Desmoplasia is a key causal feature of CCA; however, a majority of tumors develop with no apparent etiological background. The impact of the stromal compartment on tumor progression as well as resistance to therapy is in vogue, and the epithelial-stromal crosstalk may present a target for novel treatment strategies. As such, the complexity of tumor cellularity and the molecular mechanisms underlying the diversity of growth patterns of this malignancy remain a clinical concern. It is crucial to advance our present understanding of the molecular pathogenesis of CCA to improve current clinical strategies and patient outcome. This will facilitate the delineation of patient subsets and individualization for precision therapies. Many questions persevere as to the evolutionary process and cellular origin of the initial transforming event, the context of intratumoral plasticity and the causal driver action. Next-generation sequencing has begun to underline the persistent alterations, which may be the trigger of acquired drug resistance, and the cause of metastasis and disease recurrence. A complex issue that remains is to account for the heterogeneous pool of "backseat" aberrations, which in chromosomal proximity to the causative variant are likely to influence, for example, drug response. This review explores the recent advances in defining the molecular pathways implicated in the development of this devastating disease and, which present putative clinical strategies.
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Affiliation(s)
- Jesper B Andersen
- Andersen Group, Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, DK-2200, Copenhagen N, Denmark.
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23
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Goeppert B, Frauenschuh L, Renner M, Roessler S, Stenzinger A, Klauschen F, Warth A, Vogel MN, Mehrabi A, Hafezi M, Boehmer K, von Deimling A, Schirmacher P, Weichert W, Capper D. BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma. Mod Pathol 2014; 27:1028-34. [PMID: 24309328 DOI: 10.1038/modpathol.2013.206] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Accepted: 09/24/2013] [Indexed: 02/08/2023]
Abstract
BRAF mutations have emerged as an important predictive biomarker for metastasized melanoma. Other types of cancer may also benefit from BRAF mutation-targeted therapies. In biliary tract cancer, reported BRAF mutation rates are highly controversial, ranging from 0 to 33% in adenocarcinoma of the gallbladder and 0 to 22% in cholangiocarcinoma. We here analyzed tissue microarrays of a large cohort of biliary tract cancer (n=377) including 159 intrahepatic cholangiocarcinomas, 149 extrahepatic cholangiocarcinomas, and 69 adenocarcinomas of the gallbladder for BRAF V600E mutation using a highly sensitive immunohistochemical screening approach implementing the BRAF V600E protein-specific antibody VE1. All VE1-positive cases as well as 42 VE1-negative cases were additionally analyzed by Sanger sequencing. In total, only 5 VE1-positive cases were detected (5/377; 1%). BRAF V600E mutation was confirmed by direct sequencing in all cases. All 5 mutated cases were intrahepatic cholangiocarcinomas (5/159; 3%). None of the extrahepatic cholangiocarcinomas and adenocarcinomas of the gallbladder were VE1 positive. Apart from the subtype restriction of BRAF V600E mutation to intrahepatic cholangiocarcinoma and a female predominance (4 female, 1 male), no significant correlation with clinicopathological data and patient outcome was detected. In conclusion, we demonstrate that BRAF V600E mutation is a rare event in biliary tract cancer, accounting for only 1% of all subtypes, and is restricted to intrahepatic cholangiocarcinoma. In addition, we demonstrate that VE1 immunohistochemistry is a feasible approach to routinely screen for BRAF V600E mutation in biliary tract cancer patients, thereby facilitating the detection of rare patients who may benefit from BRAF mutation-targeted therapies.
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Affiliation(s)
- Benjamin Goeppert
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Lena Frauenschuh
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Marcus Renner
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | | | | | - Arne Warth
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Monika Nadja Vogel
- Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Mohammadreza Hafezi
- Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Katja Boehmer
- Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Andreas von Deimling
- 1] Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany [2] Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Wilko Weichert
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - David Capper
- 1] Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany [2] Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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24
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Chang YT, Chang MC, Huang KW, Tung CC, Hsu C, Wong JM. Clinicopathological and prognostic significances of EGFR, KRAS and BRAF mutations in biliary tract carcinomas in Taiwan. J Gastroenterol Hepatol 2014; 29:1119-1125. [PMID: 24372748 DOI: 10.1111/jgh.12505] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/05/2013] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIM Biliary tract carcinomas (BTCs) are difficult to diagnose and treat. Epidermal growth factor receptor (EGFR) represents a therapeutic target for the BTCs. Mutations of the EGFR gene and the activation of its downstream pathways, including KRAS and BRAF, predict the sensitivity to anti-EGFR treatment. The aims of this study were to analyze the EGFR, KRAS and BRAF mutations in BTCs and their association with clinical outcomes. METHODS Paraffin-embedded specimens containing 137 BTCs resected at the National Taiwan University Hospital between 1995 and 2004 were analyzed. The exons 18-21 of EGFR gene, the codon 12, 13 and 61 of KRAS gene, and BRAF V600E mutation were analyzed. We examined the correlation between these mutations and the overall survival, tumor location, stage, and differentiation in BTCs. RESULTS Thirteen (9.5%) BTC patients had EGFR mutations while 23 (16.8%) patients had KRAS mutations. Only one patient had BRAF mutation. Factors influencing survival on univariate analysis were tumor stage, tumor differentiation, and EGFR mutation. On multivariate analysis, EGFR mutation and tumor stage were independent prognostic factors. A correlation between KRAS or BRAF mutations and prognosis was not observed. CONCLUSIONS EGFR and KRAS mutations are not uncommon in BTCs. BRAF mutation is rare in BTCs. EGFR mutation was an independent prognostic marker in BTCs in addition to tumor stage and differentiation. No simultaneous EGFR and KRAS mutations in extrahepatic cholangiocarcinoma and gallbladder carcinoma were found. EGFR and KRAS mutations should be evaluated when tailoring molecular-targeted therapy to patients with BTCs.
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Affiliation(s)
- Yu-Ting Chang
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
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25
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Abstract
Biliary tract cancer (BTC) is a group of relatively rare tumors with a poor prognosis. The current standard of care consists of doublet chemotherapy (platinum plus gemcitabine); however, even with cytotoxic therapy, the median overall survival is less than 1 year. The genetic basis of BTC is now more clearly understood, allowing for the investigation of targeted therapy. Combinations of doublet chemotherapy with antiepidermal growth factor receptor agents have provided modest results in Phase II and Phase III setting, and responses with small molecule inhibitors are limited. Moving forward as we continue to characterize the genetic hallmarks of BTC, a stepwise, strategic, and cooperative approach will allow us to make progress when developing new treatments.
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Affiliation(s)
- Marcus S Noel
- James P Wilmot Cancer Center, University of Rochester, Rochester, NY, USA
| | - Aram F Hezel
- James P Wilmot Cancer Center, University of Rochester, Rochester, NY, USA
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26
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The frequency of KRAS and BRAF mutations in intrahepatic cholangiocarcinomas and their correlation with clinical outcome. Hum Pathol 2013; 44:2768-73. [PMID: 24139215 DOI: 10.1016/j.humpath.2013.07.026] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Revised: 07/18/2013] [Accepted: 07/19/2013] [Indexed: 12/18/2022]
Abstract
The incidence of intrahepatic cholangiocarcinoma is increasing worldwide. The prognosis of intrahepatic cholangiocarcinoma is poor, and a better understanding of intrahepatic cholangiocarcinoma tumor biology is needed to more accurately predict clinical outcome and to suggest potential targets for more effective therapies. v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and BRAF are frequently mutated oncogenes that promote carcinogenesis in a variety of tumor types. In this study, we analyze a large set of intrahepatic cholangiocarcinoma tumors (n = 54) for mutations in these genes and compare the clinical outcomes of wild type versus KRAS and BRAF mutant cases. Of 54 cases, 7.4% were mutant for KRAS, 7.4% were mutant for BRAF, and these were mutually exclusive. These mutant cases were associated with a higher tumor stage at time of resection and a greater likelihood of lymph node involvement. These cases were also associated with a worse long-term overall survival. Therefore, testing for KRAS and BRAF mutations could be a valuable adjunct in improving both prognosis and outcome stratification among patients with intrahepatic cholangiocarcinoma.
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27
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Faris JE, Zhu AX. Targeted therapy for biliary tract cancers. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2013; 19:326-36. [PMID: 22318523 DOI: 10.1007/s00534-011-0496-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Biliary tract cancers (BTCs) are a heterogeneous group of malignancies, with a historically poor prognosis as a whole. Until recently, the development of effective therapeutics was hampered by the relatively low incidence, heterogeneity in patients and tumors, and correspondingly poor clinical trial enrollments. With the publication of the landmark phase III ABC-02 trial demonstrating the superiority of gemcitabine and cisplatin combination chemotherapy, the landscape changed for the development of new agents. Despite this progress, there are currently no approved targeted agents for BTC. This review will focus on recent developments in targeted therapeutics, directed against several key signaling pathways in BTC, including epidermal growth factor receptor, angiogenesis, and the mitogen-activated protein kinase pathway. Data from recent phase I and II trials will be discussed, along with a preview of upcoming trials involving targeted therapies.
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Affiliation(s)
- Jason E Faris
- Harvard Medical School, Tucker Gosnell Center for Gastrointestinal Cancers, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Yawkey 7E, Boston, MA 02114, USA.
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Xu J, Knox JJ, Ibrahimov E, Chen E, Serra S, Tsao M, Cao P, Vines D, Green DE, Metran-Nascente C, McNamara MG, Hedley DW. Sequence dependence of MEK inhibitor AZD6244 combined with gemcitabine for the treatment of biliary cancer. Clin Cancer Res 2012; 19:118-27. [PMID: 23091117 DOI: 10.1158/1078-0432.ccr-12-2557] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
PURPOSE MEK inhibition has clinical activity against biliary cancers and might therefore be successfully combined with gemcitabine, one of the most active chemotherapy agents for these cancers. As gemcitabine is active in S-phase, and the extracellular signal-regulated kinase (ERK) pathway has a major role driving cell-cycle progression, concurrent use of a MEK inhibitor could potentially antagonize the effect of gemcitabine. We therefore tested the sequence dependence of the combination of gemcitabine and the MEK inhibitor AZD6244 using a series of biliary cancer models. EXPERIMENTAL DESIGN Primary xenografts were established from patients with gallbladder and distal bile duct cancer and grown in severe combined immunodeficient (SCID) mice at the subcutaneous site. Plasma and tumor drug levels and the time course for recovery of ERK signaling and S-phase were measured in tumor-bearing mice treated for 48 hours with AZD6244 and then monitored for 48 hours off treatment. On the basis of these results, two different treatment schedules combining AZD6244 with gemcitabine were tested in four different biliary cancer models. RESULTS DNA synthesis was suppressed during treatment with AZD6244, and reentry into S-phase was delayed by approximately 48 hours after treatment. Strong schedule dependence was seen in all four biliary cancer models tested, suggesting that combined treatment with AZD6244 plus gemcitabine would be more active in patients with biliary cancer when gemcitabine is given following a 48-hour interruption in AZD6244 dosing, rather than concurrently. CONCLUSIONS The combination of AZD6244 plus gemcitabine is highly schedule dependent, and predicted to be more effective in the clinic using sequential rather than simultaneous dosing protocols.
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Affiliation(s)
- Junyao Xu
- Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada
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Abstract
PURPOSE OF REVIEW Intrahepatic cholangiocarcinoma (ICC) is a treatment-refractory disease with a dismal outcome. Limited success in the clinical management and a persistent increase in the incidence world-wide have made ICC one of the most lethal and fastest growing malignancies. However, recent advancements in genome-wide technologies combined with the application of integrative multidimensional analytical approaches have begun to provide both detailed insight into the underlying biological traits of ICC and identified new therapeutic opportunities. RECENT FINDINGS In comparison with other cancers, genomic studies of ICC have been limited. We and others have recently procured large cohorts of ICC patients intended for genome-wide analyses. In our study, samples from ICC patients were obtained from three cancer centers and subjected to integrated genetic and genomic analyses. We provided new insights into both pathogenesis and optimal treatment options demonstrating the presence of unique subclasses of patients, based partly on KRAS mutations and increased levels of receptor tyrosine kinase signaling. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes regulating inflammation and proteasome activities, suggesting a combination of tyrosine kinase inhibitors and anti-inflammatory drugs as a new therapeutic option for these patients. SUMMARY We have critically examined the progress in genome-wide studies of ICC including genetic profiling, transcriptomics, and epigenomics. Current limitations in applying these technologies to archival samples and the insufficient access to fresh-frozen material are partly the cause of the delayed implementation of the omics-based investigations of ICC compared to other hepatobiliary diseases. Thus, selected candidate single-gene studies will also be discussed.
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Bekaii-Saab T, Phelps MA, Li X, Saji M, Goff L, Kauh JSW, O'Neil BH, Balsom S, Balint C, Liersemann R, Vasko VV, Bloomston M, Marsh W, Doyle LA, Ellison G, Grever M, Ringel MD, Villalona-Calero MA. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol 2011; 29:2357-63. [PMID: 21519026 PMCID: PMC3107751 DOI: 10.1200/jco.2010.33.9473] [Citation(s) in RCA: 238] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2010] [Accepted: 02/14/2011] [Indexed: 12/29/2022] Open
Abstract
PURPOSE Biliary cancers (BCs) carry a poor prognosis, but targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is of significance. Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC. PATIENTS AND METHODS This was a multi-institutional phase II study of selumetinib at 100 mg given orally twice per day to patients with advanced BC. The primary end point was response rate. All patients were required to provide tissue before enrolling. The levels of phosphorylated ERK (pERK) and AKT (pAKT) were assessed by immunohistochemistry. Tumors were genotyped for the presence of BRAF- and/or RAS-activating mutations. RESULTS Twenty-eight eligible patients with a median age of 55.6 years were enrolled. Thirty-nine percent of patients had received one prior systemic therapy. Three patients (12%) had a confirmed objective response. Another 17 patients (68%) experienced stable disease (SD), 14 of whom (56%) experienced prolonged SD (> 16 weeks). Patients gained an average nonfluid weight of 8.6 pounds. Median progression-free survival was 3.7 months (95% CI, 3.5 to 4.9) and median overall survival was 9.8 months (95% CI, 5.97 to not available). Toxicities were mild, with rash (90%) and xerostomia (54%) being most frequent. Only one patient experienced grade 4 toxicity (fatigue). All patients had tissue available for analysis. No BRAF V600E mutations were found. Two patients with short-lived SD had KRAS mutations. Absence of pERK staining was associated with lack of response. CONCLUSION Selumetinib displays interesting activity and acceptable tolerability in patients with metastatic BC. Our results warrant further evaluation of selumetinib in patients with metastatic BC.
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Affiliation(s)
- Tanios Bekaii-Saab
- The Ohio State University Comprehensive Cancer Center--James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA.
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Bekaii-Saab T, Phelps MA, Li X, Saji M, Goff L, Kauh JSW, O'Neil BH, Balsom S, Balint C, Liersemann R, Vasko VV, Bloomston M, Marsh W, Doyle LA, Ellison G, Grever M, Ringel MD, Villalona-Calero MA. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol 2011. [PMID: 21519026 DOI: 10.1200/jco2010.33.9473] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
PURPOSE Biliary cancers (BCs) carry a poor prognosis, but targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is of significance. Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC. PATIENTS AND METHODS This was a multi-institutional phase II study of selumetinib at 100 mg given orally twice per day to patients with advanced BC. The primary end point was response rate. All patients were required to provide tissue before enrolling. The levels of phosphorylated ERK (pERK) and AKT (pAKT) were assessed by immunohistochemistry. Tumors were genotyped for the presence of BRAF- and/or RAS-activating mutations. RESULTS Twenty-eight eligible patients with a median age of 55.6 years were enrolled. Thirty-nine percent of patients had received one prior systemic therapy. Three patients (12%) had a confirmed objective response. Another 17 patients (68%) experienced stable disease (SD), 14 of whom (56%) experienced prolonged SD (> 16 weeks). Patients gained an average nonfluid weight of 8.6 pounds. Median progression-free survival was 3.7 months (95% CI, 3.5 to 4.9) and median overall survival was 9.8 months (95% CI, 5.97 to not available). Toxicities were mild, with rash (90%) and xerostomia (54%) being most frequent. Only one patient experienced grade 4 toxicity (fatigue). All patients had tissue available for analysis. No BRAF V600E mutations were found. Two patients with short-lived SD had KRAS mutations. Absence of pERK staining was associated with lack of response. CONCLUSION Selumetinib displays interesting activity and acceptable tolerability in patients with metastatic BC. Our results warrant further evaluation of selumetinib in patients with metastatic BC.
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Affiliation(s)
- Tanios Bekaii-Saab
- The Ohio State University Comprehensive Cancer Center--James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA.
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Deshpande V, Nduaguba A, Zimmerman SM, Kehoe SM, Macconaill LE, Lauwers GY, Ferrone C, Bardeesy N, Zhu AX, Hezel AF. Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma. BMC Cancer 2011; 11:60. [PMID: 21303542 PMCID: PMC3045359 DOI: 10.1186/1471-2407-11-60] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Accepted: 02/08/2011] [Indexed: 02/06/2023] Open
Abstract
Background The genetics of advanced biliary tract cancers (BTC), which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined. Methods To better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases. Results Mutations among three genes, KRAS, NRAS and PIK3CA were confirmed in this cohort. Activating mutations in PIK3CA were identified exclusively in GBC (4/32, 12.5%). KRAS mutations were identified in 3 (13%) intra-hepatic cholangiocarcinomas and 1 (33%) perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma. Conclusions The presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors.
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Affiliation(s)
- Vikram Deshpande
- Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA
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Zhu AX, Hezel AF. Development of molecularly targeted therapies in biliary tract cancers: reassessing the challenges and opportunities. Hepatology 2011; 53:695-704. [PMID: 21274890 DOI: 10.1002/hep.24145] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Biliary tract cancers (BTCs), which encompass intra- and extrahepatic cholangiocarcinomas as well as gallbladder carcinomas, are a genetically diverse collection of cancers. Most patients with BTC will present with unresectable or metastatic disease. Although the standard systemic chemotherapy approaches are emerging, the prognosis remains poor. Development of molecularly targeted therapies in advanced BTC remains challenging. Recent early-stage clinical trials with targeted therapies appear promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored. Here we summarize the relevant molecular pathogenesis, recent and ongoing clinical trials with targeted agents, and the key issues in clinical trial design in BTC.
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Affiliation(s)
- Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
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Xu RF, Sun JP, Zhang SR, Zhu GS, Li LB, Liao YL, Xie JM, Liao WJ. KRAS and PIK3CA but not BRAF genes are frequently mutated in Chinese cholangiocarcinoma patients. Biomed Pharmacother 2010; 65:22-6. [PMID: 21051183 DOI: 10.1016/j.biopha.2010.06.009] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2010] [Accepted: 06/21/2010] [Indexed: 12/31/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a rare but lethal malignancy arising from the biliary tract epithelium. It has a poor prognosis largely due to the difficulties of early diagnosis and the lack of effective therapies. It is thus imperative to develop new and effective treatments for CCA, which depends heavily on the mechanistic understanding of the disease. Previous studies have suggested that somatic mutations in KRAS, BRAF, and PIK3CA genes are frequently found in several types of human cancers including colon, breast, and lung carcinomas as well as CCA. Yet, the frequency and the involvement of these oncogenic mutations in CCA in Chinese population have not been investigated. In this study, we evaluated the hotspot mutations of KRAS, BRAF, and PIK3CA genes in 34 Chinese CCA patients. Sequencing analysis revealed 13 (38.2%) and 11 (32.4%) patients bearing KRAS and PIK3CA mutations, in which two (5.9%) of them harbored both KRAS and PIK3CA mutations. Surprisingly, no BRAF mutation was detected in all 34 CCA samples. Our findings indicate that somatic mutations in KRAS and PIK3CA but not BRAF oncogenes are closely associated with the development of CCA in Chinese population and provide new potential targets for future therapeutic treatments of the disease.
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Affiliation(s)
- Rui Feng Xu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou Avenue North 1838, Guangzhou, Guangdong Province 510515, P R China
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Hezel AF, Deshpande V, Zhu AX. Genetics of biliary tract cancers and emerging targeted therapies. J Clin Oncol 2010; 28:3531-40. [PMID: 20547994 PMCID: PMC2982782 DOI: 10.1200/jco.2009.27.4787] [Citation(s) in RCA: 171] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2009] [Accepted: 04/28/2010] [Indexed: 12/13/2022] Open
Abstract
Biliary tract cancers (BTC), which encompass intra- and extrahepatic cholangiocarcinomas and gallbladder carcinomas, are a genetically diverse collection of cancers. Evidence suggests distinct models of molecular and pathologic progression, and a growing body of genetics data points to a heterogeneous collection of underlying mutations in key oncogenes and tumor suppressor genes. Although tumor genetics have been used to tailor individual treatment regimens and guide clinical decision making in other cancers, these principles have not been applied in BTC. Recent clinical trials with targeted therapies seem promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored. Here, we summarize the molecular pathogenesis and genetics of BTCs and animal modeling and relate these to recent and ongoing clinical trials with targeted agents.
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Affiliation(s)
- Aram F Hezel
- James P Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, NY 14642, USA.
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Chuang TCY, Chuang AYC, Poeta L, Koch WM, Califano JA, Tufano RP. Detectable BRAF mutation in serum DNA samples from patients with papillary thyroid carcinomas. Head Neck 2010; 32:229-34. [PMID: 19626635 DOI: 10.1002/hed.21178] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND.: An activating point mutation of the BRAF oncogene results in a V600E amino acid missense mutation found in a majority of papillary thyroid carcinomas (PTC). METHODS.: In this study, 28 matched tumor and serum samples obtained from patients with both benign and malignant thyroid disorders were analyzed for BRAF mutation using a gap-ligase chain reaction technique. RESULTS.: The BRAF mutation was absent in tumor DNA samples obtained from patients with benign adenomas, follicular neoplasms or carcinoma, and thyroid lymphoma. In contrast, 5 of 14 PTC tumors were positive for the BRAF mutation. Moreover, 3 of 14 patients with PTC were positive for BRAF mutation in serum and tumor. Of these 3 patients, 2 had lymph node metastasis and 2 had PTC in background of the Hashimoto's thyroiditis. CONCLUSIONS.: The detection of free circulating mutant BRAF in patients with PTC is possible and future studies are warranted to determine its clinical significance.
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Affiliation(s)
- Tony C Y Chuang
- Department of Otolaryngology Head and Neck Surgery, Division of Head and Neck Cancer Research, Johns Hopkins Medical Institutions, Baltimore, MD 21287-0910, USA
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Kim T, Roh JH, Park HJ, Kwon JE, Kang SY, Choi YL, Oh YL. The Frequency ofBRAFMutation in Very Small Papillary Thyroid Carcinomas. KOREAN JOURNAL OF PATHOLOGY 2010. [DOI: 10.4132/koreanjpathol.2010.44.3.308] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Taeeun Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji-Hyun Roh
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee-Jung Park
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jee Eun Kwon
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - So-Young Kang
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yoon-La Choi
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Lyun Oh
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Yoshimoto T, Takahashi M, Nagayama S, Watanabe G, Shimada Y, Sakasi Y, Kubo H. RNA mutations of prox1 detected in human esophageal cancer cells by the shifted termination assay. Biochem Biophys Res Commun 2007; 359:258-62. [PMID: 17533110 DOI: 10.1016/j.bbrc.2007.05.071] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2007] [Accepted: 05/10/2007] [Indexed: 01/12/2023]
Abstract
We have recently reported a novel finding that a candidate tumor suppressor gene prox1 suffered adenosine-to-inosine (A-to-I) RNA mutation without genomic mutation in a subset of human cancer cells and lost its function. Hence, screening of mutations in both cDNA and genomic DNA could be important in the analysis of causes for cancers. Here, we applied a sensitive, accurate, and simple method, called shifted termination assay (STA) for detection of an A-to-I RNA mutation (R334G) in prox1. We prepared PCR-amplified samples containing the target base of RNA mutation from cDNAs and genomic DNAs of various cell lines and clinical samples, to demonstrate that the STA method can be used to identify not only genomic mutations but also RNA mutations more effectively compared to sequencing. By means of STA, we found prox1 R334G RNA mutations but not genomic DNA mutations in 4 of 8 cases of esophageal cancers. This method can help us to detect RNA mutation effectively and progress research of a potential oncogenic principle.
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Affiliation(s)
- Takanobu Yoshimoto
- Molecular & Cancer Research Unit, HMRO, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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