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Kim Y, Jee S, Kim H, Paik SS, Choi D, Yoo SH, Shin SJ. EGFR, HER2, and MET gene amplification and protein expression profiles in biliary tract cancer and their prognostic significance. Oncologist 2024; 29:e1051-e1060. [PMID: 38709907 PMCID: PMC11299936 DOI: 10.1093/oncolo/oyae076] [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: 01/30/2024] [Accepted: 04/03/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND There are limited conventional chemotherapy options for biliary tract cancers (BTCs), a heterogenous group of lethal, rare malignancies. The receptor tyrosine kinase (RTK) is closely associated with the progression of human malignancies through the regulation of cell cycle. Overexpression or amplification of RTKs has been investigated as a potential biomarker and therapeutic target in BTC; herein, we investigate the value of such interventions. MATERIALS AND METHODS Overexpression of RTK proteins was examined by immunohistochemistry in 193 BTC samples, of which 137 were gallbladder carcinoma, 29 were perihilar cholangiocarcinoma, and 27 were intrahepatic cholangiocarcinoma. Silver in situ hybridization of MET and HER2 was performed to assess gene amplification. RESULTS In the entire cancer group, gallbladder, perihilar, and intrahepatic, MET amplification rates were 15.7%, 19.0%, 3.4%, and 14.8%, respectively, and of HER2 amplification rates were 22.4%, 27.2%, 17.2%, and 3.7%, respectively. MET and HER2 protein expressions were significantly correlated with their gene amplification status. RTKs were significantly associated with adverse clinicopathologic features such as advanced pT category and lymph node metastasis. Overall survival was significantly shorter in MET-amplified (P = .024) and EGFR-overexpressed cases (P = .045). Recurrence-free survival was significantly correlated with HER2-amplified (P = .038) and EGFR-overexpressed cases (P = .046) in all patient groups. Overall and recurrence-free survival were significantly shorter in patients who were double positive for HER2 and EGFR. CONCLUSION Our data suggested that MET, HER2, and EGFR might be potential therapeutic targets and that their co-expression is a strong prognostic factor for BTCs.
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Affiliation(s)
- Yeseul Kim
- Department of Pathology, University of Korea College of Medicine, Anam Hospital, Seoul, Republic of Korea
| | - Seungyun Jee
- Departments of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyunsung Kim
- Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Seung Sam Paik
- Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Dongho Choi
- Department of Surgery, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Su Hyun Yoo
- Department of Pathology, National Police Hospital, Seoul, Republic of Korea
| | - Su-Jin Shin
- Departments of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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Chung HH, Seo SH, Kim H, Kim Y, Kim DW, Lee KH, Lee KT, Heo JS, Han IW, Park SM, Jang KT, Lee JK, Park JK. Postoperative Prognostic Predictors of Bile Duct Cancers: Clinical Analysis and Immunoassays of Tissue Microarrays. Gut Liver 2023; 17:159-169. [PMID: 36317517 PMCID: PMC9840923 DOI: 10.5009/gnl220044] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/02/2022] [Accepted: 04/14/2022] [Indexed: 01/14/2023] Open
Abstract
Background/Aims Cholangiocarcinoma frequently recurs even after curative resection. Expression levels of proteins such as epidermal growth factor receptor (EGFR), Snail, epithelial cadherin (E-cadherin), and interleukin-6 (IL-6) examined by immunohistochemistry have been studied as potential prognostic factors for cholangiocarcinoma. The aim of this study was to investigate significant factors affecting the prognosis of resectable cholangiocarcinoma. Methods Ninety-one patients who underwent surgical resection at Samsung Medical Center for cholangiocarcinoma from 1995 to 2013 were included in this study. Expression levels of E-cadherin, Snail, IL-6, membranous EGFR, and cytoplasmic EGFR were analyzed by immunohistochemistry using tissue microarray blocks made from surgical specimens. Results Patients with high levels of membranous EGFR in tissue microarrays had significantly shorter overall survival (OS) and disease-free survival (DFS): high membranous EGFR (score 0-2) 38.0 months versus low membranous EGFR (score 3) 14.4 months (p=0.008) and high membranous EGFR (score 0-2) 23.2 months versus low membranous EGFR (score 3) 6.1 months (p=0.004), respectively. On the other hand, E-cadherin, Snail, cytoplasmic EGFR, and IL-6 did not show significant association with OS or DFS. Patients with distant metastasis had significantly higher IL-6 levels than those with locoregional recurrence (p=0.01). Conclusions This study showed that overexpression of membranous EGFR was significantly associated with shorter OS and DFS in surgically resected bile duct cancer patients. In addition, higher IL-6 expression was a predictive marker for recurrence in cholangiocarcinoma patients with distant organ metastasis after surgical resection.
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Affiliation(s)
- Hwe Hoon Chung
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Hee Seo
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyemin Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yuil Kim
- Department of Clinical Pathology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea
| | - Dong Wuk Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwang Hyuck Lee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyu Taek Lee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jin Seok Heo
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - In Woong Han
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seon Mee Park
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Kee-Taek Jang
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea,Kee-Taek Jang, ORCIDhttps://orcid.org/0000-0001-7987-4437, E-mail
| | - Jong Kyun Lee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea,Jong Kyun Lee, ORCIDhttps://orcid.org/0000-0002-9384-3079, E-mail
| | - Joo Kyung Park
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea,Corresponding AuthorJoo Kyung Park, ORCIDhttps://orcid.org/0000-0002-9652-5287, E-mail
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Hewitt DB, Aziz H, Brown ZJ, Pawlik TM. Role of genetic testing in hepatic, pancreatic, and biliary cancers. Surg Oncol 2022; 44:101844. [PMID: 36116416 DOI: 10.1016/j.suronc.2022.101844] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 08/21/2022] [Accepted: 08/24/2022] [Indexed: 12/24/2022]
Abstract
Hepatic, pancreatic, and biliary (HPB) cancers, including hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), and cholangiocarcinoma (CCA) cause a disproportionate amount of the global cancer-related mortality. Despite advances in surgical technique and improved systemic therapies, overall 5-year survival remains dismal, especially for patients with pancreatic and biliary cancer. Historically, systemic therapies for patients with HPB cancers were administered in a "one-size-fits-all" approach due to limited reliable data on efficacy for specific patient populations. However, recent advances in genetic testing techniques have greatly improved our understanding of HPB oncogenesis, shedding light on specific genetic mutations responsible for progression from physiologic cellular regulation to uninhibited cellular replication and invasive cancer. Investigations into the oncogenesis of HPB cancers have revealed multiple actionable genetic variants, as well as increased susceptibilities to currently available systemic therapies. For example, patients with PDAC and a known BRCA mutation are more likely to benefit from FOLFIRINOX or gemcitabine plus cisplatin. While patients with CCA and a IDH1 mutation may benefit from ivosidenib. As a result, many national and societal guidelines now recommend some form of genetic testing in the workup of patients with HPB cancers. We herein review the role of genetic testing in these aggressive cancers including DNA sequencing techniques, clinically relevant mutations, therapeutic implications, and current clinical recommendations.
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Affiliation(s)
- D Brock Hewitt
- Department of Surgery, The Ohio State Wexner Medical Center, Columbus, OH, USA
| | - Hassan Aziz
- Department of Surgery, Tufts University Medical Center, Boston, MA, USA
| | - Zachary J Brown
- Department of Surgery, The Ohio State Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State Wexner Medical Center, Columbus, OH, USA.
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Gray S, Lamarca A, Edeline J, Klümpen HJ, Hubner RA, McNamara MG, Valle JW. Targeted Therapies for Perihilar Cholangiocarcinoma. Cancers (Basel) 2022; 14:1789. [PMID: 35406560 PMCID: PMC8997784 DOI: 10.3390/cancers14071789] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 11/16/2022] Open
Abstract
Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient's cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy.
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Affiliation(s)
- Simon Gray
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Julien Edeline
- Centre Eugène Marquis, Av. de la Bataille Flandres Dunkerque-CS 44229, CEDEX, 35042 Rennes, France;
| | - Heinz-Josef Klümpen
- Department of Medical Oncology, Amsterdam University Medical Center, P.O. Box 7057, 1081 HV Amsterdam, The Netherlands;
| | - Richard A. Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Mairéad G. McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Juan W. Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
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Meta-analysis on prognostic value of KRAS mutation in resected mass-forming cholangiocarcinoma. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2022; 48:1455-1463. [PMID: 35317947 DOI: 10.1016/j.ejso.2022.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 02/14/2022] [Accepted: 03/08/2022] [Indexed: 11/22/2022]
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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: 20] [Impact Index Per Article: 5.0] [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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Uecker M, Lehmann U, Braubach P, Schukfeh N, Madadi-Sanjani O, Ure BM, Petersen C, Kuebler JF. Choledochal Cysts Resected during Childhood Show No Mutations of KRAS and BRAF as Early Markers of Malignancy in Cholangiocytes. Eur J Pediatr Surg 2021; 31:20-24. [PMID: 32820496 DOI: 10.1055/s-0040-1715610] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION In patients with choledochal cysts (CDC), a hyperplasia-dysplasia-carcinoma sequence can lead to biliary tract malignancy. The limited data available suggest that the risk decreases considerably after excision in childhood. We analyzed samples of resected CDC from pediatric patients histologically and performed mutational analysis of the proto-oncogenes KRAS and BRAF as early markers of malignant alteration in cholangiocytes. MATERIALS AND METHODS After institutional review board approval, patients undergoing resection for CDC in our center from 2011 to 2019 were retrospectively identified. Histopathological reports were searched for inflammation and endothelial alteration. Cases with sufficient tissue specimen were tested for KRAS codon 12/13 and BRAF codon 600 mutations by pyrosequencing. RESULTS In total, 42 patients underwent resection for choledochal cyst in the study period. Median age at surgery was 2.4 years (range = 18 days-18 years). Histopathological analysis showed no malignancy, but various degrees of inflammation or fibrosis in approximately 50% of the patients and in all age groups. Sufficient tissue for mutation analysis was available for 22 cases, all of which tested negative for KRAS or BRAF mutation. CONCLUSION In our series, chronic inflammatory changes were frequently present in CDC of infants and children. However, the lack of KRAS and BRAF mutations suggests that no malignant changes have been initiated in this group of European patients undergoing early resection.
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Affiliation(s)
- Marie Uecker
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Ulrich Lehmann
- Department of Pathology, Hannover Medical School, Hannover, Germany
| | - Peter Braubach
- Department of Pathology, Hannover Medical School, Hannover, Germany
| | - Nagoud Schukfeh
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | | | - Benno M Ure
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Claus Petersen
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Joachim F Kuebler
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
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ErBb Family Proteins in Cholangiocarcinoma and Clinical Implications. J Clin Med 2020; 9:jcm9072255. [PMID: 32708604 PMCID: PMC7408920 DOI: 10.3390/jcm9072255] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 07/09/2020] [Accepted: 07/15/2020] [Indexed: 12/19/2022] Open
Abstract
The erythroblastic leukemia viral oncogene homolog (ErBb) family consists of the receptor tyrosine kinases (RTK) epidermal growth factor receptor (EGFR; also called ERBB1), ERBB2, ERBB3, and ERBB4. This family is closely associated with the progression of cholangiocarcinoma (CC) through the regulation of cellular networks, which are enhanced during tumorigenesis, metastasis, and chemoresistance. Additionally, the constitutive activation of cellular signaling by the overexpression and somatic mutation-mediated alterations conferred by the ErBb family on cholangiocarcinoma and other cancers enhances tumor aggressiveness and chemoresistance by contributing to the tumor microenvironment. This review summarizes the recent findings on the molecular functions of the ErBb family and their mutations during the progression of cholangiocarcinoma. It also discusses the developments and applications of various devising strategies for targeting the ErBb family through different inhibitors in various stages of clinical trials, which are essential for improving targeted clinical therapies.
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Jensen LH, Andersen RF, Byriel L, Fernebro E, Jakobsen A, Lindebjerg J, Nottelmann L, Ploen J, Hansen TF. Phase II study of gemcitabine, oxaliplatin and capecitabine in patients with KRAS exon 2 mutated biliary tract cancers. Acta Oncol 2020; 59:298-301. [PMID: 31838939 DOI: 10.1080/0284186x.2019.1701201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Background: Molecular markers may identify subgroups of patients with clinically distinct behavior and response to treatment. In some gastrointestinal tumors, KRAS has prognostic value and negative predictive value. This is the first prospective study to report the outcome of combination chemotherapy in biliary tract cancer patients with KRAS mutation.Methods: From 2009 to 2015, 25 patients were included from two Scandinavian centers. Main inclusion criteria were non-resectable biliary tract cancer, ECOG performance status 0-2 and tumor KRAS mutation. A bi-weekly cycle of chemotherapy was administered as gemcitabine 1000 mg/m2 and oxaliplatin 85 mg/m2 day 1, followed by 7 days of oral capecitabine 1000 mg/m2. Response evaluation was done every six treatment and the primary endpoint was the fraction with progression free survival (PFS) at 6 months. The study also included a non-preplanned analysis of circulating tumor specific DNA.Results: Chemotherapy was given for a median of 5 months (range 0-14) and among 17 patients evaluable for response, best responses were complete response (1), partial response (2), and stable disease (14). Eighteen patients had CT-verified progression, six died between evaluations and one patient is still progression-free. Median PFS was 6.8 months (95% CI 3.1-11.0) and median overall survival (OS) was 11.2 months (95% CI 6.6-14.3). The fraction with PFS at 6 months was 52% (95% CI 31-69%). Exploratory analyses found an improved survival in patients with a low level of plasma DNA.Conclusion: Pretreatment molecular characterization was feasible in BTC, but the rate of KRAS mutations was low. The study met its primary endpoint with a fraction of PFS at six months of 52%. The effect of combination chemotherapy with gemcitabine, oxaliplatin and capecitabine in this selected population was comparable to results from unselected groups with PFS and OS of 6.8 and 11.2 months, respectively. ClinicalTrials.gov NCT00779454.
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Affiliation(s)
- Lars H. Jensen
- Vejle University Hospital and University of Southern Denmark, Vejle, Denmark
- Departments of Biochemistry, Gentics, Oncology and Pathology, Vejle University Hospital, Vejle, Denmark
| | - Rikke Fredslund Andersen
- Departments of Biochemistry, Gentics, Oncology and Pathology, Vejle University Hospital, Vejle, Denmark
| | - Lene Byriel
- Departments of Biochemistry, Gentics, Oncology and Pathology, Vejle University Hospital, Vejle, Denmark
| | - Eva Fernebro
- Department of Oncology, Växjö Hospital, Växjö, Sweden
| | - Anders Jakobsen
- Vejle University Hospital and University of Southern Denmark, Vejle, Denmark
- Departments of Biochemistry, Gentics, Oncology and Pathology, Vejle University Hospital, Vejle, Denmark
| | - Jan Lindebjerg
- Vejle University Hospital and University of Southern Denmark, Vejle, Denmark
- Departments of Biochemistry, Gentics, Oncology and Pathology, Vejle University Hospital, Vejle, Denmark
| | - Lise Nottelmann
- Departments of Biochemistry, Gentics, Oncology and Pathology, Vejle University Hospital, Vejle, Denmark
| | - John Ploen
- Departments of Biochemistry, Gentics, Oncology and Pathology, Vejle University Hospital, Vejle, Denmark
| | - Torben F. Hansen
- Vejle University Hospital and University of Southern Denmark, Vejle, Denmark
- Departments of Biochemistry, Gentics, Oncology and Pathology, Vejle University Hospital, Vejle, Denmark
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Mishra SK, Kumari N, Krishnani N. Molecular pathogenesis of gallbladder cancer: An update. Mutat Res 2019; 816-818:111674. [PMID: 31330366 DOI: 10.1016/j.mrfmmm.2019.111674] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 06/17/2019] [Accepted: 06/24/2019] [Indexed: 01/17/2023]
Abstract
Gallbladder carcinoma (GBC) is the most aggressive gastrointestinal malignancy throughout the world, with wide geographical variance. It is the subtype of biliary tract malignancy that has the poorest prognosis and lower survival among all biliary tract malignancies. Various factors are associated with GBC pathogenesis such as environmental, microbial, metabolic and molecular. Chronic inflammation of gallbladder due to presence of gallstone or microbial infection (eg. Salmonella or H. pylori) results in sustained production of inflammatory mediators in the tissue microenvironment, which can cause genomic changes linked to carcinogenesis. Genetic alterations are one of the major factors, associated with aggressiveness and prognosis. Researches have been done to explore suitable biomarker for early diagnosis and identify altered molecular pathways to develop appropriate biomarkers for early diagnosis, therapy and predicting prognosis. Different agents for targeted therapy against actionable mutations of molecules like EGFR, VEGF, mTOR, HER2, PDL-1, PD-1, MET, PI3K, N-cadherin, VEGFR, MEK1 and MEK2 are being tried. Despite these advancements, there is dismal improvement in the survival of GBC patients. Genetic aberrations other than actionable mutations and epigenetic modification including aberrant expressions of micro-RNAs, are also being studied both as diagnostic biomarker and therapeutic targets. Complex pathogenesis of GBC still needs to be unfolded. In this review we focus on the molecular pathogenesis of GBC elucidated till date along with future directions that can be explored to achieve better management of GBC patients.
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Affiliation(s)
- Shravan Kumar Mishra
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226014, India.
| | - Niraj Kumari
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226014, India.
| | - Narendra Krishnani
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226014, India.
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Tariq NUA, McNamara MG, Valle JW. Biliary tract cancers: current knowledge, clinical candidates and future challenges. Cancer Manag Res 2019; 11:2623-2642. [PMID: 31015767 PMCID: PMC6446989 DOI: 10.2147/cmar.s157092] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Biliary tract cancers (BTCs) are rare with poor prognosis. Due to the advent of genomic sequencing, new data have emerged regarding the molecular makeup of this disease. To add to the complexity, various subtypes also harbor a varied genetic composition. The commonly mutated genes associated with this cancer are KRAS, EGFR, IDH, FGFR and BAP1. Various clinical studies are looking at targeting these genetic mutations. Another therapeutic area of note is the potential for the use of immunotherapy in patients with BTC. Although BTC may be a result of chronic inflammation, this does not necessarily translate into increased immunogenicity. This literature review discusses the diverse molecular and immune-related pathways in patients with BTC and their potential therapeutic implications.
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Affiliation(s)
- Noor-Ul-Ain Tariq
- Faculty of Biomedicine and Health Sciences, Division of Cancer Sciences, University of Manchester, Manchester M13 9NT, UK,
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK,
| | - Mairéad G McNamara
- Faculty of Biomedicine and Health Sciences, Division of Cancer Sciences, University of Manchester, Manchester M13 9NT, UK,
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK,
| | - Juan W Valle
- Faculty of Biomedicine and Health Sciences, Division of Cancer Sciences, University of Manchester, Manchester M13 9NT, UK,
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK,
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12
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Kato A, Naitoh I, Miyabe K, Hayashi K, Yoshida M, Hori Y, Natsume M, Jinno N, Asano G, Kato H, Kuno T, Takahashi S, Kataoka H. An Increased Chromosome 7 Copy Number in Endoscopic Bile Duct Biopsy Specimens Is Predictive of a Poor Prognosis in Cholangiocarcinoma. Dig Dis Sci 2018; 63:3376-3381. [PMID: 30206756 DOI: 10.1007/s10620-018-5280-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 09/07/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND The ability of fluorescence in situ hybridization (FISH) assays in endoscopic transpapillary bile duct biopsy specimens to predict the prognosis of cholangiocarcinoma (CCA) has not been elucidated. AIMS We aimed to clarify the association between the results of UroVysion FISH assays and the prognosis of CCA. METHODS We retrospectively reviewed 49 specimens obtained by transpapillary forceps biopsy from consecutive patients with CCA. The copy numbers of chromosomes 3, 7, and 17 were evaluated by FISH assay using UroVysion. We compared the overall survival (OS) of CCA patients with and without increased copy numbers of chromosomes 3, 7, and 17. Furthermore, we evaluated the association between OS and the clinicopathological parameters of CCA patients. RESULTS The OS was significantly shorter in patients with than without an increased chromosome 7 copy number (log-rank p = 0.015; median OS 11.9 vs. 20.7 months). In the univariate analyses, age (p = 0.012), ECOG performance status (p = 0.046), tumor stage (p = 0.046), surgery (p = 0.006), and an increased chromosome 7 copy number (p = 0.017) were significantly associated with OS. The multivariate analysis revealed that an increased chromosome 7 copy number (hazard ratio, 2.46; 95% CI 1.15-5.27; p = 0.021) and advanced clinical stage (hazard ratio, 2.26; 95% CI 1.11-4.63; p = 0.025) were independently predictive of a poor OS. CONCLUSIONS Detection by FISH assay of an increased chromosome 7 copy number in transpapillary forceps biopsy specimens is predictive of a poor prognosis in CCA patients.
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Affiliation(s)
- Akihisa Kato
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Itaru Naitoh
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
| | - Katsuyuki Miyabe
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Kazuki Hayashi
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Michihiro Yoshida
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Yasuki Hori
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Makoto Natsume
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Naruomi Jinno
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Go Asano
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Hiroyuki Kato
- Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Toshiya Kuno
- Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
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13
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Jeong WK, Jamshidi N, Felker ER, Raman SS, Lu DS. Radiomics and radiogenomics of primary liver cancers. Clin Mol Hepatol 2018; 25:21-29. [PMID: 30441889 PMCID: PMC6435966 DOI: 10.3350/cmh.2018.1007] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/16/2018] [Indexed: 02/07/2023] Open
Abstract
Concurrent advancements in imaging and genomic biomarkers have created opportunities to identify non-invasive imaging surrogates of molecular phenotypes. In order to develop such imaging surrogates radiomics and radiogenomics/imaging genomics will be necessary; there has been consistent progress in these fields for primary liver cancers. In this article we evaluate the current status of the field specifically with regards to hepatocellular carcinoma and intrahepatic cholangiocarcinoma, highlighting some of the up and coming results that were presented at the annual Radiological Society of North America Conference in 2017. There are an increasing number of studies in this area with a bias towards quantitative feature measurement, which is expected to benefit reproducibility of the findings and portends well for the future development of biomarkers for diagnosis, prognosis, and treatment response assessment. We review some of the advancements and look forward to some of the exciting future applications that are anticipated as the field develops.
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Affiliation(s)
- Woo Kyoung Jeong
- Department of Radiological Science, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.,Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Center for Imaging Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Neema Jamshidi
- Department of Radiological Science, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Ely Richard Felker
- Department of Radiological Science, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Steven Satish Raman
- Department of Radiological Science, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - David Shinkuo Lu
- Department of Radiological Science, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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14
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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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15
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Pellino A, Loupakis F, Cadamuro M, Dadduzio V, Fassan M, Guido M, Cillo U, Indraccolo S, Fabris L. Precision medicine in cholangiocarcinoma. Transl Gastroenterol Hepatol 2018; 3:40. [PMID: 30148225 DOI: 10.21037/tgh.2018.07.02] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 07/03/2018] [Indexed: 12/19/2022] Open
Abstract
Cholangiocarcinoma is one of the epithelial cancers with the poorest prognosis and the narrowest therapeutic choice in humans. Compared with other cancer types, cholangiocarcinoma has been often neglected by oncology and liver research studies, thereby leaving many issues unsolved. Apart from the early and marked aggressiveness, one of the main reasons of the still unsatisfying clinical management of cholangiocarcinoma is its wide tumor heterogeneity needing more than other diseases a 'precision medicine' approach. In this regard, in the last few years there has been an awakening of interest aimed at dissecting the complex molecular and genomic profile of cholangiocarcinoma. Thus, a range of molecular players have been recently identified as putative mechanistic determinants of cholangiocarcinoma invasiveness, encompassing tyrosine kinase receptors, metabolic enzymes, transcription factors, small GTPases, ubiquitin ligases, and chromatin-remodelling proteins, whose aberrant expression may derive from stochastic mutations as well as from pro-oncogenic paracrine signals released by the stromal microenvironment, which is particularly exuberant in cholangiocarcinoma. Herein, we sought to overview the most relevant observations unravelling the genomic landscape of cholangiocarcinoma, and the prognostic and predictive biomarkers that consequently have been emerging. Then, we will discuss innovative treatment approaches derived from conventional chemotherapy, targeted therapies, antiangiogenic therapies and immunotherapy, and how they are opening new avenues towards a precision medicine in cholangiocarcinoma.
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Affiliation(s)
- Antonio Pellino
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, Italy
| | - Fotios Loupakis
- Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | | | - Vincenzo Dadduzio
- Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy
| | - Maria Guido
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy
| | - Umberto Cillo
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, Italy
| | - Stefano Indraccolo
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Luca Fabris
- Department of Molecular Medicine (DMM), University of Padua, Padua, Italy.,Department of Internal Medicine, Yale Liver Center (YLC), School of Medicine, Yale University New Haven, CT, USA
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16
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Trachu N, Sirachainan E, Larbcharoensub N, Rattanadech W, Detarkom S, Monnamo N, Kamprerasart K, MunTham D, Sukasem C, Reungwetwattana T. Molecular alterations and clinical prognostic factors for cholangiocarcinoma in Thai population. Onco Targets Ther 2017; 10:4955-4968. [PMID: 29066915 PMCID: PMC5644605 DOI: 10.2147/ott.s143982] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
This study explores genomic alterations in cholangiocarcinoma (CCC) tissues in Thai patients. We identified and reviewed the records of patients who had been diagnosed with CCC and for whom sufficient tumor samples for DNA and RNA extraction were available in our database. The specimens were explored for EGFR, KRAS, BRAF, and PIK3CA mutations and ROS1 translocation in 81 samples. Immunohistochemistry staining for HER2, ALK, and Ki-67 expression was tested in 74 samples. Prevalence of EGFR, KRAS, and PIK3CA mutations in this study was 21%, 12%, and 16%, respectively. No BRAF V600 mutation or ROS1 translocation was found. Patients with T790M mutation had a significantly longer overall survival (18.84 months) than those with the other types of EGFR mutations (4.08 months; hazard ratio [HR]: 0.26, P=0.038) and also had a significantly lower median Ki-67 (22.5% vs 80%, P=0.025). Furthermore, patients with PIK3CA mutations had a significantly longer median progression-free survival (15.87 vs 7.01 months; HR: 0.46, P=0.043). Strongly positive HER2 expression was found in only 1 patient, whereas ALK expression was not found. The presence of EGFR and/or PIK3CA mutations implies that targeted drugs may provide a feasible CCC treatment in the future.
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Affiliation(s)
- N Trachu
- Research Center, Faculty of Medicine Ramathibodi Hospital.,Molecular Medicine Program, Multidisciplinary Unit, Faculty of Science
| | - E Sirachainan
- Division of Medical Oncology, Department of Medicine
| | - N Larbcharoensub
- Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University
| | - W Rattanadech
- Division of Medical Oncology, Department of Medicine
| | - S Detarkom
- Division of Medical Oncology, Department of Medicine
| | - N Monnamo
- Research Center, Faculty of Medicine Ramathibodi Hospital
| | - K Kamprerasart
- Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University
| | - D MunTham
- Section for Mathematic, Faculty of Science and Technology, Rajamangala University of Technology Suvarnabhumi
| | - C Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology.,Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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17
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Berretta M, Cavaliere C, Alessandrini L, Stanzione B, Facchini G, Balestreri L, Perin T, Canzonieri V. Serum and tissue markers in hepatocellular carcinoma and cholangiocarcinoma: clinical and prognostic implications. Oncotarget 2017; 8:14192-14220. [PMID: 28077782 PMCID: PMC5355172 DOI: 10.18632/oncotarget.13929] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 10/28/2016] [Indexed: 12/12/2022] Open
Abstract
HCC represents the sixth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options for advanced HCC remain limited and unsuccessful, resulting in a poor prognosis. Despite the major advances achieved in the diagnostic management of HCC, only one third of the newly diagnosed patients are presently eligible for curative treatments. Advances in technology and an increased understanding of HCC biology have led to the discovery of novel biomarkers. Improving our knowledge about serum and tissutal markers could ultimately lead to an early diagnosis and better and early treatment strategies for this deadly disease. Serum biomarkers are striking potential tools for surveillance and early diagnosis of HCC thanks to the non-invasive, objective, and reproducible assessments they potentially enable. To date, many biomarkers have been proposed in the diagnosis of HCC. Cholangiocarcinoma (CCA) is an aggressive malignancy, characterized by early lymph node involvement and distant metastasis, with 5-year survival rates of 5%-10%. The identification of new biomarkers with diagnostic, prognostic or predictive value is especially important as resection (by surgery or combined with a liver transplant) has shown promising results and novel therapies are emerging. However, the relatively low incidence of CCA, high frequency of co-existing cholestasis or cholangitis (primary sclerosing cholangitis –PSC- above all), and difficulties with obtaining adequate samples, despite advances in sampling techniques and in endoscopic visualization of the bile ducts, have complicated the search for accurate biomarkers. In this review, we attempt to analyze the existing literature on this argument.
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Affiliation(s)
| | - Carla Cavaliere
- Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital of Taranto Taranto, Italy
| | - Lara Alessandrini
- Division of Pathology, National Cancer Institute, Aviano (PN), Italy
| | - Brigida Stanzione
- Department of Medical Oncology, National Cancer Institute, Aviano (PN), Italy
| | - Gaetano Facchini
- Department of Medical Oncology, National Cancer Institute, "G. Pascale" Foundation, Naples, Italy
| | - Luca Balestreri
- Department of Radiology, National Cancer Institute, Aviano (PN), Italy
| | - Tiziana Perin
- Division of Pathology, National Cancer Institute, Aviano (PN), Italy
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18
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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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19
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Noguchi R, Yamaguchi K, Ikenoue T, Terakado Y, Ohta Y, Yamashita N, Kainuma O, Yokoi S, Maru Y, Nagase H, Furukawa Y. Genetic alterations in Japanese extrahepatic biliary tract cancer. Oncol Lett 2017; 14:877-884. [PMID: 28693246 DOI: 10.3892/ol.2017.6224] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 11/30/2016] [Indexed: 02/07/2023] Open
Abstract
Biliary tract cancer (BTC) is one of the most devastating types of malignant neoplasms worldwide. However, the mechanisms underlying the development and progression of BTC remain unresolved. BTC includes extrahepatic bile duct carcinoma (EBDC), gallbladder carcinoma (GBC) and ampulla of Vater carcinoma (AVC), named according to the location of the tumor. Although genetic alterations of intrahepatic cholangiocarcinoma have been investigated, those of EBDC, GBC and AVC have not yet been fully understood. The present study analyzed somatic mutations of 50 cancer-associated genes in 27 Japanese BTC cells, including: 11 EBDC, 14 GBC and 2 AVC. Next-generation sequencing using an Ion AmpliSeq Cancer Panel identified a total of 44 somatic mutations across 14 cancer-associated genes. Among the 44 mutations, 42 were judged as pathological mutations. Frequent mutations were identified in tumor protein 53 (TP53) (14/27), SMAD family member 4 (SMAD4) (6/27), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA) (6/27), and Kirsten rat sarcoma (KRAS) (6/27); no significant differences were identified between EBDC and GBC tissues. Notably, the frequency of the PIK3CA mutation was higher when compared with previous reports. This result may suggest that the activation of the PIK3CA-protein kinase B signaling pathway, in addition to the abrogation of p53, SMAD4 and RAS mitogen-activated protein kinase may have a crucial role in the carcinogenesis of Japanese BTC. These findings may be useful for the development of personalized therapies for BTC.
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Affiliation(s)
- Rei Noguchi
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Kiyoshi Yamaguchi
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Tsuneo Ikenoue
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Yumi Terakado
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Yasunori Ohta
- Department of Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Naohide Yamashita
- Department of Advanced Medical Science, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Osamu Kainuma
- Department of Gastroenterological Surgery, Chiba Cancer Center Hospital, Chiba 260-8718, Japan
| | - Sana Yokoi
- Division of Translational Genetics, Chiba Cancer Center Research Institute, Chiba 260-8718, Japan
| | - Yoshiaki Maru
- Division of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8718, Japan
| | - Hiroki Nagase
- Division of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8718, Japan
| | - Yoichi Furukawa
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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20
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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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21
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Marks EI, Yee NS. Molecular genetics and targeted therapeutics in biliary tract carcinoma. World J Gastroenterol 2016; 22:1335-47. [PMID: 26819503 PMCID: PMC4721969 DOI: 10.3748/wjg.v22.i4.1335] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [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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22
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Abstract
OPINION STATEMENT A paradigm shift towards molecular-based, personalized cancer therapeutics has occurred in recent years and a number of targeted drugs have emerged. Various targeted therapies like erlotinib, trastuzumab, and cetuximab have been approved in lung, breast, and colon cancers, respectively. Numerous clinical trials involving targeted drugs in biliary tract cancers are currently in progress, though none have been approved for this disease. Biliary tract cancers are divided into separate entities both anatomically and in terms of pathogenesis but are grouped together in most trials given their rarity. Combination chemotherapy involving cisplatin and gemcitabine is the current standard of care in the metastatic setting. In this review, we will discuss the various molecular pathways implicated in biliary tract cancers and potential therapeutic targets.
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Affiliation(s)
- Amartej Merla
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461 USA
| | - Kenneth G. Liu
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461 USA
| | - Lakshmi Rajdev
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461 USA
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23
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Chandrasegaram MD, Chiam SC, Chen JW, Khalid A, Mittinty ML, Neo EL, Tan CP, Dolan PM, Brooke-Smith ME, Kanhere H, Worthley CS. Distribution and pathological features of pancreatic, ampullary, biliary and duodenal cancers resected with pancreaticoduodenectomy. World J Surg Oncol 2015; 13:85. [PMID: 25890023 PMCID: PMC4348158 DOI: 10.1186/s12957-015-0498-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 02/01/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Pancreatic cancer (PC) has the worst survival of all periampullary cancers. This may relate to histopathological differences between pancreatic cancers and other periampullary cancers. Our aim was to examine the distribution and histopathologic features of pancreatic, ampullary, biliary and duodenal cancers resected with a pancreaticoduodenectomy (PD) and to examine local trends of periampullary cancers resected with a PD. METHODS A retrospective review of PD between January 2000 and December 2012 at a public metropolitan database was performed. The institutional ethics committee approved this study. RESULTS There were 142 PDs during the study period, of which 70 cases were pre-2010 and 72 post-2010, corresponding to a recent increase in the number of cases. Of the 142 cases, 116 were for periampullary cancers. There were also proportionately more PD for PC (26/60, 43% pre-2010 vs 39/56, 70% post-2010, P = 0.005). There were 65/116 (56%) pancreatic, 29/116 (25%), ampullary, 17/116 (15%) biliary and 5/116 (4%) duodenal cancers. Nodal involvement occurred more frequently in PC (78%) compared to ampullary (59%), biliary (47%) and duodenal cancers (20%), P = 0.002. Perineural invasion was also more frequent in PC (74%) compared to ampullary (34%), biliary (59%) and duodenal cancers (20%), P = 0.002. Microvascular invasion was seen in 57% pancreatic, 38% ampullary, 41% biliary and 20% duodenal cancers, P = 0.222. Overall, clear margins (R0) were achieved in fewer PC 41/65 (63%) compared to ampullary 27/29 (93%; P = 0.003) and biliary cancers 16/17 (94%; P = 0.014). CONCLUSIONS This study highlights that almost half of PD was performed for cancers other than PC, mainly ampullary and biliary cancers. The volume of PD has increased in recent years with an increased proportion being for PC. PC had higher rates of nodal and perineural invasion compared to ampullary, biliary and duodenal cancers.
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Affiliation(s)
- Manju D Chandrasegaram
- HPB Surgery Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia. .,Division of Surgery, School of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia.
| | - Su C Chiam
- HPB Surgery Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia.
| | - John W Chen
- HPB Surgery Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia. .,Flinders Medical Centre, Flinders Drive, Bedford Park, Adelaide, SA, 5042, Australia. .,Flinders University, Sturt Rd, Bedford Park, Adelaide, SA, 5042, Australia.
| | - Aisha Khalid
- Flinders Medical Centre, Flinders Drive, Bedford Park, Adelaide, SA, 5042, Australia.
| | - Murthy L Mittinty
- School of Population Health, University of Adelaide, 178 North Terrace, Adelaide, SA, 5005, Australia.
| | - Eu L Neo
- HPB Surgery Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia. .,Flinders Medical Centre, Flinders Drive, Bedford Park, Adelaide, SA, 5042, Australia.
| | - Chuan P Tan
- HPB Surgery Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia.
| | - Paul M Dolan
- HPB Surgery Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia.
| | - Mark E Brooke-Smith
- HPB Surgery Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia. .,Flinders Medical Centre, Flinders Drive, Bedford Park, Adelaide, SA, 5042, Australia. .,Flinders University, Sturt Rd, Bedford Park, Adelaide, SA, 5042, Australia.
| | - Harsh Kanhere
- Division of Surgery, School of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia. .,HPB Surgery Unit, Queen Elizabeth Hospital, 28 Woodville Road, Adelaide, SA, 5011, Australia.
| | - Chris S Worthley
- HPB Surgery Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia.
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24
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Ochi N, Goto D, Yamane H, Yamagishi T, Honda Y, Monobe Y, Kawamoto H, Takigawa N. Obstructive jaundice caused by intraductal metastasis of lung adenocarcinoma. Onco Targets Ther 2014; 7:1847-50. [PMID: 25336976 PMCID: PMC4199794 DOI: 10.2147/ott.s68757] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Obstructive jaundice caused by metastases to the porta hepatis is often observed in patients with various advanced cancers; however, metastasis of lung cancer to the common bile duct with subsequent development of jaundice is rare. A 75-year-old female with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutation (15-bp in-frame deletion in exon 19 and T790M in exon 20) developed obstructive jaundice during therapy. Obstruction of the common bile duct caused by an intraductal tumor was identified by computed tomography, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography. Although primary cholangiocarcinoma was highly suspected according to the imaging findings, immunohistochemical evaluation of the intraductal tumor demonstrated thyroid transcription factor-1 positive adenocarcinoma. Furthermore, peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp analysis showed that the tumor contained the same EGFR mutation as that in the primary lung cancer. Thus, we confirmed intraductal metastasis from a lung adenocarcinoma. To our knowledge, this is the second report of obstructive jaundice caused by intraductal metastasis of lung cancer.
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Affiliation(s)
- Nobuaki Ochi
- Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan
| | - Daisuke Goto
- Department of General Internal Medicine 2, Kawasaki Medical School, Okayama, Japan
| | - Hiromichi Yamane
- Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan
| | - Tomoko Yamagishi
- Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan
| | - Yoshihiro Honda
- Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan
| | - Yasumasa Monobe
- Department of Pathology, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan
| | - Hirofumi Kawamoto
- Department of General Internal Medicine 2, Kawasaki Medical School, Okayama, Japan
| | - Nagio Takigawa
- Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan
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25
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Haga H, Patel T. Molecular diagnosis of intrahepatic cholangiocarcinoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2014; 22:114-23. [PMID: 25267595 DOI: 10.1002/jhbp.156] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Intrahepatic cholangiocarcinomas (iCCA) are primary intrahepatic malignancies originating from biliary epithelia. While both hepatocellular cancer and iCCA can present as mass lesions within the liver, these cancers are distinct in their morphology, etiology, pathology, natural history and response to therapy. There is a need for accurate and sensitive molecular markers for the diagnosis of iCCA. Recent advances in elucidating molecular and genetic characteristics of iCCA offer the potential of molecular-based diagnosis of iCCA. Specific genetic mutations of IDH1/2, BAP1, p53, and KRAS, FGFR gene fusions and alterations in microRNA have all been described in iCCA. Although there are no accurate serum or biliary biomarkers currently available for diagnosis of iCCA, several potential candidates have been identified. Knowledge of specific genetic or molecular abnormalities offers potential for individualized approaches for the treatment of patients with iCCA in the future.
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Affiliation(s)
- Hiroaki Haga
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
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