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Yamada D, Kobayashi S, Doki Y, Eguchi H. Genomic landscape of biliary tract cancer and corresponding targeted treatment strategies. Int J Clin Oncol 2025; 30:1069-1079. [PMID: 40281353 PMCID: PMC12122590 DOI: 10.1007/s10147-025-02761-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 03/27/2025] [Indexed: 04/29/2025]
Abstract
Biliary tract cancers (BTCs) are classified on the basis of their anatomical origin, and the feasibility of surgical resection depends on the tumor location and extent of progression. However, for unresectable BTCs, systemic therapy has been uniformly applied. Gemcitabine and cisplatin (GC) therapy and GC-based therapies were established as the first-line standard BTC treatment. However, no highly effective second-line therapy has been established, and the prognosis remains poor, highlighting the need for further therapeutic advancements. Meanwhile, the era of precision medicine has expanded the use of genetic testing, leading to the identification of actionable molecular targets in BTC. Several targeted therapies, including FGFR inhibitors and IDH1 inhibitors, have been developed, offering new second-line treatment options and the potential for first-line use in appropriate cases. Notably, the frequency of these genetic alterations varies depending on the tumor location, demonstrating the molecular heterogeneity of BTC. Therefore, it has been recognized that a tailored treatment approach for each BTC patient may be more effective than uniform systemic therapy. Consequently, although routine genetic testing before initiating systemic treatment is currently limited by the medical environment (e.g., cost, accessibility, regional differences), it is recommended in ESMO guideline and might be increasingly advocated. However, BTC harbors a wide range of genetic alterations, and numerous targeted therapies are being developed accordingly. This review provides an overview of the reported genetic alterations in BTC, the frequencies of these alterations, and the corresponding targeted therapies, emphasizing the evolving role of precision medicine in BTC treatment.
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Affiliation(s)
- Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2E2, Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2E2, Yamadaoka, Suita City, Osaka, 565-0871, Japan.
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2E2, Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2E2, Yamadaoka, Suita City, Osaka, 565-0871, Japan
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Li Y, Yu J, Zhang Y, Peng C, Song Y, Liu S. Advances in targeted therapy of cholangiocarcinoma. Ann Med 2024; 56:2310196. [PMID: 38359439 PMCID: PMC10877652 DOI: 10.1080/07853890.2024.2310196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 01/20/2024] [Indexed: 02/17/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a malignant tumor originating in the bile duct and its branching epithelium. Due to its high heterogeneity, there are no specific clinical indications at the early stage, the diagnosis is often in advanced CCA. With surgical resection, the 5-year postoperative survival rate (long-term survival rate) is very poor. The regimen of gemcitabine combined with platinum has been used as the first-line chemotherapy for advanced patients. In recent years, targeted therapy for a variety of malignant tumors has made great progress, showing good efficacy and safety in advanced CCA. However, the current targeted therapy of CCA still has many challenges, such as adverse reactions, drug resistance, and individual differences. Therefore, the researches need to further explore the targeted therapy mechanism of CCA malignancies in depth, develop more effective and safe drugs, and accurately formulate plans based on patient characteristics to further improve patient prognosis in the future. This article reviews the recent progress of targeted therapy for CCA, aiming to provide a strategy for the research and clinical work of targeted therapy for CCA.
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Affiliation(s)
- Yuhang Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
| | - Jianfeng Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
- Central Laboratory, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, China
| | - Yujing Zhang
- Central Laboratory, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, China
| | - Chuang Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
- Hunan Provincial Key Laboratory of Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
- Clinical Medical Technology Research Center of Hunan Provincial for Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
| | - Yinghui Song
- Central Laboratory, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, China
| | - Sulai Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan Province, China
- Central Laboratory, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, China
- Hunan Provincial Key Laboratory of Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
- Clinical Medical Technology Research Center of Hunan Provincial for Biliary Disease Prevention and Treatment, Changsha, Hunan Province, China
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Taghizadeh H, Dong Y, Gruenberger T, Prager GW. Perioperative and palliative systemic treatments for biliary tract cancer. Ther Adv Med Oncol 2024; 16:17588359241230756. [PMID: 38559612 PMCID: PMC10981863 DOI: 10.1177/17588359241230756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 01/18/2024] [Indexed: 04/04/2024] Open
Abstract
Due to the fact biliary tract cancer (BTC) is often diagnosed at an advanced stage, thus, not eligible for resection, and due to the aggressive tumor biology, it is considered as one of the cancer types with the worst prognosis. Advances in diagnosis, surgical techniques, and molecular characterization have led to an improvement of the prognosis of BTC patients, recently. Although neoadjuvant therapy is expected to improve surgical outcomes by reducing tumor size, its routine is not well established. The application of neoadjuvant therapy in locally advanced disease may be indicated, the routine use of systemic therapy prior to surgery for cholangiocarcinoma patients with an upfront resectable disease is less well established, but discussed and performed in selected cases. In advanced disease, only combination chemotherapy regimens have been demonstrated to achieve disease control in untreated patients. Molecular profiling of the tumor has demonstrated that many BTC might bear actionable targets, which might be addressed by biological treatments, thus improving the prognosis of the patients. Furthermore, the addition of the immunotherapy to standard chemotherapy might improve the prognosis in a subset of patients. This review seeks to give a comprehensive overview about the role of neoadjuvant as well as palliative systemic treatment approaches and an outlook about novel systemic treatment concept in BTC.
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Affiliation(s)
- Hossein Taghizadeh
- Division of Oncology, Department of Internal Medicine I, University Hospital St. Pölten, St. Pölten, Austria
- Karl Landsteiner University of Health Sciences, Krems, Austria
- Karl Landsteiner Institute for Oncology and Nephrology, St. Pölten, Austria
- Medical University of Vienna, Center for Cancer Research, Vienna, Austria
- Medical University of Vienna, Department of Medicine I, Vienna, Austria
| | - Yawen Dong
- Department of Surgery, HPB Center, Health Network Vienna, Clinic Favoriten, Vienna, Austria
| | - Thomas Gruenberger
- Department of Surgery, HPB Center, Health Network Vienna, Clinic Favoriten, Vienna, Austria
| | - Gerald W. Prager
- Department of Medicine I, Medical University of Vienna, Comprehensive Cancer Center Vienna, Spitalgasse 23, Vienna AT1090, Austria
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Mirza-Aghazadeh-Attari M, Afyouni S, Zandieh G, Yazdani Nia I, Mohseni A, Borhani A, Madani SP, Shahbazian H, Ansari G, Kim A, Kamel IR. Utilization of Radiomics Features Extracted From Preoperative Medical Images to Detect Metastatic Lymph Nodes in Cholangiocarcinoma and Gallbladder Cancer Patients: A Systemic Review and Meta-analysis. J Comput Assist Tomogr 2024; 48:184-193. [PMID: 38013233 DOI: 10.1097/rct.0000000000001557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
OBJECTIVES This study aimed to determine the methodological quality and evaluate the diagnostic performance of radiomics features in detecting lymph node metastasis on preoperative images in patients with cholangiocarcinoma and gallbladder cancer. METHODS Publications between January 2005 and October 2022 were considered for inclusion. Databases such as Pubmed/Medline, Scopus, Embase, and Google Scholar were searched for relevant studies. The quality of the methodology of the manuscripts was determined using the Radiomics Quality Score and Quality Assessment of Diagnostic Accuracy Studies 2. Pooled results with corresponding 95% confidence intervals (CIs) were calculated using the DerSimonian-Liard method (random-effect model). Forest plots were used to visually represent the diagnostic profile of radiomics signature in each of the data sets pertaining to each study. Fagan plot was used to determine clinical applicability. RESULTS Overall sensitivity was 0.748 (95% CI, 0.703-0.789). Overall specificity was 0.795 (95% CI, 0.742-0.839). The combined negative likelihood ratio was 0.299 (95% CI, 0.266-0.350), and the positive likelihood ratio was 3.545 (95% CI, 2.850-4.409). The combined odds ratio of the studies was 12.184 (95% CI, 8.477-17.514). The overall summary receiver operating characteristics area under the curve was 0.83 (95% CI, 0.80-0.86). Three studies applied nomograms to 8 data sets and achieved a higher pooled sensitivity and specificity (0.85 [0.80-0.89] and 0.85 [0.71-0.93], respectively). CONCLUSIONS The pooled analysis showed that predictive models fed with radiomics features achieve good sensitivity and specificity in detecting lymph node metastasis in computed tomography and magnetic resonance imaging images. Supplementation of the models with biological correlates increased sensitivity and specificity in all data sets.
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Affiliation(s)
| | - Shadi Afyouni
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Ghazal Zandieh
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Iman Yazdani Nia
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Alireza Mohseni
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Ali Borhani
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Seyedeh Panid Madani
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Haneyeh Shahbazian
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Golnoosh Ansari
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
| | - Amy Kim
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ihab R Kamel
- From the Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital
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Gupta A, Sahai P, Prasad M, Yadav HP, Srivastava G, Nakhro N, Kumar G, Sharma N. Treatment Response and Survival with Chemotherapy for Unresectable, Nonmetastatic Cholangiocarcinoma. Euroasian J Hepatogastroenterol 2024; 14:5-8. [PMID: 39022199 PMCID: PMC11249901 DOI: 10.5005/jp-journals-10018-1396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 08/11/2023] [Indexed: 07/20/2024] Open
Abstract
Background and objectives Limited studies have dwelt upon the treatment of unresectable, nonmetastatic cholangiocarcinoma as a separate entity. Hence, the management protocols are not clearly defined for this subgroup of patients. We aimed to analyze patients treated for unresectable, nonmetastatic cholangiocarcinoma. Materials and methods We analyzed the treatment of patients with unresectable, nonmetastatic cholangiocarcinoma retrospectively. Results A total of 162 cases of cholangiocarcinoma were reported to our center from 2016 to 2019, out of which 54 were unresectable and nonmetastatic. Thirty patients opted for treatment and were the subjects of this study. Of 30 patients, 24 had hyperbilirubinemia, out of which 10 received chemotherapy after biliary drainage procedure. Out of 30 patients, a total of 16 patients had received chemotherapy, while 14 did not. Gemcitabine/Cisplatin was the first-line chemotherapy administered to 9 patients, whereas 5 received Gemcitabine/Capecitabine and 2 received single-agent gemcitabine. Partial response was documented in 6 patients, and 4 patients had stable disease. The median overall survival was 12.04 months in patients who had received chemotherapy and 6.02 months in those who did not receive chemotherapy (p = 0.005). The median progression-free survival was 6.53 months for patients who had received chemotherapy. The aHR for mortality with chemotherapy compared with no chemotherapy was 0.353 (95% CI: 0.154-0.807). Conclusion The study data demonstrate that gemcitabine combined with cisplatin- or capecitabine-based chemotherapy prolongs survival in patients with unresectable and nonmetastatic cholangiocarcinoma. In patients with cholangiocarcinoma associated with jaundice, biliary drainage procedure enables giving chemotherapy. Hyperbilirubinemia persisting despite drainage procedures portends poor prognosis and represents an unmet need. How to cite this article Gupta A, Sahai P, Prasad M, et al. Treatment Response and Survival with Chemotherapy for Unresectable, Nonmetastatic Cholangiocarcinoma. Euroasian J Hepato-Gastroenterol 2024;14(1):5-8.
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Affiliation(s)
- Ajay Gupta
- Department of Medical Oncology, Indraprastha Apollo Hospital, New Delhi, India
| | - Puja Sahai
- Department of Radiation Oncology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Manya Prasad
- Department of Epidemiology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Hanuman Prasad Yadav
- Department of Radiation Oncology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Gagan Srivastava
- Department of Medical Oncology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Nuneno Nakhro
- Department of Medical Oncology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
| | - Guresh Kumar
- Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Namita Sharma
- Department of Medical Oncology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India
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Moroney J, Trivella J, George B, White SB. A Paradigm Shift in Primary Liver Cancer Therapy Utilizing Genomics, Molecular Biomarkers, and Artificial Intelligence. Cancers (Basel) 2023; 15:2791. [PMID: 37345129 PMCID: PMC10216313 DOI: 10.3390/cancers15102791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/02/2023] [Accepted: 05/10/2023] [Indexed: 06/23/2023] Open
Abstract
Primary liver cancer is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Conventional therapies offer limited survival benefit despite improvements in locoregional liver-directed therapies, which highlights the underlying complexity of liver cancers. This review explores the latest research in primary liver cancer therapies, focusing on developments in genomics, molecular biomarkers, and artificial intelligence. Attention is also given to ongoing research and future directions of immunotherapy and locoregional therapies of primary liver cancers.
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Affiliation(s)
- James Moroney
- Division of Vascular and Interventional Radiology, Department of Radiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Juan Trivella
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ben George
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Sarah B. White
- Division of Vascular and Interventional Radiology, Department of Radiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Zeng W, Mao R, Zhang Z, Chen X. Combination Therapies for Advanced Biliary Tract Cancer. J Clin Transl Hepatol 2023; 11:490-501. [PMID: 36643047 PMCID: PMC9817051 DOI: 10.14218/jcth.2022.00277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 08/09/2022] [Accepted: 08/18/2022] [Indexed: 01/18/2023] Open
Abstract
Biliary tract cancers (BTCs) are a group of malignant neoplasms that have recently increased in incidence and have a poor prognosis. Surgery is the only curative therapy. However, most patients are only indicated for palliative therapy because of advanced-stage disease at diagnosis and rapid progression. The current first-line treatment for advanced BTC is gemcitabine and cisplatin chemotherapy. Nonetheless, many patients develop resistance to this regimen. Over the years, few chemotherapy regimens have managed to improve the overall survival of patients. Accordingly, novel therapies such as targeted therapy have been introduced to treat this patient population. Extensive research on tumorigenesis and the genetic profiling of BTC have revealed the heterogenicity and potential target pathways, such as EGFR, VEGF, MEK/ERK, PI3K and mTOR. Moreover, mutational analysis has documented the presence of IDH1, FGFR2, HER2, PRKACA, PRKACB, BRAF, and KRAS gene aberrations. The emergence of immunotherapy in recent years has expanded the treatment landscape for this group of malignancies. Cancer vaccines, adoptive cell transfer, and immune checkpoint inhibitors have been extensively investigated in trials of BTC. Therefore, patient stratification and a combination of various therapies have become a reasonable and important clinical strategy to improve patient outcomes. This review elaborates the literature on combined treatment strategies for advanced BTC from the past few years and ongoing clinical trials to provide new inspiration for the treatment of advanced BTC.
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Affiliation(s)
- Weifeng Zeng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ruiqi Mao
- Clinic Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Correspondence to: Zhanguo Zhang and Xiaoping Chen, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, 1095 Jiefang Avenue, Wuhan, Hubei 430030, China. ORCID: https://orcid.org/0000-0002-4527-4975 (ZZ). Tel: +86-27-83663400, Fax: +86-27-83662851, E-mail: (ZZ) and (XC)
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Hubei key laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Correspondence to: Zhanguo Zhang and Xiaoping Chen, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, 1095 Jiefang Avenue, Wuhan, Hubei 430030, China. ORCID: https://orcid.org/0000-0002-4527-4975 (ZZ). Tel: +86-27-83663400, Fax: +86-27-83662851, E-mail: (ZZ) and (XC)
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Du J, Lv X, Zhang Z, Huang Z, Zhang E. Revisiting targeted therapy and immunotherapy for advanced cholangiocarcinoma. Front Immunol 2023; 14:1142690. [PMID: 36936931 PMCID: PMC10014562 DOI: 10.3389/fimmu.2023.1142690] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 02/20/2023] [Indexed: 03/05/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a rare and aggressive type of malignant tumor. In the past few years, there has been an increase in the incidence of CCA. Surgery is the only effective treatment but is only suitable for a small percentage of patients. Comprehensive treatment is the normal therapy for terminal CCA patients, depending basically on gemcitabine and cisplatin combination chemotherapy. In the past decade, the emergence of next-generation sequencing technology can be used for the identification of important molecular features of CCA, and several studies have demonstrated that different CCA subtypes have unique genetic aberrations. Targeting fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH) and epidermal growth factor receptor 2 (EGFR2) are emerging targeted therapies. In addition, researches have indicated that immunotherapy has a key function in CCA. There is ongoing research on programmed cell death protein 1 inhibitors (PD-1), chimeric antigen receptor T cells (CAR-T) and tumor-infiltrating leukocyte (TILs). Researches have shown that targeted therapy, immunotherapy, and conventional chemotherapy in CCA had certain mechanistic links, and the combination of those can greatly improve the prognosis of advanced CCA patients. This study aimed to review the research progress of targeted therapy and immunotherapy for CCA.
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Affiliation(s)
| | | | | | - Zhiyong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Erlei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Yang M, Zhao Y, Li Y, Cui X, Liu F, Wu W, Wang XA, Li M, Liu Y, Liu Y. Afatinib in combination with GEMOX chemotherapy as the adjuvant treatment in patients with ErbB pathway mutated, resectable gallbladder cancer: study protocol for a ctDNA-based, multicentre, open-label, randomised, controlled, phase II trial. BMJ Open 2023; 13:e061892. [PMID: 36854604 PMCID: PMC9980349 DOI: 10.1136/bmjopen-2022-061892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2023] Open
Abstract
INTRODUCTION Gallbladder cancer (GBC) is an aggressive type of digestive system cancer with a dismal outcome. Given the lack of effective treatment options, the disease rapidly reoccurs and 5-year survival rate is <5%. Our team previously found that a significant percentage of GBC tissues harboured mutations of the ErbB-related pathway. Afatinib is a chemically synthesised drug specifically targeting the ErbB pathway mutations. However, its efficacy in the treatment of patients with GBC remains unknown. Circulating tumour DNA (ctDNA) refers to a proportion of cell-free DNA in the blood which is released by apoptotic and necrotic cells from tumours in situ, metastatic foci or circulating tumour cells. ctDNA-based liquid biopsy is a non-invasive pathological detection method that offers additional value to evaluate the therapeutic efficacy of antitumour drugs. METHODS AND ANALYSIS We conduct a multicentre and randomised study on afatinib combined with gemcitabine and oxaliplatin (GEMOX) in patients with ErbB pathway mutated GBC. Clinical and biological evaluation involving ErbB pathway ctDNA detection will be made during the 3-year follow-up after participation. The primary objective of this clinical trial is to evaluate the clinical efficacy of afatinib. Disease-free survival is the primary end point and will be correlated with plasma ctDNA of patients in the treatment with afatinib. In addition, we will evaluate the sensitivity and specificity of plasma ctDNA for monitoring tumour recurrence and progression. Finally, we will assess the safety of afatinib by keeping an eye on the safety indicators. ETHICS AND DISSEMINATION The study was approved by the medical-ethical review committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The clinical trials results, even inconclusive, will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER NCT04183712.
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Affiliation(s)
- Mao Yang
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Yuhao Zhao
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Yongsheng Li
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Xuya Cui
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Fatao Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Wenguang Wu
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Xu-An Wang
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Maolan Li
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Yun Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
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Yan X, Zou H, Lai Y, Ung COL, Hu H. Efficacy and Safety of First-Line Targeted Treatment and Immunotherapy for Patients with Biliary Tract Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel) 2022; 15:39. [PMID: 36612035 PMCID: PMC9817514 DOI: 10.3390/cancers15010039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/06/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Biliary tract cancer is one of the most aggressive and fatal tumours. Gemcitabine with cisplatin chemotherapy has long been the first-line treatment, but the prognosis is poor. In recent years, targeted treatment and immunotherapy have produced encouraging outcomes requiring a thorough review and meta-analysis. METHOD For this systematic review and meta-analysis, we searched four databases, starting from the inception dates of databases to 11 January 2022. This study comprised randomised clinical trials and cohort studies that used immunotherapy or targeted treatment as the first line of treatment for patients with biliary tract cancer. RESULTS From the 888 studies extracted, 33 trials were examined and found to meet the criteria. These included 3087 patients, 16 single-arm trials, 13 RCTs, one nRCT, a prospective single-arm pilot study, and a clinical setting in the real world. From 2010 to 2020, 33 studies were conducted using targeted treatment or immunologic therapies as first-line treatments for BTC patients, and 18 of those studies had positive outcomes. CONCLUSION This study demonstrates that immunotherapy combined with chemotherapy as first-line treatment can provide survival benefits by improving the objective response rate for patients with unresectable biliary tract cancer. The potential for combination therapy to become a new trend in clinical treatment is promising but needs further clinical evaluation.
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Affiliation(s)
- Xin Yan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Huimin Zou
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Yunfeng Lai
- School of Public Health and Management, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Carolina Oi Lam Ung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao SAR, China
| | - Hao Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao SAR, China
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11
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Horesh N, Bomze D, Lim C, Markel G, Meirson T, Azoulay D. Systemic review of the robustness of randomized controlled trials for the treatment of cholangiocarcinoma in three domains: survival-inferred fragility index, restricted mean survival time, and the spin effect. Hepatobiliary Surg Nutr 2022; 11:861-869. [PMID: 36523938 PMCID: PMC9745612 DOI: 10.21037/hbsn-21-118] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 07/09/2021] [Indexed: 03/20/2025]
Abstract
BACKGROUND The vast majority of patients with cholangiocarcinoma (CC) have advanced disease at diagnosis and are candidates for palliative treatment only. The robustness of the randomized controlled trials regarding the treatment of CC are assessed. METHODS A systematic review of all randomized control trials (RCT) of treatments for both intra- and extrahepatic CC between 2010 and 2020 was performed. The survival-inferred fragility index (SIFI; the minimum number of reassignments of the best survivors between arms that would overturn the statistical outcomes) was calculated. In addition, the gain, or loss, in survival in RCTs was evaluated by the restricted mean survival time (RMST) difference. Finally, the level of spin i.e., misrepresentation of study outcomes, was measured in inconclusive studies to assess distorted reporting strategies. RESULTS Out of 6,167 studies retrieved, 11 could be retained for full text revision (7 with both intra- and extrahepatic CC, 3 with peri-hilar CC, and 1 with peri-hilar or distal CC). Only 3 studies included resected patients (2 with both intra- and extrahepatic CC and 1 with peri-hilar or distal CC). Nine studies investigated systemic chemotherapy (including 3 after surgical resection), one study evaluated photodynamic therapy, and another investigated the use of an endoscopically inserted stent in the biliary tract. The median SIFI was -2 [interquartile range (IQR): -6.25, -0.25] across all studies. Overall, the median RMST difference was 0.56 months (IQR: 0.10, 0.95). Finally, for inconclusive studies, the level of spin was high, moderate, and low in respectively 12.5%, 25%, and 62.5% of the studies. CONCLUSIONS RCTs of CC showed a low degree of robustness with a frequent proportion of associated spin.
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Affiliation(s)
- Nir Horesh
- Unit of Hepatobiliary and Pancreatic Surgery and Transplantation, Sheba Medical Center, Faculty of Medicine Tel Aviv University, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - David Bomze
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Chetana Lim
- Centre Hépato-Biliaire, Department of Hepatobiliary and Pancreatic Surgery and Transplantation, Pitié Salpetriere Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Gal Markel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva, Israel
| | - Tomer Meirson
- Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva, Israel
- Shamir Medical Center (Assaf Harofeh), Rishon Lezion, Israel
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Daniel Azoulay
- Unit of Hepatobiliary and Pancreatic Surgery and Transplantation, Sheba Medical Center, Faculty of Medicine Tel Aviv University, Tel Aviv, Israel
- Centre Hépato-Biliaire, Department of Hepatobiliary and Pancreatic Surgery and Transplantation, Paul Brousse Hospital, Assistance Publique-Hôpitaux de Paris, Université Saclay, Villejuif, France
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12
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Cheng CY, Chen CP, Wu CE. Precision Medicine in Cholangiocarcinoma: Past, Present, and Future. Life (Basel) 2022; 12:829. [PMID: 35743860 PMCID: PMC9225212 DOI: 10.3390/life12060829] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/26/2022] [Accepted: 05/30/2022] [Indexed: 02/07/2023] Open
Abstract
Cholangiocarcinoma (CCA), or biliary tract cancer, has a poor prognosis. The median survival time among patients with CCA is under 2 years from diagnosis, and the global 5-year survival rate is only 10%. First-line therapy with chemotherapeutic agents, gemcitabine plus cisplatin, has traditionally been used to treat unresectable advanced CCA. In recent years, precision medicine has become a mainstream cancer treatment due to innovative next-generation sequencing technology. Several genetic alterations, including mutations, gene fusions, and copy number variations, have been found in CCA. In this review, we summarized the current understanding of genetic profiling in CCA and targeted therapy in CCA. Owing to the high heterogeneity of CCA, tumor microenvironmental factors, and the complexity of tumor biology, only pemigatinib, infigratinib, ivosidenib, larotrbctinib, and entrectinib are currently approved for the treatment of CCA patients with fibroblast growth factor receptor 2 gene (FGFR2) fusion, isocitrate dehydrogenase gene (IDH1) mutation, and neurotrophin receptor tyrosine kinase gene (NRTK) fusion, respectively. Additional targeted therapies, including other FGFR2 inhibitors, PI3K/AKT/mTOR inhibitors, and BRAF-directed targeted therapy, have been discussed for the management of CCA, and immune checkpoint inhibitors, particularly pembrolizumab, can be administered to patients with high microsatellite instability tumors. There is a further need for improvement in precision medicine therapies in the treatment of CCA and discuss the approved and potential targeted therapies for CCA.
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Affiliation(s)
- Chi-Yuan Cheng
- Department of Pharmacy, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan;
| | - Chiao-Ping Chen
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan;
| | - Chiao-En Wu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan;
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13
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Zhang B, Li S, Liu ZY, Peiris KGK, Song LF, Liu MC, Luo P, Shang D, Bi W. Successful multimodality treatment of metastatic gallbladder cancer: A case report and review of literature. World J Clin Cases 2022; 10:3856-3865. [PMID: 35647145 PMCID: PMC9100720 DOI: 10.12998/wjcc.v10.i12.3856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/25/2021] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gallbladder cancer is the most common malignant tumor in the biliary system, and it is characterized by high aggressiveness and an extremely poor prognosis. Current treatment for advanced gallbladder cancer remains unsatisfactory. Here, we report a patient with advanced gallbladder cancer who was cured by multidisciplinary treatment.
CASE SUMMARY A 73-year-old male presented to our hospital with right abdominal pain for 3 d and was diagnosed with stage IVB gallbladder cancer with multiple liver metastases, peritoneum metastasis, diaphragm metastasis and lymph node metastases. The patient initially received chemotherapy, targeted therapy, 125I seed implantation and immunotherapy, as there were no specific indications for radical surgery. During these palliative therapies, the level of tumor markers gradually decreased but remained higher than the normal level, lymph node metastases gradually disappeared, and liver metastasis was gradually limited to the left liver. Finally, the patient received radical surgery with left hepatectomy, radical lymphadenectomy and partial diaphragmatic resection. To date, the patient has survived for more than six years posttreatment, the levels of tumor markers are normal, and imaging examinations show no signs of tumor recurrence.
CONCLUSION Currently, the prognosis of advanced gallbladder cancer remains unsatisfactory. A single treatment method is not sufficient for patients with advanced gallbladder cancer. Multidisciplinary individualized treatment is essential and should be utilized for advanced gallbladder cancer patients to further improve prognosis.
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Affiliation(s)
- Biao Zhang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Shuang Li
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Zhao-Yi Liu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | | | - Li-Fu Song
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Mu-Cang Liu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Peng Luo
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Dong Shang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Wei Bi
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
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14
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Yang H, Jiang J, Hu Z, Zhang B, Cai W, Xu L, Lu K. Clinical Experience of Diagnosis and Surgical Treatment of 6 Cases of Acute Subhepatic Appendicitis. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:4969774. [PMID: 35469233 PMCID: PMC9034925 DOI: 10.1155/2022/4969774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/19/2022] [Indexed: 11/30/2022]
Abstract
To summarize the experience of diagnosis and surgical treatment of 6 cases of acute subhepatic appendicitis. The clinical data of 6 patients with subacute appendicitis in Zhejiang Provincial People's Hospital from July 2018 to December 2019 were analyzed retrospectively. Results. There were 5 males and 1 female. All 6 cases were diagnosed as appendicitis by abdominal CT before operation. All patients underwent laparoscopic appendectomy without conversion to laparotomy. One case of ectopic appendix was located under the liver with absence of ascending colon, one case of ectopic appendix was located under the liver with ectopic ascending colon of transverse colon, one case of appendix head was located in the liver cyst, and the resection of liver cyst was performed at the same time, and three cases of retrocolonic appendix head were located under the liver. Postoperative pathology confirmed appendicitis. For patients with right upper abdominal pain and tenderness, the possibility of subhepatic appendicitis should be considered before operation. Emergency abdominal CT has more advantages than ultrasound. Laparoscopy can not only make a definite diagnosis but also perform appendectomy at the same time.
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Affiliation(s)
- Hongguo Yang
- Department of Hepatobiliary & Pancreatic Surgery, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China
| | - Junjie Jiang
- Zhejiang Chinese Medical University, Hangzhou 31001, China
| | - Zhiming Hu
- Department of Hepatobiliary & Pancreatic Surgery, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China
| | - Bing Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China
| | - Wenwei Cai
- Department of Emergency, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Liming Xu
- Department of Emergency, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
| | - Kefeng Lu
- Department of Ultrasonography, Zhejiang Provincial People's Hospital, Hangzhou 310014, China
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15
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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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16
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Kim H, Kim R, Kim HR, Jo H, Kim H, Ha SY, Park JO, Park YS, Kim ST. HER2 Aberrations as a Novel Marker in Advanced Biliary Tract Cancer. Front Oncol 2022; 12:834104. [PMID: 35252005 PMCID: PMC8896348 DOI: 10.3389/fonc.2022.834104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/18/2022] [Indexed: 11/13/2022] Open
Abstract
HER2 aberrations have been reported as a novel biomarker in HER2-directed therapy or as a prognostic marker in various tumor types. However, in advanced biliary tract cancer (BTC), there have been few studies regarding HER2 aberrations as a biomarker. We analyzed 121 advanced BTC patients who had been treated with Gemcitabine/Cisplatin (GP) as a 1st line therapy between November 2019 and April 2021. Next-generation sequencing (NGS), namely, HER2 aberrations was performed in all patients. The TruSight™ Oncology 500 assay from Illumina was used for the NGS panel. Among 121 patients with advanced BTC, HER2 aberrations were observed in 18 patients (14.9%). For subtypes of HER2 aberrations, point mutation was observed in 5 patients (27.8%), gene amplification in 11 patients (61.1%), and both point mutation and gene amplification in 2 patients (11.1%). The frequency of HER2 aberrations was significantly different according to the primary tumor (p = 0.009). In gallbladder cancer, HER2 aberrations were observed at a relatively high frequency (36.4%). The tumor response to GP did not differ between patients with and without HER2 aberrations (33.3%, vs. 26.2%, respectively, p = 0.571). The median progression-free survival (PFS) to GP was 4.7 months (95% CI, 4.0 to 5.5 months) in patients with HER2 aberrations and 7.0 months (95% CI, 5.2 to 8.8 months) without HER2 aberrations (p = 0.776). The median overall survival (OS) was not reached and not reached in patients with and without HER2 aberrations (p = 0.739), respectively. The univariate analysis for PFS to GP and OS showed that HER2 aberrations were not an independent factor for survival. This study showed that the HER2 aberrations were observed in 14.9% of advanced BTC and were not an independent biomarker for survival.
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Affiliation(s)
- Hongsik Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Division of Hematology-Oncology, Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, South Korea
| | - Ryul Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hye Ryeon Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hyunji Jo
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hana Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Sang Yun Ha
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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17
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Pavicevic S, Reichelt S, Uluk D, Lurje I, Engelmann C, Modest DP, Pelzer U, Krenzien F, Raschzok N, Benzing C, Sauer IM, Stintzing S, Tacke F, Schöning W, Schmelzle M, Pratschke J, Lurje G. Prognostic and Predictive Molecular Markers in Cholangiocarcinoma. Cancers (Basel) 2022; 14:1026. [PMID: 35205774 PMCID: PMC8870611 DOI: 10.3390/cancers14041026] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 02/05/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primary liver cancer and subsumes a heterogeneous group of malignant tumors arising from the intra- or extrahepatic biliary tract epithelium. A rising mortality from CCA has been reported worldwide during the last decade, despite significant improvement of surgical and palliative treatment. Over 50% of CCAs originate from proximal extrahepatic bile ducts and constitute the most common CCA entity in the Western world. Clinicopathological characteristics such as lymph node status and poor differentiation remain the best-studied, but imperfect prognostic factors. The identification of prognostic molecular markers as an adjunct to traditional staging systems may not only facilitate the selection of patients who would benefit the most from surgical, adjuvant or palliative treatment strategies, but may also be helpful in defining the aggressiveness of the disease and identifying patients at high-risk for tumor recurrence. The purpose of this review is to provide an overview of currently known molecular prognostic and predictive markers and their role in CCA.
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Affiliation(s)
- Sandra Pavicevic
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Sophie Reichelt
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Deniz Uluk
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Isabella Lurje
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Cornelius Engelmann
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Dominik P. Modest
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Uwe Pelzer
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Felix Krenzien
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Christian Benzing
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Igor M. Sauer
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Sebastian Stintzing
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Frank Tacke
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Wenzel Schöning
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Georg Lurje
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
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18
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Matsuhashi N, Tomita H, Tanaka H, Iwata Y, Matsui S, Imai H, Fukada M, Mizutani C, Takahashi T, Yasufuku I, Suetsugu T, Mori R, Tanaka Y, Okumura N, Futamura M, Yoshida K. Evaluation of histopathological heterogeneity of colorectal cancer liver metastasis sites after preoperative chemotherapy. Mol Clin Oncol 2022; 16:61. [PMID: 35127086 PMCID: PMC8771193 DOI: 10.3892/mco.2022.2494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 07/14/2021] [Indexed: 11/30/2022] Open
Abstract
Patients with liver metastases from colorectal cancer (CRLMs) frequently receive chemotherapy prior to liver resection. Histopathological assessment of the resected specimen can evaluate the response to chemotherapy. The present study analyzed the association between histopathological changes in the primary site and liver metastases. The present study comprised 45 patients with resectable CRLMs at the Surgical Oncology Department of Gifu University School of Medicine (Gifu, Japan) between January 2006 and August 2015. The study included 24 men and 21 women. The primary colonic tumor was located in the right side in 13 (28.9%) patients and the left side in 32 (71.9%) patients. The present study evaluated patients with metastatic colorectal cancer (31/45) after excluding those in whom histopathological heterogeneity between the primary and liver metastasis changed to grade 3 after chemotherapy. The group that underwent hepatectomy after chemotherapy (n=25) was compared with the group that underwent hepatectomy alone (n=6). In 16 (53.3%) out of 25 patients, histopathological heterogeneity of the liver metastasis was lost (P=0.04). In conclusion, chemotherapy appeared to change histopathological heterogeneity. The present study suggested that the histopathological change of intratumoral heterogeneity is reflected by the response to chemotherapy.
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Affiliation(s)
- Nobuhisa Matsuhashi
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Hidenori Tanaka
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Yoshinori Iwata
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Satoshi Matsui
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Hisashi Imai
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Masahiro Fukada
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Chika Mizutani
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Takao Takahashi
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Itaru Yasufuku
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Tomonari Suetsugu
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Ryutaro Mori
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Yoshihiro Tanaka
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Naoki Okumura
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Manabu Futamura
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
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Canale M, Monti M, Rapposelli IG, Ulivi P, Sullo FG, Bartolini G, Tiberi E, Frassineti GL. Molecular Targets and Emerging Therapies for Advanced Gallbladder Cancer. Cancers (Basel) 2021; 13:5671. [PMID: 34830826 PMCID: PMC8616432 DOI: 10.3390/cancers13225671] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 01/07/2023] Open
Abstract
Biliary tract cancers (BTCs), for their low incidence, have been often considered together. Gallbladder cancer (GBC) is the most common biliary tract malignancy, characterized by late diagnosis and poor prognosis, and although it is considered a rare tumor in western countries, other areas of the world show considerable incidence rates. In 2010, results from the large phase III ABC-02 clinical trial on GBC identified the gemcitabine and cisplatin combination as the most effective first-line regimen for both GBC and other BTCs. Since then, various systemic therapies have proven active in BTCs in both first- and second-line settings. Molecular profiling has highlighted important genetic differences between GBC and other BTCs, opening new ways for targeted therapy in advanced disease where standard chemotherapies show marginal benefit. Genome-wide data analysis have shown that GBC molecular landscape offer possible strategies for precision medicine approaches, and a better molecular understanding of the GBC is needed to better stratify patients for treatment. In this review, we discuss the molecular targetable agents for GBC, including the results that emerged by clinical trials exploring new treatment strategies.
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Affiliation(s)
- Matteo Canale
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Manlio Monti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Ilario Giovanni Rapposelli
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Paola Ulivi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Francesco Giulio Sullo
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Giulia Bartolini
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Elisa Tiberi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (F.G.S.); (G.B.); (E.T.); (G.L.F.)
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20
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Kam AE, Masood A, Shroff RT. Current and emerging therapies for advanced biliary tract cancers. Lancet Gastroenterol Hepatol 2021; 6:956-969. [PMID: 34626563 DOI: 10.1016/s2468-1253(21)00171-0] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/30/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023]
Abstract
Biliary tract cancers (cholangiocarcinomas and gallbladder cancers) are increasing in incidence and have a poor prognosis. Most patients present with advanced disease, for which the treatment is palliative chemotherapy. Over the past few years, the genomic landscape of biliary tract cancers has been examined and several targeted therapies have been developed. Molecular targets with clinically meaningful activity include fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), RAS-RAF-MEK (MAP2K1)-ERK (MAPK3), HER2 (also known as ERBB2), DNA mismatch repair, and NTRK. Pemigatinib, a FGFR1-3 inhibitor, showed encouraging response rates and survival data as second-line treatment and received US Food and Drug Administration (FDA) approval in April, 2020, for previously treated advanced or metastatic cholangiocarcinoma with FGFR2 gene fusion or rearrangements. Ivosidenib, an IDH1 inhibitor, showed improved progression-free survival versus placebo in second-line treatment in the phase 3 ClarIDHy trial. Early phase trials of dabrafenib plus trametinib (BRAF and MEK inhibition) and zanidatamab (a bispecific HER2-antibody) have yielded encouraging response rates. Immunotherapy has mainly produced responses in tumours with deficient mismatch repair or high microsatellite instability (also known as dMMR or MSI-H) or higher PD-L1 score, or both. However, early phase trials of immunotherapy plus chemotherapy in unselected patient populations appear promising. NTRK inhibitors have also shown promise in early phase trials of NTRK-fusion positive solid tumours, including cholangiocarcinoma. In this Review, we discuss current and emerging therapies for advanced biliary tract cancers, with a focus on molecularly targeted therapy.
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Affiliation(s)
- Audrey E Kam
- Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL, USA.
| | - Ashiq Masood
- Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL, USA
| | - Rachna T Shroff
- Division of Hematology and Oncology, University of Arizona Cancer Center, Tucson, AZ, USA
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21
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Establishment of a Pretreatment Nomogram to Predict the 6-Month Mortality Rate of Patients with Advanced Biliary Tract Cancers Undergoing Gemcitabine-Based Chemotherapy. Cancers (Basel) 2021; 13:cancers13133139. [PMID: 34201707 PMCID: PMC8268608 DOI: 10.3390/cancers13133139] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/12/2021] [Accepted: 06/20/2021] [Indexed: 12/30/2022] Open
Abstract
Simple Summary The development of a simple tool that uses pretreatment clinical factors to predict the 6-month mortality rate of patients with advanced biliary tract cancer is critical in order to assist physicians in evaluating treatment options and outcomes. We established a nomogram including four independent pretreatment factors—gender, monocyte to lymphocyte ratio, alkaline phosphatase, and liver metastasis—based on data from 202 patients undergoing gemcitabine-based chemotherapy. The performance of this nomogram for 6-month mortality-risk prediction was promising and feasible, providing clinicians and patients with additional information for evaluating therapeutic options. Abstract Background: The estimation of mortality risk among patients diagnosed with advanced cancer provides important information for clinicians and patients in clinical practice. Currently, gemcitabine-based chemotherapy regimens are the standard treatment for patients with advanced biliary tract cancer (BTC). We aimed to develop a nomogram to predict the 6-month mortality rate among patients with advanced BTC to help physicians evaluate treatment options and outcomes. Patients: We conducted a retrospective analysis to evaluate the 6-month mortality rate among patients with advanced BTC who underwent gemcitabine-based chemotherapy from 2012 to 2018. Data regarding pretreatment factors and the clinical response to treatment were collected. Univariate and multivariate analyses were performed to identify independent factors for nomogram creation. Results: A total of 202 advanced BTC patients who were treated with gemcitabine-based chemotherapy were included in this analysis. No difference in survival was identified between patients undergoing gemcitabine monotherapy and those treated with gemcitabine combined with other cytotoxic agents. The univariate analysis revealed 10 significant factors, while the multivariate analysis identified four independent factors, including gender, monocyte to lymphocyte ratio (MLR), alkaline phosphatase (ALP), and liver metastasis, which were used to establish the nomogram. The performance of this nomogram for the prediction of 6-month mortality risk was found to be promising and feasible based on logistic regression. Conclusion: A nomogram based on four independent pretreatment factors, including gender, MLR, ALP, and liver metastasis, was established to predict the 6-month mortality risk in patients with advanced BTC; it can provide clinicians and patients with additional information when evaluating treatment outcomes.
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22
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Aagre SV, Tonse M, Talele A, Sharma S, Advani SH. Bevacizumab based chemotherapy is a promising option in metastatic gallbladder adenocarcinoma. Mol Clin Oncol 2021; 15:153. [PMID: 34178324 DOI: 10.3892/mco.2021.2315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 03/01/2021] [Indexed: 11/06/2022] Open
Abstract
Gallbladder cancer (GBC) is one of the most frequently observed cancers in India that is usually diagnosed at an advanced stage. Although surgery remains the only curative option, the majority of GBCs are unresectable. Palliative chemotherapy with gemcitabine and cisplatin is the recommended treatment in such cases. The current study reports a case of a 47-year-old female who exhibited GBC that had metastasized to the liver and peritoneum. She was administered palliative chemotherapy with gemcitabine and cisplatin, but due to disease progression the regimen was changed and an aggressive treatment initiated with gemcitabine and oxaliplatin with additional biosimilar bevacizumab (modified Gemox-B regimen). The patient completed six chemotherapy cycles with partial response and received bevacizumab (7.5 mg/kg 3-weekly) based maintenance treatment for an additional 6 cycles, after which she demonstrated disease progression, thus having a progression free survival of ~11 months. The patient is currently receiving palliative chemotherapy with capecitabine.
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Affiliation(s)
- Suhas V Aagre
- Department of Medical Oncology, Asian Cancer Institute, Mumbai, Maharashtra 400036, India
| | - Mubarakunnisa Tonse
- Department of Medical Oncology, Asian Cancer Institute, Mumbai, Maharashtra 400036, India
| | - Avinash Talele
- Department of Medical Oncology, Asian Cancer Institute, Mumbai, Maharashtra 400036, India
| | - Sanjay Sharma
- Department of Surgical Oncology, Asian Cancer Institute, Mumbai, Maharashtra 400036, India
| | - Suresh H Advani
- Department of Medical Oncology, Asian Cancer Institute, Mumbai, Maharashtra 400036, India
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23
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Qin JM. Conversion therapy for primary liver cancer: Indications and selective strategies. Shijie Huaren Xiaohua Zazhi 2021; 29:501-510. [DOI: 10.11569/wcjd.v29.i10.501] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary liver cancer has an insidious onset and no specific symptoms at early stage. Most patients are in the middle or advanced stage when diagnosed, and only 20%-40% of patients meet the criteria for radical resection. At present, surgical resection is still the main radical treatment for primary liver cancer, but factors such as liver function decompensation, too large tumor volume, too small future liver remnant, intrahepatic multiple metastasis, tumor thrombus invading the large vessels or bile duct, and distant metastasis limit the application of surgical resection or liver transplantation. In recent years, with the advances of basic research of primary liver cancer, the development of surgical techniques and equipment, as well as the development of new molecular targeted drugs and immunotherapy drugs, a part of unresectable patients with primary liver cancer can receive conversion therapy to improve liver function, minimize tumor volume, minimize or inactivate tumor thrombus, and increase the residual liver volume. Following conversion therapy, patients with primary liver cancer can undergo surgical resection or liver transplantation, which greatly improve the therapeutic efficacy and patient survival.
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Affiliation(s)
- Jian-Min Qin
- Department of General Surgery, the Third Hospital Affiliated to Naval Military Medical University, Shanghai 201805, China
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24
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Roles of Nrf2 in Gastric Cancer: Targeting for Therapeutic Strategies. Molecules 2021; 26:molecules26113157. [PMID: 34070502 PMCID: PMC8198360 DOI: 10.3390/molecules26113157] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/15/2021] [Accepted: 05/19/2021] [Indexed: 12/12/2022] Open
Abstract
Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) is a specific transcription factor with potent effects on the regulation of antioxidant gene expression that modulates cell hemostasis under various conditions in tissues. However, the effects of Nrf2 on gastric cancer (GC) are not fully elucidated and understood. Evidence suggests that uncontrolled Nrf2 expression and activation has been observed more frequently in malignant tumors, including GC cells, which is then associated with increased antioxidant capacity, chemoresistance, and poor clinical prognosis. Moreover, Nrf2 inhibitors and the associated modulation of tumor cell redox balance have shown that Nrf2 also has beneficial effects on the therapy of various cancers, including GC. Based on previous findings on the important role of Nrf2 in GC therapy, it is of great interest to scientists in basic and clinical tumor research that Nrf2 can be active as both an oncogene and a tumor suppressor depending on different background situations.
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Lee SH, Kim JM, Lee DG, Lee J, Park JG, Han TS, Cho HS, Cho YL, Bae KH, Park YJ, Lee SJ, Lee MS, Huh YM, Jo DY, Yun HJ, Jeon HJ, Kim N, Joo M, Kim JS, Lee HJ, Min JK. Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation. Cell Death Differ 2021; 28:968-984. [PMID: 32989241 PMCID: PMC7937683 DOI: 10.1038/s41418-020-00628-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 09/20/2020] [Accepted: 09/21/2020] [Indexed: 12/14/2022] Open
Abstract
Gallbladder carcinoma (GBC) exhibits poor prognosis due to local recurrence, metastasis, and resistance to targeted therapies. Using clinicopathological analyses of GBC patients along with molecular in vitro and tumor in vivo analysis of GBC cells, we showed that reduction of Dsg2 expression was highly associated with higher T stage, more perineural, and lymphatic invasion. Dsg2-depleted GBC cells exhibited significantly enhanced proliferation, migration, and invasiveness in vitro and tumor growth and metastasis in vivo through Src-mediated signaling activation. Interestingly, Dsg2 binding inhibited Src activation, whereas its loss activated cSrc-mediated EGFR plasma membrane clearance and cytoplasmic localization, which was associated with acquired EGFR-targeted therapy resistance and decreased overall survival. Inhibition of Src activity by dasatinib enhanced therapeutic response to anti-EGFR therapy. Dsg2 status can help stratify predicted patient response to anti-EGFR therapy and Src inhibition could be a promising strategy to improve the clinical efficacy of EGFR-targeted therapy.
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Affiliation(s)
- Sang-Hyun Lee
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Jin-Man Kim
- Department of Pathology, Cancer Research Institute and Infection Control Convergence Research Center, Chungnam National University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Dong Gwang Lee
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Jangwook Lee
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Jong-Gil Park
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Tae-Su Han
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Hyun-Soo Cho
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Young-Lai Cho
- Research Center for Metabolic Regulation, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Kwang-Hee Bae
- Research Center for Metabolic Regulation, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Young-Jun Park
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Seon-Jin Lee
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Moo-Seung Lee
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Yong-Min Huh
- Department of Biochemistry & Molecular Biology and Department of Radiology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Deog Yeon Jo
- Department of Internal Medicine, Cancer Research Institute and Infection Control Convergence Research Center, Chungnam National University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Hwan-Jung Yun
- Department of Internal Medicine, Cancer Research Institute and Infection Control Convergence Research Center, Chungnam National University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Heung Jin Jeon
- Department of Internal Medicine, Cancer Research Institute and Infection Control Convergence Research Center, Chungnam National University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Nayoung Kim
- Department of Biomedical Science and Infection Control Convergence Research Center, Chungnam National University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Mina Joo
- Department of Biomedical Science and Infection Control Convergence Research Center, Chungnam National University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Jang-Seong Kim
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
| | - Hyo Jin Lee
- Department of Internal Medicine, Cancer Research Institute and Infection Control Convergence Research Center, Chungnam National University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea.
| | - Jeong-Ki Min
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
- Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
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Yang W, Sun Y. Promising Molecular Targets for the Targeted Therapy of Biliary Tract Cancers: An Overview. Onco Targets Ther 2021; 14:1341-1366. [PMID: 33658799 PMCID: PMC7920611 DOI: 10.2147/ott.s297643] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Biliary tract cancer (BTC) is a leading cause of cancer-related death, due to the limited benefits of current systematic therapies and the heterogeneity of the tumor itself. High heterogeneity means that the clinical and molecular features vary between different subtypes of BTC, while the underlying molecular mechanisms remain unclear. Targeted therapy, where inhibitors are developed to selectively combine with targeted molecules in order to block abnormal signaling pathways in BTC, has shown promise as an emerging form of treatment for various types of cancer. In this article, a comprehensive review is conducted to examine potential molecular targets for BTC targeted therapy and their mechanisms. Furthermore, preliminary data published from clinical trials is utilized to analyze the main drugs used to combat BTC. The collective information presented in this article has provided useful insights into the current understanding of BTC.
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Affiliation(s)
- Wenwei Yang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Yongkun Sun
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
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Vacchelli E, Galluzzi L, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, Kroemer G. Trial watch: Chemotherapy with immunogenic cell death inducers. Oncoimmunology 2021; 1:179-188. [PMID: 22720239 PMCID: PMC3376992 DOI: 10.4161/onci.1.2.19026] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The long-established notion that apoptosis would be immunologically silent, and hence it would go unnoticed by the immune system, if not tolerogenic, and hence it would actively suppress immune responses, has recently been revisited. In some instances, indeed, cancer cells undergo apoptosis while emitting a spatiotemporally-defined combination of signals that renders them capable of eliciting a long-term protective antitumor immune response. Importantly, only a few anticancer agents can stimulate such an immunogenic cell death. These include cyclophosphamide, doxorubicin and oxaliplatin, which are currently approved by FDA for the treatment of multiple hematologic and solid malignancies, as well as mitoxantrone, which is being used in cancer therapy and against multiple sclerosis. In this Trial Watch, we will review and discuss the progress of recent (initiated after January 2008) clinical trials evaluating the off-label use of cyclophosphamide, doxorubicin, oxaliplatin and mitoxantrone.
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Affiliation(s)
- Erika Vacchelli
- U848; Villejuif, France; INSERM; Université Paris-Sud/Paris XI; Paris, France
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Samatiwat P, Tabtimmai L, Suphakun P, Jiwacharoenchai N, Toviwek B, Kukongviriyapan V, Gleeson MP, Choowongkomon K. The Effect of the EGFR - Targeting Compound 3-[(4-Phenylpyrimidin-2-yl) Amino] Benzene-1-Sulfonamide (13f) against Cholangiocarcinoma Cell Lines. Asian Pac J Cancer Prev 2021; 22:381-390. [PMID: 33639651 PMCID: PMC8190356 DOI: 10.31557/apjcp.2021.22.2.381] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 02/05/2021] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE Cholangiocarcinoma (CCA) is a noxious malignancy of epithelium of the bile duct with a low response rate to chemotherapy. The epidermal growth factor receptor (EGFR) signaling pathway is implicated in the development of cancerous cells, especially CCA. In this study, we report detailed biological profiling of 13f identified from our earlier hit expansion studies. The aim of this work was to expand our understanding of 13f via more detailed investigations of its mechanism of action against KKU-100, KKU-452 and KKU-M156 CCA cells, as well as in comparison to the EGFR inhibitor Gefitinib and non-specific chemotherapeutic agents such as Cisplatin. METHODS Inhibiting EGFR-Kinase, cytotoxicity, clonogenic assay, wound healing and apoptosis were performed. Levels of total expression of EGFR and EGFR phosphorylation proteins were detected. RESULTS 13f was confirmed as an inhibitor of EGFR with an IC50 value against the tyrosine kinase of EGFR of 22 nM and IC50 values for 48 h incubation period were 1.3 ± 1.9, 1.5 ± 0.4 and 1.7 ± 1.1 µM of KKU-100, KKU-452 and KKU-M156, respectively through dose- and time-dependent induction of early apoptosis of CCA cells. The compound also suppressed the clonogenic ability of KKU-100 and KKU-M156 cells stronger than Gefitinib, while potently inhibiting EGF-stimulated CCA cell migratory activity in KKU-452 cells. It was observed that under normal conditions EGFR was activated in CCA cells. EGF-stimulated basal expression of EGFR in KKU-452 cells was suppressed following 13f treatment, which was significantly greater than that of the marketed EGFR inhibitor Gefitinib. CONCLUSION In summary, our study showed that 13f has potent anti-cancer activities including antiproliferation, clonogenic ability and migration through the modulation of EGFR signaling pathway in CCA for the first time. The compound represents an interesting starting point as a potential chemotherapeutic agent in ongoing efforts to improve response rate in CCA patients.
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Affiliation(s)
- Papavee Samatiwat
- Department of Pharmacology, Faculty of Medicine, Srinakharinwirot University, Bangkok, 10110, Thailand.
| | - Lueacha Tabtimmai
- Department of Biochemistry, Kasetsart University, Bangkok, 10900, Thailand.
| | - Prapasri Suphakun
- Department of Biochemistry, Kasetsart University, Bangkok, 10900, Thailand.
| | - Nattanan Jiwacharoenchai
- Genetic Engineering Interdisciplinary Program, Graduate School, Kasetsart University, 10900, Thailand.
| | | | - Veerapol Kukongviriyapan
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.
| | - M. Paul Gleeson
- Department of Biomedical Engineering, Faculty of Engineering, King Mongkut’s Institute of Technology Ladkrabang, Bangkok. Thailand.
| | - Kiattawee Choowongkomon
- Department of Biochemistry, Kasetsart University, Bangkok, 10900, Thailand.
- Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, KU Institute for Advanced Studies, Kasetsart University, Bangkok 10900, Thailand.
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Rodrigues PM, Olaizola P, Paiva NA, Olaizola I, Agirre-Lizaso A, Landa A, Bujanda L, Perugorria MJ, Banales JM. Pathogenesis of Cholangiocarcinoma. ANNUAL REVIEW OF PATHOLOGY 2021; 16:433-463. [PMID: 33264573 DOI: 10.1146/annurev-pathol-030220-020455] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered a rare cancer, the incidence of CCA is increasing globally. The silent and asymptomatic nature of these tumors, particularly in their early stages, in combination with their high aggressiveness, intra- and intertumor heterogeneity, and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. During the last few years, increasing efforts have been made to unveil the etiologies and pathogenesis of these tumors and to develop more effective therapies. In this review, we summarize current findings in the field of CCA, mainly focusing on the mechanisms of pathogenesis, cells of origin, genomic and epigenetic abnormalities, molecular alterations, chemoresistance, and therapies.
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Affiliation(s)
- Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Nuno A Paiva
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Irene Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Alona Agirre-Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Ana Landa
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
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30
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Sarkis Y, Al Soueidy A, Kourie HR. Will advanced cholangiocarcinoma become a targetable malignancy? Crit Rev Oncol Hematol 2021; 159:103233. [PMID: 33482346 DOI: 10.1016/j.critrevonc.2021.103233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 12/15/2020] [Accepted: 01/16/2021] [Indexed: 02/08/2023] Open
Abstract
Cholangiocarcinoma and biliary tract cancers are rare but aggressive tumors that are characterized by an heterogenous molecular and genetic footprint. Genetic aberrations such as FGFR2 fusion and ErBb2 amplification are common in those cancers. Recent studies aimed at exploring the efficacy and benefit of targeted therapy in the treatment of advanced cholangiocarcinoma. Many promising drugs exist and warrant additional investigations. This review will summarize available results and highlight therapeutic strategies incorporated in clinical trials.
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Affiliation(s)
- Yara Sarkis
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University of Beirut, Lebanon.
| | - Amine Al Soueidy
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University of Beirut, Lebanon
| | - Hampig Raphael Kourie
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University of Beirut, Lebanon
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31
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Balasubramanian B, Venkatraman S, Myint KZ, Janvilisri T, Wongprasert K, Kumkate S, Bates DO, Tohtong R. Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma. Pharmaceuticals (Basel) 2021; 14:51. [PMID: 33440754 PMCID: PMC7826774 DOI: 10.3390/ph14010051] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 01/01/2021] [Accepted: 01/07/2021] [Indexed: 12/18/2022] Open
Abstract
Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment options are limited, with surgical resection being the only form of treatment with curative intent. The current standard-of-care remains adjuvant and palliative chemotherapy which is ineffective in most patients. The overall survival rate is dismal, even after surgical resection and the tumor heterogeneity further complicates treatment. Together, this makes CCA a significant burden in Southeast Asia. For effective management of CCA, treatment must be tailored to each patient, individually, for which an assortment of targeted therapies must be available. Despite the increasing numbers of clinical studies in CCA, targeted therapy drugs rarely get approved for clinical use. In this review, we discuss the shortcomings of the conventional clinical trial process and propose the implementation of a novel concept, co-clinical trials to expedite drug development for CCA patients. In co-clinical trials, the preclinical studies and clinical trials are conducted simultaneously, thus enabling real-time data integration to accurately stratify and customize treatment for patients, individually. Hence, co-clinical trials are expected to improve the outcomes of clinical trials and consequently, encourage the approval of targeted therapy drugs. The increased availability of targeted therapy drugs for treatment is expected to facilitate the application of precision medicine in CCA.
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Affiliation(s)
- Brinda Balasubramanian
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (B.B.); (S.V.); (K.Z.M.)
| | - Simran Venkatraman
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (B.B.); (S.V.); (K.Z.M.)
| | - Kyaw Zwar Myint
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (B.B.); (S.V.); (K.Z.M.)
| | - Tavan Janvilisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
| | - Kanokpan Wongprasert
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
| | - Supeecha Kumkate
- Department of Biology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
| | - David O. Bates
- Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK;
| | - Rutaiwan Tohtong
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
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32
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Gkika E, Hawkins MA, Grosu AL, Brunner TB. The Evolving Role of Radiation Therapy in the Treatment of Biliary Tract Cancer. Front Oncol 2021; 10:604387. [PMID: 33381458 PMCID: PMC7768034 DOI: 10.3389/fonc.2020.604387] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 11/04/2020] [Indexed: 12/13/2022] Open
Abstract
Biliary tract cancers (BTC) are a disease entity comprising diverse epithelial tumors, which are categorized according to their anatomical location as intrahepatic (iCCA), perihilar (pCCA), distal (dCCA) cholangiocarcinomas, and gallbladder carcinomas (GBC), with distinct epidemiology, biology, and prognosis. Complete surgical resection is the mainstay in operable BTC as it is the only potentially curative treatment option. Nevertheless, even after curative (R0) resection, the 5-year survival rate ranges between 20 and 40% and the disease free survival rates (DFS) is approximately 48–65% after one year and 23–35% after three years without adjuvant treatment. Improvements in adjuvant chemotherapy have improved the DFS, but the role of adjuvant radiotherapy is unclear. On the other hand, more than 50% of the patients present with unresectable disease at the time of diagnosis, which limits the prognosis to a few months without treatment. Herein, we review the role of radiotherapy in the treatment of cholangiocarcinoma in the curative and palliative setting.
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Affiliation(s)
- Eleni Gkika
- Department of Radiation Oncology, University Medical Centre Freiburg, Freiburg, Germany
| | - Maria A Hawkins
- Medical Physics and Biomedical Engineering, University College London, London, United Kingdom
| | - Anca-Ligia Grosu
- Department of Radiation Oncology, University Medical Centre Freiburg, Freiburg, Germany
| | - Thomas B Brunner
- Department of Radiation Oncology, University of Magdeburg, Magdeburg, Germany
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33
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Loosen SH, Gaisa NT, Schmeding M, Heining C, Uhrig S, Wirtz TH, Kalverkamp S, Spillner J, Tacke F, Stenzinger A, Glimm H, Fröhling S, Trautwein C, Roderburg C, Longerich T, Neumann UP, Luedde T. Prolonged Survival of a Patient with Advanced-Stage Combined Hepatocellular-Cholangiocarcinoma. Case Rep Gastroenterol 2020; 14:658-667. [PMID: 33442346 PMCID: PMC7772835 DOI: 10.1159/000511034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 08/13/2020] [Indexed: 12/14/2022] Open
Abstract
Combined hepatocellular-cholangiocarcinoma (cHCC/CCA) represents a rare type of primary liver cancer with a very limited prognosis. Although just recently genomic studies have contributed to a better understanding of the disease's genetic landscape, therapeutic options, especially for advanced-stage patients, are limited and often experimental, as no standardized treatment protocols have been established to date. Here, we report the case of a 38-year-old male patient who was diagnosed with extensive intrahepatic cHCC/CCA in an otherwise healthy liver without signs of chronic liver disease. An interdisciplinary stepwise therapeutic approach including locoregional liver-targeted therapy, systemic chemotherapy, liver transplantation, surgical pulmonary metastasis resection, and next-generation sequencing-based targeted therapy led to a prolonged overall survival beyond 5 years with an excellent quality of life. This case report comprises several provocative treatment decisions that are extensively discussed in light of the existing literature on this rare but highly aggressive malignancy.
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Affiliation(s)
- Sven H Loosen
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Nadine T Gaisa
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | | | - Christoph Heining
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany.,Center for Personalized Oncology, NCT Dresden and University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Dresden, Germany
| | - Sebastian Uhrig
- Division of Applied Bioinformatics, DKFZ, Heidelberg, Germany.,Molecular Diagnostics Program, NCT Heidelberg and DKFZ, Heidelberg, Germany
| | - Theresa H Wirtz
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Sebastian Kalverkamp
- Department of Thoracic and Cardiovascular Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Jan Spillner
- Department of Thoracic and Cardiovascular Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Frank Tacke
- Department of Gastroenterology/Hepatology, Campus Virchow Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Hanno Glimm
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany.,Center for Personalized Oncology, NCT Dresden and University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Dresden, Germany.,Translational Functional Cancer Genomics Group, NCT Heidelberg and DKFZ, Heidelberg, Germany
| | - Stefan Fröhling
- German Cancer Consortium (DKTK), Heidelberg, Germany.,Department of Translational Medical Oncology, NCT Heidelberg and DKFZ, Heidelberg, Germany
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Christoph Roderburg
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Thomas Longerich
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Ulf Peter Neumann
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany.,Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands
| | - Tom Luedde
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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34
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Wang M, Chen Z, Guo P, Wang Y, Chen G. Therapy for advanced cholangiocarcinoma: Current knowledge and future potential. J Cell Mol Med 2020; 25:618-628. [PMID: 33277810 PMCID: PMC7812297 DOI: 10.1111/jcmm.16151] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/21/2020] [Accepted: 11/22/2020] [Indexed: 01/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a biliary epithelial tumour that can emerge at any point in the biliary tree. It is commonly classified based on its anatomical site of development into intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PCC) and distal cholangiocarcinoma (DCC), each of which is associated with varying patient demographics, molecular characteristics and treatment options. CCA patients have poor overall prognoses and 5‐year survival rates. Additionally, CCA is often diagnosed at an advanced stage, with surgical treatment restricted to early‐stage disease. Owing to an increase in the incidence of ICC, that of CCA is also on the rise, with a corresponding increase in the associated mortality, particularly in South America and Asia. Therefore, the development of an effective treatment is crucial to improve the survival of CCA patients. We aimed to systematically review the current understanding of advanced CCA treatment and discuss potential effective strategies.
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Affiliation(s)
- Mingxun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Ziyan Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Pengyi Guo
- Department of Cardiothoracic Surgery, Ningbo Yinzhou NO.2 Hospital, Ningbo, China
| | - Yi Wang
- Department of Epidemiology and Biostatistics, Public Health and Management School, Wenzhou Medical University, Wenzhou, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
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35
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Xie C, McGrath NA, Monge Bonilla C, Fu J. Systemic treatment options for advanced biliary tract carcinoma. J Gastroenterol 2020; 55:944-957. [PMID: 32748173 PMCID: PMC7519922 DOI: 10.1007/s00535-020-01712-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/25/2020] [Indexed: 02/04/2023]
Abstract
Advanced biliary tract cancers (BTC) include a diverse collection of rare and heterogenous tumors with poor prognosis. The combination of gemcitabine and cisplatin is the established first-line therapy for advanced BTC. There are no accepted standard treatments in the second line setting, though there are several ongoing clinical trials that implement chemotherapy as a therapeutic strategy. The understanding of the molecular landscape of BTC has offered hope of targeted therapies to the identified actionable genomic aberrations, such as FGFR2 gene fusions, mutations of IDH1/2, HER2, BRAC1/2 and BRAF. Pembigatinib has become the first approved targeted therapy for BTC with FGFR2 fusion or other rearrangements. Recent immunotherapy has opened new therapy avenues in BTC with pembrolizumab approved for either microsatellite instability high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors, including BTC. The combination of immunotherapy with other modalities is currently being evaluated in different clinical trials, since single agent immunotherapy appears to provide modest benefits in advanced BTC. In this review, we summarize the current status of treatment options, including systemic chemotherapy, targeted therapy, immunotherapy, and various combinations in advanced BTC.
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Affiliation(s)
- Changqing Xie
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Nicole A McGrath
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Cecilia Monge Bonilla
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jianyang Fu
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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36
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Ntanasis-Stathopoulos I, Tsilimigras DI, Gavriatopoulou M, Schizas D, Pawlik TM. Cholangiocarcinoma: investigations into pathway-targeted therapies. Expert Rev Anticancer Ther 2020; 20:765-773. [PMID: 32757962 DOI: 10.1080/14737140.2020.1807333] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Cholangiocarcinoma is a malignant disease of the biliary tract and accounts for 3% of all gastrointestinal tumors. Surgical intervention is currently the only potentially curative strategy for cholangiocarcinoma. For patients with unresectable, advanced or metastatic disease, the combination of gemcitabine with cisplatin is considered the standard treatment. However, currently available therapeutic options have only a marginal benefit, especially among patients with relapsed/refractory tumors. AREAS COVERED We reviewed targeted agents under clinical evaluation for patients with cholangiocarcinoma. FGFR and IDH inhibitors are at the most advanced stage of clinical investigation. EGFR inhibitors have demonstrated contradictory results, whereas inhibition of other molecular pathways, including the RAS/RAF/MEK/ERK, the MET, the PI3K/AKT/mTOR and angiogenetic pathways, has shown minimal or null benefit. EXPERT OPINION Several targeted approaches are being investigated for advanced cholangiocarcinoma. However, randomized clinical trials are needed to define the optimal treatment regimen and address issues including the option of monotherapy or combination regimens, the optimal sequence of different treatments, ways to overcome resistance to targeted treatments, as well as determining the right time and tissue for assessing molecular signatures. Targeted therapies and immunotherapy hold promise for improving patient outcomes in the future.
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Affiliation(s)
- Ioannis Ntanasis-Stathopoulos
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Cente , Columbus, OH, UAS
| | - Diamantis I Tsilimigras
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Cente , Columbus, OH, UAS
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra General Hospital , Athens, Greece
| | - Dimitrios Schizas
- Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens , Athens, Greece
| | - Timothy M Pawlik
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra General Hospital , Athens, Greece
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37
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Athauda A, Fong C, Lau DK, Javle M, Abou-Alfa GK, Morizane C, Steward K, Chau I. Broadening the therapeutic horizon of advanced biliary tract cancer through molecular characterisation. Cancer Treat Rev 2020; 86:101998. [PMID: 32203843 PMCID: PMC8222858 DOI: 10.1016/j.ctrv.2020.101998] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 03/06/2020] [Accepted: 03/08/2020] [Indexed: 02/06/2023]
Abstract
Biliary tract cancers (BTC) comprise a group of rare and heterogeneous poor-prognosis tumours with the incidence of intrahepatic cholangiocarcinoma increasing over recent years. Combination chemotherapy with gemcitabine and cisplatin is the established first-line treatment for advanced BTC with a significant but modest survival advantage over monotherapy. There remains no accepted standard treatment in the second-line setting, although recent results from a randomised study have shown a survival benefit with 5-fluorouracil and oxaliplatin chemotherapy. Historically, clinical trials investigating targeted therapies in unselected BTC have failed to demonstrate significant clinical benefit. More recently, advancement in molecular exploration of BTC has shed light on the complex biological heterogeneity within these tumours and has also identified actionable genomic aberrations, such as fibroblast growth factor receptor 2 (FGFR2) gene fusions, isocitrate dehydrogenase (IDH) and BRAF mutations, which offer promise with the anticipation of increased responses and durable clinical benefit in selected patients. Several targeted drugs have now entered clinical development with some encouraging results being seen. Here we review the current and rapidly evolving therapeutic landscape of advanced BTC, including targeted therapies and immunotherapy. We also discuss how recent efforts and successes in BTC are overcoming the obstacles typically associated with precision medicine in rare cancers. Ultimately, the management of advanced BTC is likely to become molecularly selected in the near future with the hope of finally improving the bleak prognosis of patients with this disease.
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Affiliation(s)
- Avani Athauda
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.
| | - Caroline Fong
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.
| | - David K Lau
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.
| | - Milind Javle
- University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Weill Medical College at Cornell University, New York, NY, USA.
| | - Chigusa Morizane
- National Cancer Center Hospital, Tsukiji, Tokyo 104-0045, Japan.
| | - Keith Steward
- QED Therapeutics Inc, 75 Federal Street, San Francisco, CA 94107, USA.
| | - Ian Chau
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.
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38
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Palmieri LJ, Lavolé J, Dermine S, Brezault C, Dhooge M, Barré A, Chaussade S, Coriat R. The choice for the optimal therapy in advanced biliary tract cancers: Chemotherapy, targeted therapies or immunotherapy. Pharmacol Ther 2020; 210:107517. [PMID: 32109491 DOI: 10.1016/j.pharmthera.2020.107517] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 02/18/2020] [Indexed: 01/09/2023]
Abstract
Biliary tract cancers (BTCs) represent a heterogeneous group that includes intrahepatic cholangiocarcinomas (CCAs), perihilar-CCAs or Klatskin tumors, extrahepatic-CCAs, and gallbladder adenocarcinoma. These entities have distinct demographics, risk factors, clinical presentation, and molecular characteristics. In advanced BTCs, the recommendations are mainly supporting a doublet chemotherapy regimen using cisplatin/gemcitabine (CisGem) with a 5-year overall survival rate close to 5% and median overall survival (mOS) of less than a year. The lack of overall efficacy stresses the need for personalized therapies. Recently, whole-genome and transcriptome sequencing highlighted the diversity of BTCs' subtypes. Distinct genetic alterations were retrieved according to the localization, with a high rate of potentially actionable alterations. Targeted therapies and immunotherapy have since then been tested for BTCs, trying to propose a more personalized treatment. This review describes the different therapeutic options, validated and in development, for patients with advanced BTCs.
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Affiliation(s)
- L-J Palmieri
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France.
| | - J Lavolé
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France
| | - S Dermine
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France
| | - C Brezault
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France
| | - M Dhooge
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France
| | - A Barré
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France
| | - S Chaussade
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France
| | - R Coriat
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France
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39
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Taghizadeh H, Müllauer L, Mader R, Prager GW. Applied precision cancer medicine in metastatic biliary tract cancer. Hepatol Int 2020; 14:288-295. [PMID: 32100259 PMCID: PMC7136181 DOI: 10.1007/s12072-020-10020-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 01/28/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Advanced therapy-refractory biliary tract cancer (BTC) has poor prognosis and constitutes a major challenge for adequate treatment strategies. By mapping the molecular profiles of advanced BTC patients, precision cancer medicine may provide targeted therapies for these patients. OBJECTIVE In this analysis, we aimed to show the potential of PCM in metastatic BTC. METHODS In this single-center, real-world retrospective analysis of our PCM platform, we describe the molecular profiling of 30 patients diagnosed with different types of metastatic BTC. Tumor samples of the patients were examined using a 161-gene next-generation sequencing panel, immunohistochemistry (IHC), and fluorescence in situ hybridization for chromosomal translocations. RESULTS In total, we identified 35 molecular aberrations in 30 patients. The predominant mutations were KRAS (n = 8), TP53 (n = 7), IDH2 (n = 4), and IDH1 (n = 3) that accounted for the majority of all molecular alterations (62.86%). BRAF mutations were observed in two patients. Less frequent alterations were noted in ARID1A, CTNNB1, ESR1, FBXW7, FGFR2, MET, NOTCH2, PIK3CA, PTCH1, SMAD4, and SRC1, each in one case. FGFR fusion gene was detected in one patient. No mutations were detected in eight patients. IHC revealed EGFR and p-mTOR expression in 28 patients. Applying these results to our patients, targeted therapy was recommended for 60% of the patients (n = 18). One patient achieved stable disease. CONCLUSIONS PCM is a feasible treatment approach and may provide molecular-guided therapy recommendations for metastatic BTC.
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Affiliation(s)
- H Taghizadeh
- Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.,Comprehensive Cancer Center Vienna, Vienna, Austria
| | - L Müllauer
- Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria
| | - R Mader
- Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.,Comprehensive Cancer Center Vienna, Vienna, Austria
| | - G W Prager
- Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria. .,Comprehensive Cancer Center Vienna, Vienna, Austria.
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40
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Ejaz A, Cloyd JM, Pawlik TM. Advances in the Diagnosis and Treatment of Patients with Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 2019; 27:552-560. [PMID: 31555936 DOI: 10.1245/s10434-019-07873-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Indexed: 12/27/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is an aggressive biliary tract cancer (BTC) that arises from the biliary tract epithelium distal to the secondary biliary radicals. Over the past decade, significant advances have been made in the diagnosis, staging, and treatment of ICC. Emerging data have highlighted the importance of lymphadenectomy for elucidating patient prognosis as well as the at-risk nodal basins based on tumor location (de Jong et al. in J Clin Oncol 29(23):3140-3145, 2011). Several large randomized controlled trials have recently been published clarifying the role of adjuvant therapy for BTCs (Cloyd and Pawlik in J Oncol Pract 14(12):723-724, 2018). In addition, the molecular understanding of ICC pathogenesis has increased over time, leading to new potential molecular biomarkers and opening opportunities for novel targeted and immunologic therapies (Rizvi et al. in Nat Rev Clin Oncol 15(2):95-111, 2018). These recent advances serve to only improve our understanding of the optimal multidisciplinary treatment of this difficult disease.
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Affiliation(s)
- Aslam Ejaz
- James Cancer Center, The Ohio State University, Columbus, OH, USA. .,Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
| | - Jordan M Cloyd
- James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Timothy M Pawlik
- James Cancer Center, The Ohio State University, Columbus, OH, USA
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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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Saeed A, Park R, Al-Jumayli M, Al-Rajabi R, Sun W. Biologics, Immunotherapy, and Future Directions in the Treatment of Advanced Cholangiocarcinoma. Clin Colorectal Cancer 2019; 18:81-90. [DOI: 10.1016/j.clcc.2019.02.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 02/15/2019] [Accepted: 02/18/2019] [Indexed: 02/07/2023]
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Kim ST, Kang JH, Lee J, Lee HW, Oh SY, Jang JS, Lee MA, Sohn BS, Yoon SY, Choi HJ, Hong JH, Kim MJ, Kim S, Park YS, Park JO, Lim HY. Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial. Ann Oncol 2019; 30:788-795. [PMID: 30785198 DOI: 10.1093/annonc/mdz058] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Capecitabine plus oxaliplatin (XELOX) has shown modest activity and tolerable toxicity in a phase II trial for biliary tract cancers (BTCs). Meanwhile, gemcitabine plus oxaliplatin (GEMOX) has been the reference arm in recent phase II and III trials for BTCs. We aimed to investigate the efficacy of XELOX versus GEMOX as first-line therapy for advanced BCTs. PATIENTS AND METHODS In this open-label, randomized, phase III, noninferiority trial, we randomly selected patients with metastatic BCTs to receive GEMOX (gemcitabine 1000 mg/m2 on days 1 and 8, and oxaliplatin 100 mg/m2 on day 1) or XELOX (capecitabine 1000 mg/m2, twice daily, on days 1-14 and oxaliplatin 130 mg/m2 on day 1) as first-line treatment, given every 3 weeks, totaling eight cycles. The primary end point was to prove the noninferiority of XELOX to GEMOX in terms of 6-month progression-free survival (PFS) rate. RESULTS In total, 114 patients randomly received GEMOX and 108 randomly received XELOX. The median PFS was 5.3 months for the GEMOX group and 5.8 months for the XELOX group. The 6-month PFS rate was 44.5% for the GEMOX group and 46.7% for the XELOX group. The 95% confidence interval of the 6-month PFS rate difference between both groups was -12% to 16%, meeting the criteria for noninferiority of XELOX to GEMOX. There was no difference in objective response (P=0.171) and median overall survival (P=0.131) between both groups. The most common grade three to four adverse events were neutropenia and thrombocytopenia. No patient died of treatment-related causes. The XELOX group had significantly lower frequencies of hospital visits than the GEMOX group (P<0.001). CONCLUSION XELOX showed significant noninferiority to GEMOX in terms of 6-month PFS rate. Thus, XELOX could be an alternative first-line treatment of BCTs. TRIAL REGISTRATION This study was registered in ClinicalTrials.gov (number NCT01470443).
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Affiliation(s)
- S T Kim
- Division of Hemato-oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - J H Kang
- Division of Hemato-oncology, Department of Medicine, Gyeongsang National University Hospital, Jinju
| | - J Lee
- Division of Hemato-oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - H W Lee
- Division of Hemato-oncology, Department of Medicine, Ajou University School of Medicine, Suwon
| | - S Y Oh
- Division of Hemato-oncology, Department of Medicine, Dong-A University School of Medicine, Busan
| | - J S Jang
- Division of Hemato-oncology, Department of Medicine, Chung-Ang University College of Medicine, Seoul
| | - M A Lee
- Division of Hemato-oncology, Department of Medicine, Seoul St Mary's Hospital, Catholic University, Seoul
| | - B S Sohn
- Division of Hemato-oncology, Department of Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul
| | - S Y Yoon
- Division of Hemato-oncology, Department of Medicine, Konkuk University Medical Center, Seoul
| | - H J Choi
- Division of Hemato-oncology, Department of Medicine, Yonsei University College of Medicine, Seoul
| | - J H Hong
- Division of Hemato-oncology, Department of Medicine, Incheon St Mary's Hospital, Catholic University, Incheon
| | - M-J Kim
- Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea
| | - S Kim
- Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea
| | - Y S Park
- Division of Hemato-oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - J O Park
- Division of Hemato-oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul.
| | - H Y Lim
- Division of Hemato-oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul.
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Gurmikov BN, Kovalenko YA, Vishnevsky VA, Chzhao AV. Molecular genetic aspects of intrahepatic cholangiocarcinoma: literature review. ADVANCES IN MOLECULAR ONCOLOGY 2019. [DOI: 10.17650/2313-805x-2019-6-1-37-43] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- B. N. Gurmikov
- A.V. Vishnevsky National Medical Research Center of Surgery, Ministry of Health of Russia
| | - Yu. A. Kovalenko
- A.V. Vishnevsky National Medical Research Center of Surgery, Ministry of Health of Russia
| | - V. A. Vishnevsky
- A.V. Vishnevsky National Medical Research Center of Surgery, Ministry of Health of Russia
| | - A. V. Chzhao
- A.V. Vishnevsky National Medical Research Center of Surgery, Ministry of Health of Russia
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Caparica R, Lengelé A, Bekolo W, Hendlisz A. FOLFIRI as second-line treatment of metastatic biliary tract cancer patients. Autops Case Rep 2019; 9:e2019087. [PMID: 31528622 PMCID: PMC6738847 DOI: 10.4322/acr.2019.087] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 05/10/2019] [Indexed: 12/24/2022]
Abstract
The combination of cisplatin and gemcitabine is the standard first-line treatment of metastatic biliary tract cancer (BTC) patients. The benefit of second-line chemotherapy in these patients is controversial. This study aims to evaluate the activity of FOLFIRI (fluorouracil and irinotecan) after failure to the first-line platinum and gemcitabine-based chemotherapy in metastatic BTC patients. We present a single-institution, retrospective cohort study. Patients with locally advanced or metastatic BTC who progressed after at least one line of chemotherapy, consecutively treated at our Institution between 2007 and 2017 were included. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), clinical benefit rate (CBR) and safety profile of FOLFIRI. Twelve patients were included in the analysis, with a median follow up of 5 months (95% CI 2.77-7.20). The median number of cycles received was 3 (range 1 to 9). Four grade 3 toxicities were recorded; no grade 4 toxicities and no treatment-related deaths occurred. The median PFS was 1.7 months (95% CI; 0.66-2.67), and median OS was 5 months (95% CI; 2.77-7.20). Two patients presented stable disease, providing a CBR of 17%. We concluded that FOLFIRI presented a favorable toxicity profile and a modest activity in metastatic BTC patients who had progressed to platinum and gemcitabine and may be considered in patients who are able to tolerate additional lines of chemotherapy. Immunotherapy and targeted therapies selected according to the tumoral genomic profile are promising alternatives to improve the outcomes of second-line treatment in BTC.
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Affiliation(s)
- Rafael Caparica
- Institut Jules Bordet and Université Libre de Bruxelles (ULB), Department of Medical Oncology, Brussels, Belgium
| | | | - Winnie Bekolo
- Douala General Hospital, University of Douala, Cameroon
| | - Alain Hendlisz
- Institut Jules Bordet and Université Libre de Bruxelles (ULB), Department of Medical Oncology, Brussels, Belgium
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Hickman L, Contreras C. Gallbladder Cancer: Diagnosis, Surgical Management, and Adjuvant Therapies. Surg Clin North Am 2019; 99:337-355. [PMID: 30846038 DOI: 10.1016/j.suc.2018.12.008] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gallbladder cancer (GBC) is an often lethal disease, but surgical resection is potentially curative. Symptoms may be misdiagnosed as biliary colic; over half of new diagnoses are made after laparoscopic cholecystectomy for presumed benign disease. Gallbladder polyps >1 cm should prompt additional imaging and cholecystectomy. For GBC diagnosed after cholecystectomy, tumors T1b and greater necessitate radical cholecystectomy. Radical cholecystectomy includes staging laparoscopy, hepatic resection, and locoregional lymph node clearance to achieve R0 resection. Patients with locally advanced disease (T3 or T4), hepatic-sided T2 tumors, node positivity, or R1 resection may benefit from adjuvant chemotherapy. Chemotherapy increases survival in unresectable disease.
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Affiliation(s)
- Laura Hickman
- Division of Surgical Oncology, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Carlo Contreras
- Division of Surgical Oncology, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
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Simile MM, Bagella P, Vidili G, Spanu A, Manetti R, Seddaiu MA, Babudieri S, Madeddu G, Serra PA, Altana M, Paliogiannis P. Targeted Therapies in Cholangiocarcinoma: Emerging Evidence from Clinical Trials. ACTA ACUST UNITED AC 2019; 55:medicina55020042. [PMID: 30743998 PMCID: PMC6409688 DOI: 10.3390/medicina55020042] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 01/28/2019] [Accepted: 02/01/2019] [Indexed: 12/13/2022]
Abstract
Cholangiocarcinoma (CCA) is a highly-aggressive malignancy arising from the biliary tree, characterized by a steady increase in incidence globally and a high mortality rate. Most CCAs are diagnosed in the advanced and metastatic phases of the disease, due to the paucity of signs and symptoms in the early stages. This fact, along with the poor results of the local and systemic therapies currently employed, is responsible for the poor outcome of CCA patients and strongly supports the need for novel therapeutic agents and strategies. In recent years, the introduction of next-generation sequencing technologies has opened new horizons for a better understanding of the genetic pathophysiology of CCA and, consequently, for the identification and evaluation of new treatments tailored to the molecular features or alterations progressively elucidated. In this review article, we describe the potential targets under investigation and the current molecular therapies employed in biliary tract cancers. In addition, we summarize the main drugs against CCA under evaluation in ongoing trials and describe the preliminary data coming from these pioneering studies.
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Affiliation(s)
- Maria Maddalena Simile
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100 Sassari, Italy.
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Imai H, Saijo K, Komine K, Otsuki Y, Ohuchi K, Sato Y, Okita A, Takahashi M, Takahashi S, Shirota H, Takahashi M, Ishioka C. Antibiotic therapy augments the efficacy of gemcitabine-containing regimens for advanced cancer: a retrospective study. Cancer Manag Res 2019; 11:7953-7965. [PMID: 31686910 PMCID: PMC6709792 DOI: 10.2147/cmar.s215697] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 07/16/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The addition of antibiotics reportedly augments the efficacy of gemcitabine (GEM) in tumor-bearing mice. However, whether this phenomenon is also observed in cancer patients remains unclear. In the present study, we aimed to assess whether antibiotics for treatment or prevention of infection augments treatment efficacies of GEM-containing regimens in patients with any type of cancer. METHODS Medical records of patients diagnosed with cancer histopathologically and treated with GEM-containing regimens (n=169) were retrospectively reviewed. Patients were assigned into two groups: antibiotics-untreated group (patients who were treated with GEM-containing regimens but without antibiotics) and antibiotics-treated group (patients who were treated with GEM-containing regimens plus antibiotics). Response rates, progression-free survival (PFS) time, and overall survival (OS) time were analyzed for each group. RESULTS The response rates of the antibiotics-untreated and antibiotics-treated groups with GEM-containing regimens were 15.1% and 27.6%, respectively. The median PFS times of the antibiotics-untreated and antibiotics-treated groups were 2.5 (95% CI: 1.86-3.73) and 4.9 (95% CI: 3.47-6.0) months, respectively. The median OS times of the antibiotics-untreated and antibiotics-treated groups were 7.53 (95% CI: 5.63-9.57) months and 13.83 (95% CI: 10.83-16.43) months, respectively. CONCLUSION The addition of antibiotics augments the treatment efficacies of GEM-containing regimens, and it may be a potential therapeutic option to improve treatment efficacies of GEM-containing regimens in patients with advanced cancer.
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Affiliation(s)
- Hiroo Imai
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Ken Saijo
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Keigo Komine
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Yasufumi Otsuki
- Department of Clinical Oncology, Institute of Developing, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Kota Ohuchi
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Yuko Sato
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Akira Okita
- Department of Clinical Oncology, Institute of Developing, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Masahiro Takahashi
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Shin Takahashi
- Department of Clinical Oncology, Institute of Developing, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Hidekazu Shirota
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Masanobu Takahashi
- Department of Clinical Oncology, Institute of Developing, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Chikashi Ishioka
- Department of Clinical Oncology, Institute of Developing, Aging and Cancer, Tohoku University, Sendai, Japan
- Correspondence: Chikashi IshiokaDepartment of Medical Oncology, Tohoku University Hospital, 4-1, Seiryo-machi, Aobaku, Sendai980-8575, JapanTel +81 22 717 8543Fax +81 22 717 8548Email
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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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Vaquero J, Lobe C, Tahraoui S, Clapéron A, Mergey M, Merabtene F, Wendum D, Coulouarn C, Housset C, Desbois-Mouthon C, Praz F, Fouassier L. The IGF2/IR/IGF1R Pathway in Tumor Cells and Myofibroblasts Mediates Resistance to EGFR Inhibition in Cholangiocarcinoma. Clin Cancer Res 2018; 24:4282-4296. [PMID: 29716918 DOI: 10.1158/1078-0432.ccr-17-3725] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 04/03/2018] [Accepted: 04/27/2018] [Indexed: 11/16/2022]
Abstract
Purpose: Cholangiocarcinoma (CCA) is a desmoplastic tumor of the biliary tree in which epidermal growth factor receptor (EGFR) is overexpressed and contributes to cancer progression. Although EGFR has been envisaged as a target for therapy, treatment with tyrosine kinase inhibitors (TKI) such as erlotinib did not provide therapeutic benefit in patients with CCA, emphasizing the need to investigate resistance mechanisms against EGFR inhibition.Experimental Design: Resistant CCA cells to EGFR inhibition were obtained upon long-time exposure of cells with erlotinib. Cell signaling, viability, migration, and spheroid growth were determined in vitro, and tumor growth was evaluated in CCA xenograft models.Results: Erlotinib-resistant CCA cells displayed metastasis-associated signatures that correlated with a marked change in cell plasticity associated with an epithelial-mesenchymal transition (EMT) and a cancer stem cell (CSC)-like phenotype. Resistant cells exhibited an upregulation of insulin receptor (IR) and insulin-like growth factor (IGF) 1 receptor (IGF1R), along with an increase in IGF2 expression. IR/IGF1R inhibition reduced EMT and CSC-like traits in resistant cells. In vivo, tumors developed from resistant CCA cells were larger and exhibited a more prominent stromal compartment, enriched in cancer-associated fibroblasts (CAF). Pharmacological coinhibition of EGFR and IR/IGF1R reduced tumor growth and stromal compartment in resistant tumors. Modeling of CCA-CAF crosstalk showed that IGF2 expressed by fibroblasts boosted IR/IGF1R signaling in resistant cells. Furthermore, IR/IGF1R signaling positively regulated fibroblast proliferation and activation.Conclusions: To escape EGFR-TKI treatment, CCA tumor cells develop an adaptive mechanism by undergoing an IR/IGF1R-dependent phenotypic switch, involving a contribution of stromal cells. Clin Cancer Res; 24(17); 4282-96. ©2018 AACR.
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Affiliation(s)
- Javier Vaquero
- Sorbonne University, INSERM, Saint-Antoine Research Center (CRSA), Paris, France
- Fondation ARC, Villejuif, France
- LPP, CNRS, Ecole Polytech., Univ. Paris-Sud, Observatoire de Paris, Univ. Paris-Saclay, Sorbonne University, PSL Research University, Paris, France
| | - Cindy Lobe
- Sorbonne University, INSERM, Saint-Antoine Research Center (CRSA), Paris, France
| | - Sylvana Tahraoui
- Sorbonne University, INSERM, Saint-Antoine Research Center (CRSA), Paris, France
| | - Audrey Clapéron
- Sorbonne University, INSERM, Saint-Antoine Research Center (CRSA), Paris, France
| | - Martine Mergey
- Sorbonne University, INSERM, Saint-Antoine Research Center (CRSA), Paris, France
| | - Fatiha Merabtene
- Sorbonne University, INSERM, Saint-Antoine Research Center (CRSA), Paris, France
| | - Dominique Wendum
- Sorbonne University, INSERM, Saint-Antoine Research Center (CRSA), Paris, France
- Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, Department of Pathology, Paris, France
| | - Cédric Coulouarn
- INSERM, INRA, Univ Rennes 1, Univ Bretagne Loire, Nutrition Metabolisms and Cancer (NuMeCan), Rennes, France
| | - Chantal Housset
- Sorbonne University, INSERM, Saint-Antoine Research Center (CRSA), Paris, France
- Assistance Publique-Hôpitaux de Paris, Saint-Antoine Hospital, Hepatology Department, Paris, France
| | | | - Françoise Praz
- Sorbonne University, INSERM, Saint-Antoine Research Center (CRSA), Paris, France
| | - Laura Fouassier
- Sorbonne University, INSERM, Saint-Antoine Research Center (CRSA), Paris, France.
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