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Luo D, Liu Y, Lu Z, Huang L. Targeted therapy and immunotherapy for gastric cancer: rational strategies, novel advancements, challenges, and future perspectives. Mol Med 2025; 31:52. [PMID: 39923010 PMCID: PMC11806620 DOI: 10.1186/s10020-025-01075-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 01/10/2025] [Indexed: 02/10/2025] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors worldwide, and its treatment has been a focus of medical research. Herein we systematically review the current status of and advancements in targeted therapy and immunotherapy for GC, which have emerged as important treatment strategies in recent years with great potential, and summarize the efficacy and safety of such treatments. Targeted therapies against key targets in GC, including epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR), have shown remarkable therapeutic efficacies by inhibiting tumor progression and/or blood supply. In particular, markable breakthroughs have been made in HER2-targeting drugs for HER2-positive GC patients. To address intrinsic and acquired resistances to HER2-targeting drugs, novel therapeutic agents including bispecific antibodies and antibody-drug conjugates (ADC) targeting HER2 have been developed. Immunotherapy enhances the recognition and elimination of cancer cells by activating body anticancer immune system. Programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) antibodies are the most commonly used immunotherapeutic agents and have been used with some success in GC treatment. Innovative immunotherapy modalities, including adoptive immune cell therapy, tumor vaccines, and non-specific immunomodulators therapy, and oncolytic viruses have shown promise in early-stage clinical trials for GC. Clinical trials have supported that targeted therapy and immunotherapy can significantly improve the survival and quality of life of GC patients. However, the effects of such therapies need to be further improved and more personalized, with advancement in researches on tumor immune microenvironment. Further studies remain needed to address the issues of drug resistance and adverse events pertaining to such therapies for GC. The combined application of such therapies and individualized treatment strategies should be further explored with novel drugs developed, to provide more effective treatments for GC patients.
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Affiliation(s)
- Dong Luo
- Department of Gastroenterology, National Clinical Research Center for Digestive Diseases, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
- Center of Structural Heart Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yunmei Liu
- School of Cultural Heritage and Information Management, Shanghai University, Shanghai, 200444, China.
| | - Zhengmao Lu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
| | - Lei Huang
- Department of Gastroenterology, National Clinical Research Center for Digestive Diseases, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China.
- National Key Laboratory of Immunity and Inflammation, Changhai Clinical Research Unit, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China.
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Li F, Huang F, Tang Y, Zhang F, Jiang H, Chen J, Lv B. Causal association of folic acid supplementary therapy and gastric ulcer: a Mendelian randomisation study. Br J Nutr 2024; 132:1348-1355. [PMID: 39444310 DOI: 10.1017/s0007114524002368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Previous research has suggested a potential link between folic acid (FA) supplementary therapy and gastric ulcers (GU). To investigate this relationship further, we conducted a Mendelian randomisation (MR) analysis using data from the UK Biobank. Our analysis primarily employed inverse-variance weighted (IVW) methods, including both fixed-effect and random-effect models. To ensure the robustness of our findings, additional methods such as the simple median, the weighted median and the penalised weighted median were also applied. The MR analysis aimed to explore the causal effect of FA supplementary therapy on GU. Seven SNP at genetic loci associated with FA supplementary therapy were identified. Both the random-effect and fixed-effect IVW models indicated that genetically predicted FA supplementary therapy significantly reduced the risk of GU (OR, 0·870; 95 % CI 0·826, 0·917, P < 0·001). This result was consistent across other methods, with similar outcomes observed using the simple median (OR, 0·835; 95 % CI 0·773, 0·901, P < 0·001), the weighted median (OR, 0·854; 95 % CI 0·794, 0·919, P < 0·001) and the penalised weighted median (OR, 0·849; 95 % CI 0·789, 0·914, P < 0·001). Leave-one-out sensitivity analysis confirmed that no individual SNP significantly drove the association between FA supplementary therapy and GU. This MR study provides genetic evidence that FA supplementary therapy may decrease the risk of GU.
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Affiliation(s)
- Fuhao Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou310006, Zhejiang, People's Republic of China
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, Zhejiang310006, People's Republic of China
| | - Fengming Huang
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou310006, Zhejiang, People's Republic of China
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, Zhejiang310006, People's Republic of China
| | - Yulong Tang
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou310053, Zhejiang, People's Republic of China
| | - Fan Zhang
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, Zhejiang310006, People's Republic of China
- Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Hao Jiang
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, Zhejiang310006, People's Republic of China
| | - Jun Chen
- Department of Cardiology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310000, People's Republic of China
| | - Bin Lv
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou310006, Zhejiang, People's Republic of China
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hubin Campus, Hangzhou, Zhejiang310006, People's Republic of China
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Li X, Xu J, Xie J, Yang W. Research progress in targeted therapy and immunotherapy for gastric cancer. Chin Med J (Engl) 2022; 135:1299-1313. [PMID: 35830242 PMCID: PMC9433086 DOI: 10.1097/cm9.0000000000002185] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Indexed: 11/26/2022] Open
Abstract
ABSTRACT Gastric cancer (GC) is one of the most common malignant tumors worldwide. Its incidence ranks the 5th among all malignant tumors globally, and it is the 3rd leading cause of death among patients with cancer. Surgical treatment is the first choice in clinical practice. However, targeted therapy, immunotherapy, and other treatment methods have also become research hotspots at home and abroad with the development of individualized precision therapy in recent years, besides traditional radiotherapy and chemotherapy. At present, targeted therapy and immunotherapy are methods used for treating GC, and they have important clinical application value and prospects. This study aimed to review the research progress of targeted therapy and immunotherapy for GC, focusing on its mechanism of action and related important clinical trials, hoping to provide references for the clinical treatment of GC.
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Affiliation(s)
- Xuewei Li
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Jun Xu
- Department of Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Jun Xie
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Wenhui Yang
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi 030032, China
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Ivey A, Pratt H, Boone BA. Molecular pathogenesis and emerging targets of gastric adenocarcinoma. J Surg Oncol 2022; 125:1079-1095. [PMID: 35481910 PMCID: PMC9069999 DOI: 10.1002/jso.26874] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/15/2022] [Accepted: 03/19/2022] [Indexed: 12/24/2022]
Abstract
Gastric adenocarcinoma (GC) is a devastating disease and is the third leading cause of cancer deaths worldwide. This heterogeneous disease has several different classification systems that consider histological appearance and genomic alterations. Understanding the etiology of GC, including infection, hereditary conditions, and environmental factors, is of particular importance and is discussed in this review. To improve survival in GC, we also must improve our therapeutic strategies. Here, we discuss new targets that warrant further exploration.
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Affiliation(s)
- Abby Ivey
- Department of Cancer Cell Biology, West Virginia University Cancer Institute, West Virginia University, Morgantown, West Virginia, USA
| | - Hillary Pratt
- Department of Cancer Cell Biology, West Virginia University Cancer Institute, West Virginia University, Morgantown, West Virginia, USA
| | - Brian A Boone
- Department of Cancer Cell Biology, West Virginia University Cancer Institute, West Virginia University, Morgantown, West Virginia, USA
- Department of Surgery, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, West Virginia, USA
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Xin L, Tang F, Song B, Yang M, Zhang J. Objective Quantitation of EGFR Protein Levels using Quantitative Dot Blot Method for the Prognosis of Gastric Cancer Patients. J Gastric Cancer 2021; 21:335-351. [PMID: 35079437 PMCID: PMC8753283 DOI: 10.5230/jgc.2021.21.e32] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/21/2021] [Accepted: 10/28/2021] [Indexed: 11/23/2022] Open
Abstract
Purpose An underlying factor for the failure of several clinical trials of anti-epidermal growth factor receptor (EGFR) therapies is the lack of an effective method to identify patients who overexpress EGFR protein. The quantitative dot blot method (QDB) was used to measure EGFR protein levels objectively, absolutely, and quantitatively. Its feasibility was evaluated for the prognosis of overall survival (OS) of patients with gastric cancer. Materials and Methods Slices of 2×5 μm from formalin-fixed paraffin-embedded gastric cancer specimens were used to extract total tissue lysates for QDB measurement. Absolutely quantitated EGFR protein levels were used for the Kaplan-Meier OS analysis. Results EGFR protein levels ranged from 0 to 772.6 pmol/g (n=246) for all gastric cancer patients. A poor correlation was observed between quantitated EGFR levels and immunohistochemistry scores with ρ=0.024 and P=0.717 in Spearman's correlation analysis. EGFR was identified as an independent negative prognostic biomarker for gastric cancer patients only through absolute quantitation, with a hazard ratio of 1.92 (95% confidence interval, 1.05–3.53; P=0.034) in multivariate Cox regression OS analysis. A cutoff of 208 pmol/g was proposed to stratify patients with a 3-year survival probability of 44% for patients with EGFR levels above the cutoff versus 68% for those below the cutoff based on Kaplan-Meier OS analysis (log rank test, P=0.002). Conclusions A QDB-based assay was developed for gastric cancer specimens to measure EGFR protein levels absolutely, quantitatively, and objectively. This assay should facilitate clinical trials aimed at evaluation of anti-EGFR therapies retrospectively and prospectively for gastric cancer.
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Affiliation(s)
- Lei Xin
- Department of Gastrointestinal Surgery, Yantaishan Hospital, Yantai, China
| | - Fangrong Tang
- Yantai Quanticision Diagnostics, Inc. (Division of Quanticision Diagnostics, Inc. of USA), Yantai, China
| | - Bo Song
- Department of Gastroenterology, Yantaishan Hospital, Yantai, China
| | - Maozhou Yang
- Yantai Quanticision Diagnostics, Inc. (Division of Quanticision Diagnostics, Inc. of USA), Yantai, China
| | - Jiandi Zhang
- Yantai Quanticision Diagnostics, Inc. (Division of Quanticision Diagnostics, Inc. of USA), Yantai, China
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Maron SB, Xu J, Janjigian YY. Targeting EGFR in Esophagogastric Cancer. Front Oncol 2020; 10:553876. [PMID: 33364187 PMCID: PMC7753114 DOI: 10.3389/fonc.2020.553876] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 11/05/2020] [Indexed: 12/24/2022] Open
Abstract
Esophagogastric cancer (EGC) remains a major cause of cancer-related mortality. Overall survival in the metastatic setting remains poor, with few molecular targeted approaches having been successfully incorporated into routine care to-date: only first line anti-HER2 therapy in ERBB2-expressing tumors, second line anti-VEGFR2 therapy with ramucirumab in unselected patients, and pembrolizumab in PD-L1 expressing or MSI-H patients. EGFR inhibitors were extensively studied in EGC, including phase III trials with cetuximab (EXPAND), panitumumab (REAL3), and gefitinib (COG). All three trials were conducted in unselected populations, and therefore, failed to demonstrate clinical benefit. Here, we review previous attempts at targeting EGFR in EGC and potential future biomarkers for targeting this pathway in patients with EGFR-amplified tumors.
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Affiliation(s)
- Steven B Maron
- Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - James Xu
- Computer Engineering Program, Columbia University, New York, NY, United States
| | - Yelena Y Janjigian
- Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
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Systematic Elucidation of the Mechanism of Quercetin against Gastric Cancer via Network Pharmacology Approach. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3860213. [PMID: 32964029 PMCID: PMC7486643 DOI: 10.1155/2020/3860213] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 06/25/2020] [Indexed: 12/24/2022]
Abstract
This study was aimed at elucidating the potential mechanisms of quercetin in the treatment of gastric cancer (GC). A network pharmacology approach was used to analyze the targets and pathways of quercetin in treating GC. The predicted targets of quercetin against GC were obtained through database mining, and the correlation of these targets with GC was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Next, the protein-protein interaction (PPI) network was constructed, and overall survival (OS) analysis of hub targets was performed using the Kaplan–Meier Plotter online tool. Finally, the mechanism was further analyzed via molecular docking of quercetin with the hub targets. Thirty-six quercetin-related genes were identified, 15 of which overlapped with GC-related targets. These targets were further mapped to 319 GO biological process terms and 10 remarkable pathways. In the PPI network analysis, six hub targets were identified, including AKT1, EGFR, SRC, IGF1R, PTK2, and KDR. The high expression of these targets was related to poor OS in GC patients. Molecular docking analysis confirmed that quercetin can bind to these hub targets. In conclusion, this study provided a novel approach to reveal the therapeutic mechanisms of quercetin on GC, which will ease the future clinical application of quercetin in the treatment of GC.
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Hsu A, Chudasama R, Almhanna K, Raufi A. Targeted therapies for gastroesophageal cancers. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1104. [PMID: 33145323 PMCID: PMC7576008 DOI: 10.21037/atm-20-3265] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/30/2020] [Indexed: 12/18/2022]
Abstract
Gastroesophageal cancers are some of the most common malignancies worldwide. A significant portion of patients are diagnosed with advanced or metastatic disease given the insidious nature of gastroesophageal cancers. In the instance where surgical resection for cure is no longer an option, the prognosis is poor and generally less than a year. Traditionally, standard front-line chemotherapy included two- to three-drug regimens with modest improvements in overall survival. Over the past two decades, with increased understanding of the biology of cancer, targeted therapies have been developed to stop the actions of molecules that are key in the growth and spread of cancer cells and have been successful in a number of cancers. In gastroesophageal cancer, these gains have been more modest with limited approval-trastuzumab being incorporated into front-line use in HER2-positive disease, and ramucirumab alone or in combination with paclitaxel becoming the preferred second-line regimen in progressive disease. However, with increased understanding of the biology of cancer, new and promising targeted therapies have emerged along with novel strategies in combining targeted therapies with traditional chemotherapy and immunotherapy. In this article, we will review the use of targeted therapies in the treatment of gastroesophageal cancer and touch upon future treatment strategies and therapeutics currently under investigation.
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Affiliation(s)
- Andrew Hsu
- Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Rhode Island Hospital, Providence, RI, USA
| | - Rani Chudasama
- Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Rhode Island Hospital, Providence, RI, USA
| | - Khaldoun Almhanna
- Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Rhode Island Hospital, Providence, RI, USA
| | - Alexander Raufi
- Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Rhode Island Hospital, Providence, RI, USA
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Garvey CM, Lau R, Sanchez A, Sun RX, Fong EJ, Doche ME, Chen O, Jusuf A, Lenz HJ, Larson B, Mumenthaler SM. Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance. Cancers (Basel) 2020; 12:cancers12061393. [PMID: 32481658 PMCID: PMC7352975 DOI: 10.3390/cancers12061393] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/13/2020] [Accepted: 05/22/2020] [Indexed: 12/12/2022] Open
Abstract
Targeted agents have improved the efficacy of chemotherapy for cancer patients, however, there remains a lack of understanding of how these therapies affect the unsuspecting bystanders of the stromal microenvironment. Cetuximab, a monoclonal antibody therapy targeting the epidermal growth factor receptor (EGFR), is given in combination with chemotherapy as the standard of care for a subset of metastatic colorectal cancer patients. The overall response to this treatment is underwhelming and, while genetic mutations that confer resistance have been identified, it is still not known why this drug is ineffective for some patients. We discovered that cancer-associated fibroblasts (CAFs), a major cellular subset of the tumor stroma, can provide a source of cancer cell resistance. Specifically, we observed that upon treatment with cetuximab, CAFs increased their secretion of EGF, which was sufficient to render neighboring cancer cells resistant to cetuximab treatment through sustained mitogen-activated protein kinases (MAPK) signaling. Furthermore, we show the cetuximab-induced EGF secretion to be specific to CAFs and not to cancer cells or normal fibroblasts. Altogether, this work emphasizes the importance of the tumor microenvironment and considering the potential unintended consequences of therapeutically targeting cancer-driving proteins on non-tumorigenic cell types.
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Affiliation(s)
- Colleen M. Garvey
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA; (C.M.G.); (R.L.); (A.S.); (R.X.S.); (E.J.F.); (M.E.D.); (O.C.); (A.J.)
| | - Roy Lau
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA; (C.M.G.); (R.L.); (A.S.); (R.X.S.); (E.J.F.); (M.E.D.); (O.C.); (A.J.)
| | - Alyssa Sanchez
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA; (C.M.G.); (R.L.); (A.S.); (R.X.S.); (E.J.F.); (M.E.D.); (O.C.); (A.J.)
| | - Ren X. Sun
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA; (C.M.G.); (R.L.); (A.S.); (R.X.S.); (E.J.F.); (M.E.D.); (O.C.); (A.J.)
| | - Emma J. Fong
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA; (C.M.G.); (R.L.); (A.S.); (R.X.S.); (E.J.F.); (M.E.D.); (O.C.); (A.J.)
| | - Michael E. Doche
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA; (C.M.G.); (R.L.); (A.S.); (R.X.S.); (E.J.F.); (M.E.D.); (O.C.); (A.J.)
| | - Oscar Chen
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA; (C.M.G.); (R.L.); (A.S.); (R.X.S.); (E.J.F.); (M.E.D.); (O.C.); (A.J.)
| | - Anthony Jusuf
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA; (C.M.G.); (R.L.); (A.S.); (R.X.S.); (E.J.F.); (M.E.D.); (O.C.); (A.J.)
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;
| | - Brent Larson
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Shannon M. Mumenthaler
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA; (C.M.G.); (R.L.); (A.S.); (R.X.S.); (E.J.F.); (M.E.D.); (O.C.); (A.J.)
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;
- Correspondence: ; Tel.: +1-323-442-2529
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Feng L, Du J, Yao C, Jiang Z, Li T, Zhang Q, Guo X, Yu M, Xia H, Shi L, Jia J, Tong Y, Ju L, Liu J, Lou J, Lemos B. Ribosomal DNA copy number is associated with P53 status and levels of heavy metals in gastrectomy specimens from gastric cancer patients. ENVIRONMENT INTERNATIONAL 2020; 138:105593. [PMID: 32120062 DOI: 10.1016/j.envint.2020.105593] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 02/15/2020] [Accepted: 02/18/2020] [Indexed: 06/10/2023]
Abstract
The ribosomal DNA (rDNA) can act as a sensor and responder of cancer-associated stress. Here we investigated rDNA copy number in gastric cancers and its association with existing biomarkers and metals exposure. This study was performed on paired tumor and adjacent normal tissues obtained from 65 gastric cancer patients who underwent gastrectomy. Immunohistochemistry was used to assess HER-2, E-cadherin, EGFR, CK (pan), CK20, CK7, TopoⅡ, CAM5.2, P53, and Ki-67 expression. Inductively coupled plasma mass spectrometry (ICP-MS) was used to detect the concentrations of 17 metals in gastric tissues. rDNA copy number was detected by qPCR in genomic DNA isolated from tissue samples. Associations between the expression of existing markers, metal concentrations, and rDNA copy number were evaluated. Within patients with gastric cancer, the copy number of the 45S rDNA components (18S, 5.8S, 28S) and the 5S rDNA in tumor tissues were significantly higher than those in adjacent normal tissues, whereas mitochondrial DNA (mtDNA) copy number was significantly lower in tumor tissues than that in adjacent normal tissues. Further analysis revealed that the increase in 18S, 5.8S, and 28S rDNA copy number in tumor tissues was diminished in the context of EGFR and P53 loss. Moreover, analysis of metals revealed particularly high concentrations of As, Cd, Cr, Cu and Fe in the gastric tissues of these patients. Intriguingly, rDNA copy number variation across individuals was correlated with the concentrations of some metals. The rDNA was amplified in tumor tissues of gastric cancer patients, and its amplification may be associated with metals exposure. The expression of EGFR and P53 may influence rDNA copy number, with diminished amplification of the rDNA in cancers that were negative for these biomarkers. Our observation further our understanding of rDNA copy number in gastric cancer and its potential as a simple and useful marker in gastric cancer monitoring.
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Affiliation(s)
- Lingfang Feng
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Jing Du
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, Hangzhou, China; People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Chunji Yao
- Institute of Hygiene, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Zhaoqiang Jiang
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Tao Li
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Quan Zhang
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, China
| | - Xinnian Guo
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Min Yu
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Hailing Xia
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Li Shi
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Junlin Jia
- Center for Biostatistics, Bioinformatics and Big Data, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yan Tong
- Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Li Ju
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Jiaqi Liu
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Jianlin Lou
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China.
| | - Bernardo Lemos
- Department of Environmental Health, Harvard University T.H. Chan School of Public Health, Boston, USA
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Pellino A, Riello E, Nappo F, Brignola S, Murgioni S, Djaballah SA, Lonardi S, Zagonel V, Rugge M, Loupakis F, Fassan M. Targeted therapies in metastatic gastric cancer: Current knowledge and future perspectives. World J Gastroenterol 2019; 25:5773-5788. [PMID: 31636471 PMCID: PMC6801189 DOI: 10.3748/wjg.v25.i38.5773] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 08/26/2019] [Accepted: 09/28/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) represents a leading cause of cancer related morbidity and mortality worldwide accounting for more than 1 million of newly diagnosed cases and thousands of deaths every year. In the last decade, the development of targeted therapies and the optimization of already available chemotherapeutic drugs has expanded the available treatment options for advanced GC and granted better survival expectations to the patients. At the same time, global efforts have been undertaken to investigate in detail the genomic and epigenomic heterogeneity of this disease, resulting in the identification of new specific and sensitive predictive and prognostic biomarkers and in innovative molecular classifications based on gene expression profiling. Nonetheless, several randomized studies aimed at exploring new innovative agents, such as immune checkpoint inhibitors, failed to demonstrate clinically meaningful survival advantages. Therefore, it is essential to further improve the molecular characterization of GC subgroups in order to provide researchers and medical oncologists with new tools for patients’ selection and stratification in future clinical development programs and subsequent trials. The aim of the present manuscript is to provide a global overview of the recent molecular classifications from The Cancer Genome Atlas and the Asian Cancer Research Group and to present key promising developments in the field of immunotherapy and targeted therapies in metastatic GC.
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Affiliation(s)
- Antonio Pellino
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua 35100, Italy
| | - Erika Riello
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
- Surgical Pathology & Cytopathology Unit, Department of Medicine, University of Padua, Padua 35100, Italy
| | - Floriana Nappo
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua 35100, Italy
| | - Stefano Brignola
- Surgical Pathology & Cytopathology Unit, Department of Medicine, University of Padua, Padua 35100, Italy
| | - Sabina Murgioni
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
| | | | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
| | - Vittorina Zagonel
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
| | - Massimo Rugge
- Surgical Pathology & Cytopathology Unit, Department of Medicine, University of Padua, Padua 35100, Italy
- Veneto Cancer Registry, Padua 35100, Italy
| | - Fotios Loupakis
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
| | - Matteo Fassan
- Surgical Pathology & Cytopathology Unit, Department of Medicine, University of Padua, Padua 35100, Italy
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Malka D, François E, Penault-Llorca F, Castan F, Bouché O, Bennouna J, Ghiringhelli F, de la Fouchardière C, Borg C, Samalin E, Bachet JB, Raoul JL, Miglianico L, Bengrine-Lefèvre L, Dahan L, Lecaille C, Aparicio T, Stanbury T, Perrier H, Cayre A, Laurent-Puig P, Gourgou S, Emile JF, Taïeb J. FOLFOX alone or combined with rilotumumab or panitumumab as first-line treatment for patients with advanced gastroesophageal adenocarcinoma (PRODIGE 17-ACCORD 20-MEGA): a randomised, open-label, three-arm phase II trial. Eur J Cancer 2019; 115:97-106. [PMID: 31129386 DOI: 10.1016/j.ejca.2019.04.020] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 04/07/2019] [Accepted: 04/12/2019] [Indexed: 01/03/2023]
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) and hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathways, which promote tumour growth and proliferation, are often deregulated in advanced gastroesophageal adenocarcinomas. We assessed whether adding panitumumab (an EGFR inhibitor) or rilotumumab (a HGF inhibitor) to first-line fluoropyrimidine-based and platinum-based chemotherapy (modified oxaliplatin, leucovorin and fluorouracil [mFOLFOX6]) benefits to patients with advanced gastroesophageal adenocarcinoma. PATIENTS AND METHODS This phase II, open-label, randomised, three-arm study enrolled patients ≥18 years, with advanced gastroesophageal adenocarcinoma, Eastern Cooperative Oncology Group performance status 0-1 and no known HER2 overexpression. Patients were randomly assigned (1:1:1) mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h) alone or combined with panitumumab (6 mg/kg) or rilotumumab (10 mg/kg) every 2 weeks until limiting toxicity, patient's refusal or disease progression. The primary end-point was the 4-month progression-free survival (PFS) rate. Secondary end-points included overall survival (OS) and tolerance. RESULTS The study enrolled 162 patients in 29 French centres. The median follow-up was 23.6 months (interquartile range = 16.4-29.0). The 4-month PFS rate was 71% (95% confidence interval [CI] = 57-82) with chemotherapy alone, 57% (95% CI = 42-71) combined with panitumumab and 61% (95% CI = 47-74) combined with rilotumumab. Median OS was 13.1 months (95% CI = 8.7-16.9) with chemotherapy alone, 8.3 months (95% CI = 6.2-13.2) combined with panitumumab and 11.5 months (95% CI = 7.9-17.1) combined with rilotumumab. Adverse events grade ≥III occurred less frequently with chemotherapy alone (62%) than with panitumumab (83%) and rilotumumab (89%). CONCLUSIONS We found no benefit in adding panitumumab or rilotumumab to mFOLFOX6 first-line chemotherapy to treat advanced gastroesophageal adenocarcinoma patients. TRIAL REGISTRATION European Clinical Trials Database, number 2009-012797-12.
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Affiliation(s)
- David Malka
- Department of Cancer Medicine, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
| | - Eric François
- Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France
| | - Frédérique Penault-Llorca
- Pathology Unit, Centre Jean Perrin, UMR 1240 INSERM IMoST, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Florence Castan
- Biometrics Unit, Institut du Cancer de Montpellier-Val d'Aurelle, Université de Montpellier, Montpellier, France
| | - Olivier Bouché
- Department of Hepatogastroenterology and Digestive Oncology, Hôpital Robert Debré, Reims, France
| | - Jaafar Bennouna
- Department of Medical Oncology, Institut de Cancérologie de l'Ouest René Gauducheau, Saint-Herblain, France
| | | | | | - Christophe Borg
- Cancer Immunotherapy, INSERM U1098 EFS/BFC, Besançon, France
| | - Emmanuelle Samalin
- Digestive Oncology Unit, Institut du Cancer de Montpellier-Val d'Aurelle, Montpellier, Université de Montpellier, France
| | - Jean-Baptiste Bachet
- Sorbonne Université, Hôpitaux Universitaires Pitié-Salpétrière, Department of Hepatogastroenterology, APHP, Paris, France
| | - Jean-Luc Raoul
- Department of Medical Oncology, Institut Paoli Calmettes, Marseille, France
| | - Laurent Miglianico
- Department of Radiotherapy, Centre Hospitalier Privé Saint Grégoire, Saint Grégoire, France
| | | | - Laetitia Dahan
- Department of Digestive Oncology, Centre Hospitalier La Timone, Marseille, France
| | - Cédric Lecaille
- Department of Hepatogastroenterology, Polyclinique Bordeaux Nord Aquitaine, Bordeaux, France
| | - Thomas Aparicio
- Department of Gastroenterology and Digestive Cancerology, Hôpital Avicenne, HUPSSD, Bobigny, Paris 13 University, Sorbonne, Paris Cité, France
| | | | - Hervé Perrier
- Department of Medical Oncology, Hôpital Saint Joseph, Marseille, France
| | - Anne Cayre
- Department of Pathology, LBM OncoGenAuvergne, Clermont Ferrand, France
| | - Pierre Laurent-Puig
- Université Paris Descartes, Centre de Ressources Biologiques EPIGENETEC, Unité INSERM U775U1147, Paris, France
| | - Sophie Gourgou
- Biometrics Unit, Institut du Cancer de Montpellier-Val d'Aurelle, Université de Montpellier, Montpellier, France
| | - Jean-François Emile
- Department of Pathology & EA4340, Hôpital Ambroise Paré & Versailles University, Boulogne Billancourt, France
| | - Julien Taïeb
- Department of Hepatogastroenterology and Gastrointestinal Oncology, Hôpital Européen Georges Pompidou, Paris, Sorbonne Paris Cité, Paris Descartes University, France
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Randomised phase II trial comparing four front-line doublets in Asian patients with metastatic gastric cancer. Eur J Cancer 2019; 112:20-28. [PMID: 30901609 DOI: 10.1016/j.ejca.2018.11.029] [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: 08/17/2018] [Revised: 11/12/2018] [Accepted: 11/25/2018] [Indexed: 11/21/2022]
Abstract
INTRODUCTION Consensus has not been reached regarding the standard regimen for front-line chemotherapy of recurrent/metastatic gastric cancer. In this randomised phase II study, we compared four doublet regimens: S-1 and cisplatin (SP); oxaliplatin and 5-FU (FOLFOX); docetaxel and 5-FU (DF) and paclitaxel and 5-FU (PF). PATIENTS AND METHODS Patients without prior history of chemotherapy for recurrent/metastatic gastric cancer were randomised evenly to each regimen. The primary end-point was progression-free survival (PFS). The secondary end-points were overall survival (OS), response rate (RR) and safety profile. RESULTS A total of 179 Korean patients were enrolled from March 2010 to May 2015. The study was prematurely terminated because of slow accrual. At data cut-off, the median PFS was 8.4 months for SP, 5.8 months for FOLFOX, 5.7 months for DF and 4.2 months for PF (P = 0.023). The median OS was 14.7 months for SP, 11.3 months for FOLFOX, 11.7 months for DF and 10.8 months for PF (P = 0.143). RR was 18%, 23%, 16% and 32% for SP, FOLFOX, DF and PF, respectively. The platinum group displayed a longer PFS trend than the taxane group (7.2 versus 4.9 months, P = 0.058), but no significant difference in OS was found. Notably, 105 patients were exposed to all three drugs (platinum, taxane and fluoropyrimidine) throughout the treatment course, and OS was identical whether starting with platinum or taxane (13.3 versus 13.3 months, P = 0.997). All regimens were well tolerated. CONCLUSION SP showed the most favourable results in PFS, whereas a significant difference in OS was not observed among the four regimens.
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Kim HJ, Oh SC. Novel Systemic Therapies for Advanced Gastric Cancer. J Gastric Cancer 2018; 18:1-19. [PMID: 29629216 PMCID: PMC5881006 DOI: 10.5230/jgc.2018.18.e3] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/14/2018] [Accepted: 02/26/2018] [Indexed: 12/27/2022] Open
Abstract
Gastric cancer (GC) is the second leading cause of cancer mortality and the fourth most commonly diagnosed malignant diseases. While continued efforts have been focused on GC treatment, the introduction of trastuzumab marked the beginning of a new era of target-specific treatments. Considering the diversity of mutations in GC, satisfactory results obtained from various target-specific therapies were expected, yet most of them were unsuccessful in controlled clinical trials. There are several possible reasons underlying the failures, including the absence of patient selection depending on validated predictive biomarkers, the inappropriate combination of drugs, and tumor heterogeneity. In contrast to targeted agents, immuno-oncologic agents are designed to regulate and boost immunity, are not target-specific, and may overcome tumor heterogeneity. With the successful establishment of predictive biomarkers, including Epstein-Barr virus pattern, microsatellite instability status, and programmed death-ligand 1 (PD-L1) expression, as well as ideal combination regimens, a new frontier in the immuno-oncology of GC treatment is on the horizon. Since the field of immuno-oncology has witnessed innovative, practice-changing successes in other cancer types, several trials on GC are ongoing. Among immuno-oncologic therapies, immune checkpoint inhibitors are the mainstay of clinical trials performed on GC. In this article, we review target-specific agents currently used in clinics or are undergoing clinical trials, and highlight the future clinical application of immuno-oncologic agents in inoperable GC.
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Affiliation(s)
- Hong Jun Kim
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Sang Cheul Oh
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
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15
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Das S, Gibson MK. Evolving Management Strategies for Metastatic Esophageal and Gastroesophageal Junction Adenocarcinoma. ACTA ACUST UNITED AC 2018; 14:82-88. [PMID: 31119034 PMCID: PMC6527138 DOI: 10.17925/ohr.2018.14.2.82] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Metastatic or unresectable esophageal and gastroesophageal junction adenocarcinoma represent a devastating disease with 5-year survival rate of <5%. Although cytotoxic chemotherapy with platinum-doublet-based regimens is initially effective, patients inevitably progress. Patients often decline rapidly after this initial progression, making later lines of therapy a challenge to successfully administer There have been multiple efforts to incorporate biologic agents, targeting pathways known to be dysregulated in esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma, into existing chemotherapy backbones. Other than therapeutics targeting human epidermal growth factor receptor-2 (HER2) and vascular endothelial growth factor receptor (VEGFR), other strategies have failed. Given the mixed success of biologic agents, along with the promise of immunotherapy to generate durable and sometimes complete responses, immune-agent based trials are a major area of interest for patients with this disease. Checkpoint inhibitors blocking programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have demonstrated modest single-agent efficacy in patients with progressive esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma. However, other approaches such as novel checkpoint combinations, vaccine-based approaches and autologous T cells hold more promise to change the trajectory of disease.
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Affiliation(s)
- Satya Das
- Department of Internal Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, US
| | - Michael K Gibson
- Department of Internal Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, US
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16
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He YM, Yu C, Li WB, Li ZP, Xu N. Evaluation of short-term effectiveness of eight targeted agents combined with chemotherapy for treating esophageal-gastric junction adenocarcinoma: A network meta-analysis. J Cell Biochem 2018; 119:1183-1192. [PMID: 28708307 DOI: 10.1002/jcb.26288] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 07/12/2017] [Indexed: 12/18/2022]
Abstract
This study aimed to evaluate the short-term effectiveness of eight targeted agents (ramucirumab, bevacizumab, rilotumumab, panitumumab, cetuximab, trebananib, trastuzumab, matuzumab) plus chemotherapy in esophageal-gastric junction adenocarcinoma (EGJA) by a network meta-analysis (NMA). PubMed, Embase, and Cochrane Library databases were systematically retrieved for randomized clinical trials (RCTs) concerning targeted agents plus chemotherapy in the treatment of EGJA. This NMA combined both direct and indirect evidence to evaluate odds ratio (OR) and to draw the surface under the cumulative ranking curve (SUCRA). In total 11 RCTs with 3649 EGJA patients (1907 patients treated with targeted agents plus chemotherapy were regarded as the case group, and 1742 patients with placebo plus chemotherapy were assigned into the control group) were enrolled in this study. Targeted agents in terms of stable disease (SD), partial response (PR), disease control rate (DCR), and overall response ratio (ORR) with the SUCRA values of 0.838, 0.807, 0.934, and 0.793, respectively. Cetuximab and trastuzumab, with the SUCRA values of 0.884 and 0.758, came on top as the best outcomes for treating EGJA in terms of progressive disease (PD) and complete response (CR). Cluster analysis results indicated that ramucirumab plus chemotherapy might be the optimal treatment for EGJA. Our findings indicated that ramucirumab plus chemotherapy might be the optimal treatment for EGJA amongst the nine treatment regimens, which provided clinical guidance for clinicians in the treatment of EGJA.
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Affiliation(s)
- Yong-Ming He
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Chen Yu
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Wei-Bing Li
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Zhi-Peng Li
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Nan Xu
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
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17
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MiR-146a functions as a small silent player in gastric cancer. Biomed Pharmacother 2017; 96:238-245. [DOI: 10.1016/j.biopha.2017.09.138] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2017] [Revised: 09/16/2017] [Accepted: 09/26/2017] [Indexed: 12/22/2022] Open
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Kim BJ, Kim JH, Jang HJ, Kim HS. The role of anti-EGFR agents in the first-line treatment of advanced esophago-gastric adenocarcinoma: a meta-analysis. Oncotarget 2017; 8:99033-99040. [PMID: 29228748 PMCID: PMC5716788 DOI: 10.18632/oncotarget.20958] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 08/28/2017] [Indexed: 12/22/2022] Open
Abstract
The role of anti-epidermal growth factor receptor (EGFR) therapy is controversial in patients with esophago-gastric adenocarcinoma. We performed this meta-analysis to evaluate whether the addition of an anti-EGFR agent to chemotherapy can produce survival benefits in patients with advanced esophageal adenocarcinoma, gastric adenocarcinoma, or gastroesophageal junction adenocarcinoma. Electronic databases were searched for eligible randomized studies. From six studies, 1,817 patients were included in the meta-analysis of hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS). Compared with chemotherapy alone, anti-EGFR agents in combination with chemotherapy were significantly associated with shorter PFS (HR = 1.14 [95% confidence interval {CI}, 1.01-1.28], P = 0.03). In terms of OS, the addition of an anti-EGFR agent to chemotherapy showed no advantage (HR = 1.10 [95% CI, 0.98-1.23], P = 0.11). In addition, the combination of an anti-EGFR agent with chemotherapy significantly increased some grade 3/4 toxicities including diarrhea (risk ratio {RR} = 1.42, [95% CI, 1.03-1.94], P = 0.03), mucositis (RR = 3.30 [95% CI, 1.54-7.07], P = 0.002), and skin rash (RR = 6.82 [95% CI, 3.15-14.78], P < 0.00001). In conclusion, this meta-analysis indicates that the addition of an anti-EGFR agent to chemotherapy conveys no additional benefit for patients with advanced esophago-gastric adenocarcinoma. As of now, anti-EGFR agents should not be used in the first-line treatment of adenocarcinoma of the upper gastrointestinal tract.
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Affiliation(s)
- Bum Jun Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea.,Department of Internal Medicine, National Army Capital Hospital, The Armed Forces Medical Command, Seongnam 13574, Republic of Korea
| | - Jung Han Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea
| | - Hyun Joo Jang
- Division of Gastroenterology, Department of Internal Medicine, Dongtan Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Hwasung 18450, Republic of Korea
| | - Hyeong Su Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea
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Wang X, Fu R, Hu Y, Du H, Li S, Li Z, Liu Y, Li Q, Zhang L, Ji J. EGFR gene status predicts response and survival benefit in a preclinical gastric cancer trial treating patient‑derived xenografts with cetuximab. Oncol Rep 2017; 38:2387-2393. [PMID: 28849161 DOI: 10.3892/or.2017.5907] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 06/21/2017] [Indexed: 11/05/2022] Open
Abstract
Cetuximab has been evaluated as a first-line treatment with conflicting results. The aim of the present study was to investigate the relationship between epidermal growth factor receptor (EGFR) status, and response and survival benefit following cetuximab treatment in gastric cancer (GC). Using 20 patient-derived GC xenograft (PDX) models, the mice (10 mice/model) were randomly assigned into two groups. The control group and treatment group were treated with PBS and cetuximab, respectively. The drug response was evaluated by monitoring tumor growth. Survival benefit was evaluated by comparing the survival curves corresponding to the time for the tumors to reach 600 mm3. Our results revealed that the PDX models treated with cetuximab had better survival than that noted for the non-treated group (P<0.05). The EGFR status was measured by FISH, qPCR, RNAish and immunohistochemistry, respectively. Four cases in the treated group were identified as responsive to cetuximab. EGFR mRNA and protein overexpression were associated with the response to cetuximab (P<0.05). EGFR amplification, mRNA and protein overexpression were associated with prolonged survival in the cetuximab-treated PDX models. Moreover, in the PDX models with EGFR amplification, mRNA or protein overexpression, cetuximab treatment was associated with a better survival compared with that noted in the untreated group in the PDX models (P<0.05), while the survival was not statistically different in the other cases (P>0.05). In conclusion, cetuximab provided survival benefit in the trial. The level of EGFR amplification and overexpression significantly predicted response and survival benefit, particularly the mRNA and protein expression level. A combination of mRNA and protein expression may predict efficacy of cetuximab more efficiently.
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Affiliation(s)
- Xiaohong Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Tissue Bank, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Runjia Fu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Ying Hu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Tissue Bank, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Hong Du
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Shuangxi Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Ziyu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Yiqiang Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Qixiang Li
- Crown Bioscience Inc., Light Muller Building, Changping Sector of Zhongguancun Science Park, Changping, Beijing 102200, P.R. China
| | - Lianhai Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Jiafu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
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Liu X, Guo W, Zhang W, Yin J, Zhang J, Zhu X, Liu T, Chen Z, Wang B, Chang J, Lv F, Hong X, Wang H, Wang J, Zhao X, Wu X, Li J. A multi-center phase II study and biomarker analysis of combined cetuximab and modified FOLFIRI as second-line treatment in patients with metastatic gastric cancer. BMC Cancer 2017; 17:188. [PMID: 28288572 PMCID: PMC5348753 DOI: 10.1186/s12885-017-3174-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 03/04/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND To evaluate the efficacy of cetuximab combined with modified FOLFIRI (mFOLFIRI) as a second-line treatment in metastatic gastric cancer patients and to identify potential biomarkers of clinical outcomes. METHODS All 61 patients received an initial intravenous (IV) dose of cetuximab (400 mg/m2) and weekly doses (250 mg/m2) thereafter, starting on day 1. On day 2 of each 14-day period, patients received IV irinotecan (180 mg/m2), leucovorin (200 mg/m2), and an IV bolus dose of 5-FU (400 mg/m2) followed by a continuous infusion of 5-FU (2400 mg/m2) for 46 h. The primary endpoint was time-to-progression (TTP). RESULTS The response rate (RR) was 33.3% among 54 evaluable patients. In the intention-to-treat analysis, median TTP was 4.6 months (95% confidential interval [CI]: 3.6-5.6 months) and median overall survival (OS) was 8.6 months (95% CI: 7.3-9.9 months). In univariate analyses, plasma vascular endothelial growth factor (VEGF) levels were correlated with clinical outcome. In patients with low (≤12.6 pg/ml) and high (>12.6 pg/ml) baseline plasma VEGF levels, RR values were 55.0% and 5.3%, respectively (P = 0.001); median TTP values were 6.9 months and 2.8 months, respectively (P = 0.0005); and median OS values were 12 months and 5 months, respectively (P <0.0001). None of these patients exhibited KRAS, BRAF, or PIK3CA mutations. CONCLUSIONS Combination therapy comprising cetuximab and mFOLFIRI was well tolerated and active as a second-line treatment for patients with metastatic gastric cancer. Patients with low baseline plasma VEGF levels were associated with better clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov. NCT00699881 . Registered 17 June 2008 (retrospectively registered).
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Affiliation(s)
- Xin Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Weijian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Wen Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jiliang Yin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jun Zhang
- Department of Oncology, Ruijin Hospital of Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Xiaodong Zhu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China
| | - Zhiyu Chen
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Biyun Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jianhua Chang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Fangfang Lv
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Xiaonan Hong
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Huijie Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jialei Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Xinmin Zhao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Xianghua Wu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jin Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China.
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21
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Mizrak Kaya D, Harada K, Shimodaira Y, Amlashi FG, Lin Q, Ajani JA. Advanced gastric adenocarcinoma: optimizing therapy options. Expert Rev Clin Pharmacol 2017; 10:263-271. [PMID: 28094573 DOI: 10.1080/17512433.2017.1279969] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
INTRODUCTION Gastric adenocarcinoma (GAC) is the fifth most common cancer and third leading cause of cancer related mortality worldwide. When localized, cure is achievable with surgery and adjunctive therapies in some patients, however, once advanced, GAC is not a curable condition. Only two targeted agents (trastuzumab and ramucirumab) have been approved and apatinib was approved only in China. Because of the heterogeneous nature of GAC, it is not possible to assess a standard therapeutic approach. Areas covered: In this review, we aimed to describe the optimal systemic therapy regimens for advanced GAC. A literature search was performed to identify all phase II-III studies about advanced GAC from PubMed, clinicaltrials.gov, American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) websites. Expert commentary: A combination of a platinum compound and a fluoropyrimidine is ideal as first line therapy. Trastuzumab should be added if the tumor is HER2 positive. In the second line setting, paclitaxel/ramucirumab is preferred over ramucirumab alone. Recently, two similar molecular classifications for GAC have been proposed. A better understanding of molecular and immune biology of GAC could identify new therapeutic targets.
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Affiliation(s)
- Dilsa Mizrak Kaya
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Kazuto Harada
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Yusuke Shimodaira
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Fatemeh G Amlashi
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Quan Lin
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Jaffer A Ajani
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
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22
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Kneissl J, Hartmann A, Pfarr N, Erlmeier F, Lorber T, Keller S, Zwingenberger G, Weichert W, Luber B. Influence of the HER receptor ligand system on sensitivity to cetuximab and trastuzumab in gastric cancer cell lines. J Cancer Res Clin Oncol 2016; 143:573-600. [PMID: 27933395 PMCID: PMC5352771 DOI: 10.1007/s00432-016-2308-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 11/17/2016] [Indexed: 12/18/2022]
Abstract
Purpose Gastric cancer remains a major health concern, and improvement of the therapeutic options is crucial. Treatment with targeted therapeutics such as the EGFR-targeting antibody cetuximab or the HER2-targeting antibody trastuzumab is either ineffective or moderately effective in this disease, respectively. In this study, we analysed the involvement of the HER receptor ligands amphiregulin (AREG), epidermal growth factor (EGF), heparin-binding epidermal growth factor (HB-EGF) and transforming growth factor alpha (TGFα) in the responsiveness of gastric cancer cell lines to cetuximab and trastuzumab. Methods A panel of 11 gastric cancer cell lines was characterized for cetuximab and trastuzumab sensitivity, ligand secretion and expression and activation of the HER receptors using WST-1 cell proliferation assays, ELISAs and Western blot analyses. We further investigated the effects of an exogenous ligand application on the cetuximab and trastuzumab sensitivity. Results We found no correlation between TGFα secretion and the sensitivity to cetuximab or trastuzumab. For AREG, we confirmed previous results indicating that this ligand is a positive predictor of cetuximab sensitivity. Exogenous HB-EGF was effective in rescuing sensitive cell lines from inhibition of cell proliferation by both, cetuximab and trastuzumab. Conclusions Our data indicate that HB-EGF may be a useful marker for the prediction of trastuzumab sensitivity in gastric cancer. Electronic supplementary material The online version of this article (doi:10.1007/s00432-016-2308-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Julia Kneissl
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Anja Hartmann
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Nicole Pfarr
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Franziska Erlmeier
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Thomas Lorber
- Institute for Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031, Basel, Switzerland
| | - Simone Keller
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Gwen Zwingenberger
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Wilko Weichert
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Birgit Luber
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany.
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23
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Riquelme I, Saavedra K, Espinoza JA, Weber H, García P, Nervi B, Garrido M, Corvalán AH, Roa JC, Bizama C. Molecular classification of gastric cancer: Towards a pathway-driven targeted therapy. Oncotarget 2016; 6:24750-79. [PMID: 26267324 PMCID: PMC4694793 DOI: 10.18632/oncotarget.4990] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 07/17/2015] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer mortality worldwide. Although surgical resection is a potentially curative approach for localized cases of GC, most cases of GC are diagnosed in an advanced, non-curable stage and the response to traditional chemotherapy is limited. Fortunately, recent advances in our understanding of the molecular mechanisms that mediate GC hold great promise for the development of more effective treatment strategies. In this review, an overview of the morphological classification, current treatment approaches, and molecular alterations that have been characterized for GC are provided. In particular, the most recent molecular classification of GC and alterations identified in relevant signaling pathways, including ErbB, VEGF, PI3K/AKT/mTOR, and HGF/MET signaling pathways, are described, as well as inhibitors of these pathways. An overview of the completed and active clinical trials related to these signaling pathways are also summarized. Finally, insights regarding emerging stem cell pathways are described, and may provide additional novel markers for the development of therapeutic agents against GC. The development of more effective agents and the identification of biomarkers that can be used for the diagnosis, prognosis, and individualized therapy for GC patients, have the potential to improve the efficacy, safety, and cost-effectiveness for GC treatments.
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Affiliation(s)
- Ismael Riquelme
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Kathleen Saavedra
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Jaime A Espinoza
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Helga Weber
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Patricia García
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Bruno Nervi
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marcelo Garrido
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alejandro H Corvalán
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
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24
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Wang S, Yuan L. Predictive biomarkers for targeted and cytotoxic agents in gastric cancer for personalized medicine. Biosci Trends 2016; 10:171-80. [PMID: 27251446 DOI: 10.5582/bst.2016.01078] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer. The treatment of GC remains challenging as the outcomes achieved with surgery alone or adjuvant or neoadjuvant chemotherapy and radiotherapy are relatively poor. New treatment strategies are emerging and are being tested in solid tumors including GC. Over the past few years, the treatment of metastatic colorectal cancer (CRC) has made great advances, but strategies to manage GC have improved little. Multiple drug resistance is common in GC chemotherapy and targeted therapy; some patients appear to receive treatment that is suboptimal or even inefficacious. Unfortunately, there are few validated predictive biomarkers to guide the tailored treatment of GC. ToGA and AVAGAST are two phase III trials that tested the efficacy and safety of targeted agents in advanced gastric cancer (AGC), and results clearly indicated that patients need to be selected and that targeted agents are the best hope for better results. This review aims to provide an overview of potential predictive biomarkers for cytotoxic and targeted agents in GC.
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Affiliation(s)
- Shalong Wang
- Geriatric Surgery Department, Second Xiangya Hospital Affiliated with Central South University
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25
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Sibertin-Blanc C, Ciccolini J, Norguet E, Lacarelle B, Dahan L, Seitz JF. Monoclonal antibodies for treating gastric cancer: promises and pitfalls. Expert Opin Biol Ther 2016; 16:759-69. [PMID: 26971395 DOI: 10.1517/14712598.2016.1164137] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Gastric cancer (GC) presents dismal prognosis when diagnosed at advanced stages, standard chemotherapy having shown little efficacy. Introduction of biotherapies interfering with novel targets and signaling pathways is currently an emerging strategy. AREAS COVERED Only two monoclonal antibodies (trastuzumab and ramucirumab) have been approved, mostly in association with cytotoxics. Conversely, testing other promising biotherapies (panitumumab, cetuximab, bevacizumab, rilotumumab) have yielded conflicting results, since encouraging early clinical trials have failed to be confirmed in larger phase-III studies. Empirical and underpowered strategies when designing combinational studies, lack of comprehensive knowledge of pharmacokinetics/pharmacodynamics (PK/PD) relationships, and underestimation of the large inter-patient variability in drug exposure levels with monoclonal antibodies, could explain the failures in developing biotherapies in gastric cancer. This review covers the achievements and limits of monoclonal antibodies in gastric cancer and proposes clues to overcome current failures. EXPERT OPINION Trastuzumab efficacy could be improved thanks to its combination with triplet chemotherapy or with another anti-HER2 agents or in continuation during second-line chemotherapy. Concerning ramucirumab, further studies are necessary to prove its interest in first line treatment of advanced GC, to use the optimal dose in each patient-given the large inter-patients variability, and to find predictive biomarkers of efficacy.
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Affiliation(s)
- Camille Sibertin-Blanc
- a Department of Digestive Oncology , Aix-Marseille University - Assistance Publique Hôpitaux de Marseille , Marseille , France
| | - Joseph Ciccolini
- b Laboratoire de Pharmacocinétique , SMARTc Inserm S_911 CRO2 Aix Marseille University , Marseille , France
| | - Emmanuelle Norguet
- a Department of Digestive Oncology , Aix-Marseille University - Assistance Publique Hôpitaux de Marseille , Marseille , France
| | - Bruno Lacarelle
- b Laboratoire de Pharmacocinétique , SMARTc Inserm S_911 CRO2 Aix Marseille University , Marseille , France
| | - Laetitia Dahan
- a Department of Digestive Oncology , Aix-Marseille University - Assistance Publique Hôpitaux de Marseille , Marseille , France
| | - Jean-François Seitz
- a Department of Digestive Oncology , Aix-Marseille University - Assistance Publique Hôpitaux de Marseille , Marseille , France
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26
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Park JS, Kim HS, Bae YS, Cheong JH, Rha SY, Noh SH, Kim H. Prognostic significance and frequency of EGFR expression and amplification in surgically resected advanced gastric cancer. Jpn J Clin Oncol 2016; 46:507-16. [PMID: 27008850 DOI: 10.1093/jjco/hyw030] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Accepted: 02/14/2016] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE The aim of this study is to find the frequency and the role of epidermal growth factor receptor expression as a prognostic biomarker in gastric cancer. METHODS We evaluated the prognostic value and frequency of epidermal growth factor receptor expression and amplification using immunohistochemistry and silver in situ hybridization in a large cohort of curatively resected gastric cancer. RESULTS Of the total of 935 cases, 294 (31.4%), 101 (10.8%) and 36 (3.9%) patients showed epidermal growth factor receptor 1+, 2+ and 3+ expression on immunohistochemistry, respectively. Epidermal growth factor receptor-positive (2+/3+) patients more frequently had intestinal type than epidermal growth factor receptor-negative (0/1+) patients (82.5 vs. 44.1%, P < 0.001). After adjusting for sex, age, stage and adjuvant chemotherapy, epidermal growth factor receptor-positive patients had a favorable overall survival outcome compared with epidermal growth factor receptor-negative patients (hazard ratio, 0.734; 95% confidence interval, 0.541-0.997; P = 0.047), especially in Stage III disease (hazard ratio, 0.676; 95% confidence interval, 0.472-0.968; P = 0.033). Among the 393 cases available for in situ hybridization, the correlation between immunohistochemistry and in situ hybridization was statistically significant (P = 0.001). Thirteen patients with gene amplification (3.3%) did not show different survival outcome with others (P = 0.359). CONCLUSION Epidermal growth factor receptor positivity was an independent favorable prognostic factor for gastric cancer, especially in Stage III disease.
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Affiliation(s)
- Ji Soo Park
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul Department of Internal Medicine, Yonsei University College of Medicine, Seoul
| | - Hyo Song Kim
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul Department of Internal Medicine, Yonsei University College of Medicine, Seoul
| | - Yoon Sung Bae
- Department of Pathology, Yonsei University College of Medicine, Seoul
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sun Young Rha
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul Department of Internal Medicine, Yonsei University College of Medicine, Seoul
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul
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27
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Xiao H, Zhang Y, Kim Y, Kim S, Kim JJ, Kim KM, Yoshizawa J, Fan LY, Cao CX, Wong DTW. Differential Proteomic Analysis of Human Saliva using Tandem Mass Tags Quantification for Gastric Cancer Detection. Sci Rep 2016; 6:22165. [PMID: 26911362 PMCID: PMC4766442 DOI: 10.1038/srep22165] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 02/04/2016] [Indexed: 02/07/2023] Open
Abstract
Novel biomarkers and non-invasive diagnostic methods are urgently needed for the screening of gastric cancer to reduce its high mortality. We employed quantitative proteomics approach to develop discriminatory biomarker signatures from human saliva for the detection of gastric cancer. Salivary proteins were analyzed and compared between gastric cancer patients and matched control subjects by using tandem mass tags (TMT) technology. More than 500 proteins were identified with quantification, and 48 of them showed significant difference expression (p < 0.05) between normal controls and gastric cancer patients, including 7 up-regulated proteins and 41 down-regulated proteins. Five proteins were selected for initial verification by ELISA and three were successfully verified, namely cystatin B (CSTB), triosephosphate isomerase (TPI1), and deleted in malignant brain tumors 1 protein (DMBT1). All three proteins could differentiate gastric cancer patients from normal control subjects, dramatically (p < 0.05). The combination of these three biomarkers could reach 85% sensitivity and 80% specificity for the detection of gastric cancer with accuracy of 0.93. This study provides the proof of concept of salivary biomarkers for the non-invasive detection of gastric cancer. It is highly encouraging to turn these biomarkers into an applicable clinical test after large scale validation.
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Affiliation(s)
- Hua Xiao
- State Key Laboratory of Microbial Metabolism, Laboratory of Bioseparation and Analytical Biochemistry, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yan Zhang
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yong Kim
- Dental Research Institute, School of Dentistry, University of California-Los Angeles, Los Angeles, California, 90095, USA
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 030031, Korea
| | - Jae Joon Kim
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 030031, Korea
| | - Kyoung Mee Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 030031, Korea
| | - Janice Yoshizawa
- Dental Research Institute, School of Dentistry, University of California-Los Angeles, Los Angeles, California, 90095, USA
| | - Liu-Yin Fan
- State Key Laboratory of Microbial Metabolism, Laboratory of Bioseparation and Analytical Biochemistry, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Cheng-Xi Cao
- State Key Laboratory of Microbial Metabolism, Laboratory of Bioseparation and Analytical Biochemistry, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - David T W Wong
- Dental Research Institute, School of Dentistry, University of California-Los Angeles, Los Angeles, California, 90095, USA
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28
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Tomasello G, Ghidini M, Liguigli W, Ratti M, Toppo L, Passalacqua R. Targeted therapies in gastric cancer treatment: where we are and where we are going. Invest New Drugs 2016; 34:378-93. [PMID: 26873643 DOI: 10.1007/s10637-016-0330-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 02/09/2016] [Indexed: 12/12/2022]
Abstract
Gastric cancer (GC) is one of the most common malignancies and a major cause of cancer-related deaths worldwide. Its incidence has significantly declined over the last few decades, probably due to the identification of specific etiologic agents such as Helicobacter pylori and other dietary and environmental risk factors. Nevertheless, most of the cases are unfortunately diagnosed at an advanced stage justifying median overall survival rates frequently not exceeding one year. Palliative combination chemotherapy usually represented by a platinum-based doublet is the mainstay of treatment in the metastatic setting. Adding a third drug such as an anthracycline or a taxane has been shown to improve response rate and provide limited survival benefits in fit selected patients. Unlike other tumors, the introduction of molecularly targeted drugs in the medical armamentarium for GC is relatively recent with trastuzumab and ultimately ramucirumab constituting the only agents approved to date. Recent advances in the understanding of GC biology have led to the development of novel targeted therapies holding the promise to further improve treatment outcomes. The aim of this paper is to review the main available data coming from clinical trials of targeted drugs and to describe some of the most interesting molecules in clinical development in GC. These include drugs targeting EGFR, angiogenesis, c-MET, FGFR2, mTOR and immune checkpoints.
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Affiliation(s)
- Gianluca Tomasello
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy.
| | - Michele Ghidini
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
| | - Wanda Liguigli
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
| | - Margherita Ratti
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
| | - Laura Toppo
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
| | - Rodolfo Passalacqua
- Oncology Division, Azienda Socio Sanitaria Territoriale di Cremona, Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy
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29
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Yazici O, Sendur MAN, Ozdemir N, Aksoy S. Targeted therapies in gastric cancer and future perspectives. World J Gastroenterol 2016; 22:471-89. [PMID: 26811601 PMCID: PMC4716053 DOI: 10.3748/wjg.v22.i2.471] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Revised: 10/05/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023] Open
Abstract
Advanced gastric cancer (AGC) is associated with a high mortality rate and, despite multiple new chemotherapy options, the survival rates of patients with AGC remains poor. After the discovery of targeted therapies, research has focused on the new treatment options for AGC. In the last two decades, many targeted molecules were developed against AGC. Currently, two targeted therapy molecules have been approved for patients with AGC. In 2010, trastuzumab was the first molecule shown to improve survival in patients with HER2-positive AGC as part of a first-line combination regimen. In 2014, ramucirumab was the second targeted molecule to improve survival rates and was suggested as treatment for patients with AGC who had progressed after first-line platinum plus fluoropyrimidine with or without anthracycline chemotherapy. Ramucirumab was the first targeted therapy acting as a single agent in patients with advanced gastroesophageal cancers. Although these two molecules were introduced into clinical use, many other promising molecules have been tested in phase I-II trials. It is obvious that in the near future many different targeted therapies will be in use for treatment of AGC. In this review, the current status of targeted therapies in the treatment of AGC and gastroesophageal junction tumors, including HER (2-3) inhibitors, epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, antiangiogenic agents, c-MET inhibitors, mammalian target of rapamycin inhibitors, agents against other molecular pathways fibroblast growth factor, Claudins, insulin-like growth factor, heat shock proteins, and immunotherapy, will be discussed.
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Affiliation(s)
- Ozan Yazici
- Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara 06100, Turkey
| | - M Ali Nahit Sendur
- Department of Medical Oncology, Yildirim Beyazit University, Ankara 06100, Turkey
| | - Nuriye Ozdemir
- Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara 06100, Turkey
| | - Sercan Aksoy
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara 06100, Turkey
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30
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Kim JW, Kim DK, Min A, Lee KH, Nam HJ, Kim JH, Kim JS, Kim TY, Im SA, Park IA. Amphiregulin confers trastuzumab resistance via AKT and ERK activation in HER2-positive breast cancer. J Cancer Res Clin Oncol 2016; 142:157-65. [PMID: 26195282 DOI: 10.1007/s00432-015-2012-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 07/01/2015] [Indexed: 11/26/2022]
Abstract
PURPOSE Human epidermal growth factor receptor 2 (HER2) heterodimerizes and shares common signaling pathways with epidermal growth factor receptor (EGFR). In this study, we investigated the clinical implication of amphiregulin, a ligand for EGFR, on trastuzumab therapy in HER2-positive breast cancer. METHODS Serum amphiregulin levels were quantified in 50 consecutive patients with HER2-positive metastatic breast cancer who received first-line trastuzumab plus taxane chemotherapy between October 2004 and July 2009. In addition, in vitro experiments were carried out to validate the results. RESULTS The median serum amphiregulin level was 1.0 ng/mL with a maximum level of 4.4 ng/mL. Patients with high serum amphiregulin levels (≥0.5 ng/mL) had significantly shorter progression-free survival (15.1 months vs. not reached; P = 0.018). Colony-forming assays demonstrated that the addition of amphiregulin resulted in increased proliferation of cells. In addition, the anti-proliferative effect of trastuzumab was decreased in the presence of amphiregulin. Western blot analysis showed that amphiregulin activated AKT and ERK pathways. In addition, in the presence of amphiregulin, sustained phosphorylation of AKT and ERK pathways was observed after trastuzumab treatment. CONCLUSIONS High serum amphiregulin levels were associated with early disease progression in these patients, possibly due to AKT and ERK signaling activation by amphiregulin.
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Affiliation(s)
- Ji-Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro-173-beon-gil, Seongnam, 463-707, Korea
| | - Debora K Kim
- Seoul International School, 15 Seongnam-daero-1518-beon-gil, Seongnam, 461-830, Korea
| | - Ahrum Min
- Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea.
| | - Kyung-Hun Lee
- Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea.
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
| | - Hyun-Jin Nam
- Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro-173-beon-gil, Seongnam, 463-707, Korea
| | - Jin-Soo Kim
- Department of Internal Medicine, SMG-SNU Boramae Medical Center, 20 Boramae-ro-5-gil, Seoul, 156-707, Korea
| | - Tae-Yong Kim
- Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea
| | - Seock-Ah Im
- Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea
| | - In Ae Park
- Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Seoul, 110-744, Korea
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Higaki E, Kuwata T, Nagatsuma AK, Nishida Y, Kinoshita T, Aizawa M, Nitta H, Nagino M, Ochiai A. Gene copy number gain of EGFR is a poor prognostic biomarker in gastric cancer: evaluation of 855 patients with bright-field dual in situ hybridization (DISH) method. Gastric Cancer 2016; 19:63-73. [PMID: 25487305 DOI: 10.1007/s10120-014-0449-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 11/17/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND EGFR overexpression is a prognostic biomarker and is expected to be a predictive biomarker for anti-EGFR therapies in gastric cancer. However, few studies have reported the clinical impact of EGFR gene copy number (GCN) and its correlation with EGFR overexpression. METHODS We used dual in situ hybridization (DISH) to detect EGFR GCN and chromosome 7 centromere (CEN7) in a set of tissue microarrays representing 855 patients with gastric cancer. These data were compared with those of immunohistochemical (IHC) analysis of EGFR expression to evaluate prognostic value. RESULTS EGFR GCN gain (≥ 2.5 EGFR signals per cell) was detected in 194 patients (22.7%) and indicated poor prognosis. Among 194 patients, EGFR amplification (EGFR/CEN7 ≥ 2.0) was observed in 29 patients (14.9%), which was almost identical to the IHC 3+ subgroup and worst prognostic subgroup. Patients with EGFR GCN gain but not amplification, including those exhibiting polysomy, also exhibited poorer prognosis than GCN non-gain patients and were distributed between IHC 0/1+ and 2+ subgroups. GCN gain was frequently observed in patients with more advanced disease, but served as an independent prognostic factor regardless of the pathological stage. CONCLUSIONS EGFR GCN gain is a more accurate prognostic biomarker than EGFR overexpression in patients with gastric cancer.
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Affiliation(s)
- Eiji Higaki
- Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Department of Gastric Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takeshi Kuwata
- Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Department of Pathology and Clinical Laboratory, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Akiko Kawano Nagatsuma
- Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yasunori Nishida
- Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Department of Gastric Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Takahiro Kinoshita
- Department of Gastric Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Masaki Aizawa
- Department of Digestive Surgery, Niigata Cancer Center Hospital, 2-15-3 Kawagishi-cho, Chuo-ku, Niigata, 951-8566, Japan
| | - Hiroaki Nitta
- Technology and Applied Research, Ventana Medical Systems, Inc., 1910 E Innovation Park Drive, Tucson, AZ, 85755, USA
| | - Masato Nagino
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Atsushi Ochiai
- Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
- Department of Pathology and Clinical Laboratory, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
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Woo J, Cohen SA, Grim JE. Targeted therapy in gastroesophageal cancers: past, present and future. Gastroenterol Rep (Oxf) 2015; 3:316-29. [PMID: 26510453 PMCID: PMC4650980 DOI: 10.1093/gastro/gov052] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 09/09/2015] [Indexed: 12/12/2022] Open
Abstract
Gastroesophageal cancer is a significant global problem that frequently presents at an incurable stage and has very poor survival with standard chemotherapy approaches. This review will examine the epidemiology and molecular biology of gastroesophageal cancer and will focus on the key deregulated signaling pathways that have been targeted in the clinic. A comprehensive overview of clinical data highlighting successes and failures with targeted agents will be presented. Most notably, HER2-targeted therapy with the monoclonal antibody trastuzumab has proven beneficial in first-line therapy and has been incorporated into standard practice. Targeting the VEGF pathway has also proven beneficial, and the VEGFR-targeted monoclonal antibody ramucirumab is now approved for second-line therapy. In contrast to these positive results, agents targeting the EGFR and MET pathways have been evaluated extensively in gastroesophageal cancer but have repeatedly failed to show benefit. An increased understanding of the molecular predictors of response to targeted therapies is sorely needed. In the future, improved molecular pathology approaches should subdivide this heterogeneous disease entity to allow individualization of cancer therapy based on integrated and global identification of deregulated signaling pathways. Better patient selection, rational combinations of targeted therapies and incorporation of emerging immunotherapeutic approaches should further improve the treatment of this deadly disease.
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Affiliation(s)
- Janghee Woo
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Division of Medical Oncology, University of Washington, Seattle, WA, USA and
| | - Stacey A Cohen
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Division of Medical Oncology, University of Washington, Seattle, WA, USA and
| | - Jonathan E Grim
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Division of Medical Oncology, University of Washington, Seattle, WA, USA and Hospital and Specialty Medicine, VA Puget Sound Health Care System, Seattle, WA, USA
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Sudo K, Yamada Y. Advancing pharmacological treatment options for advanced gastric cancer. Expert Opin Pharmacother 2015; 16:2293-305. [PMID: 26359224 DOI: 10.1517/14656566.2015.1080238] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
INTRODUCTION Gastric cancer is the third most common cause of cancer-related deaths worldwide. Improvement of conventional chemotherapy has been modest in the past decades. AREAS COVERED We review recent important studies of metastatic or recurrent gastric cancer. For human epidermal growth factor receptors 2 (HER2) negative cancer, standard treatments are combinations of fluoropyrimidine and platinum with or without epirubicin or docetaxel in first-line therapy. Controversy exists regarding the use of triplet chemotherapies due to their toxicity. For HER2 positive cancer, standard treatments are combinations of fluoropyrimidine and cisplatin with trastuzumab. As second- or third-line treatment, taxanes or irinotecan prolonged survival compared with best supportive care alone, but the extension of overall survival was only 1 - 2 months. A recent study demonstrated that ramucirumab plus paclitaxel improved survival as a second-line therapy. EXPERT OPINION Most trials have failed to demonstrate a benefit of targeted agents. It is important to identify predictive biomarkers to enrich an appropriate patient population for targeted agents such as HER2 status for trastuzumab.
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Affiliation(s)
- Kazuki Sudo
- a 1 National Cancer Center Hospital , 5-1-1 Tsukiji, Chuo-ku, 104-0045 Tokyo, Japan +81 3 3542 2511 ; +81 3 3542 3815 ; .,b 2 Juntendo University Graduate School of Medicine, Advanced Clinical Research of Cancer , Tokyo, Japan
| | - Yasuhide Yamada
- a 1 National Cancer Center Hospital , 5-1-1 Tsukiji, Chuo-ku, 104-0045 Tokyo, Japan +81 3 3542 2511 ; +81 3 3542 3815 ;
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Wainberg ZA, Soares HP, Patel R, DiCarlo B, Park DJ, Liem A, Wang HJ, Yonemoto L, Martinez D, Laux I, Brennan M, Hecht JR. Phase II trial of everolimus in patients with refractory metastatic adenocarcinoma of the esophagus, gastroesophageal junction and stomach: possible role for predictive biomarkers. Cancer Chemother Pharmacol 2015; 76:61-7. [PMID: 25969130 DOI: 10.1007/s00280-015-2744-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 03/31/2015] [Indexed: 12/19/2022]
Abstract
PURPOSE Our study was designed to evaluate the efficacy and safety of everolimus in patients with pre-treated metastatic gastric and esophagus cancers in a US-based population focusing on biomarker correlation. METHODS Patients with advanced upper GI adenocarcinomas who progressed after 1-2 prior regimens received everolimus 10 mg PO daily. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression-free survival (PFS), toxicity, overall survival (OS) and biomarker correlatives of the mTOR pathway. Target accrual was 50 patients based on one-sided type I error of 10 % and power of 90 %. RESULTS Forty-five patients were evaluable, 21 gastric, 11 esophagus and 13 from the GEJ. The median age was 64 (range 38-73); all patients had an ECOG of 0 or 1; and 18 patients (40 %) had only 1 prior regimen. The most common grade 3-4 adverse events included fatigue (24 %) and thrombocytopenia (22 %). We observed 1 partial response with 39 % of evaluable patients having stable disease. Median OS was 3.4 months (95 % CI 2.7-5.6 months), and PFS was 1.8 months (95 % CI 1.7-2.2 months). There was a strong correlation between ≥2 + IHC staining for p-S6 in tumor samples with better PFS (p < 0.0001) and DCR (p = 0.0001). CONCLUSIONS Our clinical outcomes were inferior to the Asian studies, which may be explained by disease heterogeneity. However, there was a similar strong correlation between clinical benefit and tumor high pS6. Testing this biomarker in patient samples from the randomized phase III Granite trial may lead to a positive predictive marker.
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Affiliation(s)
- Zev A Wainberg
- Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA,
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Kearns JD, Bukhalid R, Sevecka M, Tan G, Gerami-Moayed N, Werner SL, Kohli N, Burenkova O, Sloss CM, King AM, Fitzgerald JB, Nielsen UB, Wolf BB. Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic. Mol Cancer Ther 2015; 14:1625-36. [PMID: 25911688 DOI: 10.1158/1535-7163.mct-14-0772] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 04/17/2015] [Indexed: 12/16/2022]
Abstract
Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by high-affinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor-antagonist interactions. Model simulations suggested that an oligoclonal antibody combination may overcome signal amplification within the EGFR:ERK pathway driven by all EGFR ligands. Based on this, we designed MM-151, a combination of three fully human IgG1 monoclonal antibodies that can simultaneously engage distinct, nonoverlapping epitopes on EGFR with subnanomolar affinities. In signaling studies, MM-151 antagonized high-affinity EGFR ligands more effectively than cetuximab, leading to an approximately 65-fold greater decrease in signal amplification to ERK. In cell viability studies, MM-151 demonstrated antiproliferative activity against high-affinity EGFR ligands, either singly or in combination, while cetuximab activity was largely abrogated under these conditions. We confirmed this finding both in vitro and in vivo in a cell line model of autocrine high-affinity ligand expression. Together, these preclinical studies provide rationale for the clinical study of MM-151 and suggest that high-affinity EGFR ligand expression may be a predictive response marker that distinguishes MM-151 from other anti-EGFR therapeutics.
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Affiliation(s)
| | | | - Mark Sevecka
- Merrimack Pharmaceuticals, Cambridge, Massachusetts
| | - Gege Tan
- Merrimack Pharmaceuticals, Cambridge, Massachusetts
| | | | | | - Neeraj Kohli
- Merrimack Pharmaceuticals, Cambridge, Massachusetts
| | | | | | - Anne M King
- Merrimack Pharmaceuticals, Cambridge, Massachusetts
| | | | | | - Beni B Wolf
- Merrimack Pharmaceuticals, Cambridge, Massachusetts
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Aoyagi K, Kouhuji K, Kizaki J, Isobe T, Hashimoto K, Shirouzu K. Molecular targeting to treat gastric cancer. World J Gastroenterol 2014; 20:13741-55. [PMID: 25320512 PMCID: PMC4194558 DOI: 10.3748/wjg.v20.i38.13741] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 01/13/2014] [Accepted: 05/23/2014] [Indexed: 02/06/2023] Open
Abstract
Trastuzumab that targets human epidermal growth factor receptor 2 (HER2) protein is the only approved molecular targeting agent for treating gastric cancer in Japan and the outcomes have been favorable. However, trastuzumab is effective for only 10% to 20% of the population with gastric cancer that expresses HER2 protein. Molecular targeting therapy with bevacizumab against vascular endothelial growth factors (VEGF) and with cetuximab and panitumumab against the epidermal growth factors pathway that have been approved for treating colorectal cancer are not considered effective for treating gastric cancer according to several clinical trials. However, ramucirumab that targets VEGF receptor-2 prolonged overall survival in a large phase III clinical trial and it might be an effective molecular targeting therapy for gastric cancer. The significance of molecular targeting therapy for gastric cancer remains controversial. A large-scale randomized clinical trial of novel molecular targeting agents with which to treat gastric cancer is needed.
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37
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Zhang X, Xu J, Liu H, Yang L, Liang J, Xu N, Bai Y, Wang J, Shen L. Predictive biomarkers for the efficacy of cetuximab combined with cisplatin and capecitabine in advanced gastric or esophagogastric junction adenocarcinoma: a prospective multicenter phase 2 trial. Med Oncol 2014; 31:226. [PMID: 25234930 DOI: 10.1007/s12032-014-0226-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 09/02/2014] [Indexed: 12/17/2022]
Abstract
Cetuximab presents a potential therapy for gastric or esophagogastric junction adenocarcinoma. We aim to evaluate the predictive value of potential biomarkers of cetuximab efficacy. In this prospective phase 2 trial (NCT00477711), we enrolled untreated 47 patients with un-resectable or metastatic gastric or esophagogastric junction adenocarcinoma from seven sites in China. Patients with histologically confirmed adenocarcinoma were given cisplatin (80 mg/m2, triweekly), capecitabine (2,000 mg/m2, triweekly for 2 weeks), and cetuximab weekly (400 mg/m2 at first infusion and 250 mg/m2 subsequently). Sample size was calculated using Simon's two-stage design. The primary endpoint was the objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), toxicity, and predictive biomarkers. The ORR was 53.2%, median PFS 5.2 months, and OS 10.8 months. The most frequent toxicities included neutropenia (25.0%), nausea/vomiting (11.5%), and rash/desquamation (9.6%). Patients with grade 2-4 rash achieved a significantly better ORR, longer PFS, and OS than those with grade 0-1 rash. Seven patients (15.9%) with epidermal growth factor receptor (EGFR) strong expression (3+) showed great tumor shrinkage, longer PFS (7.1 months), and OS (16.6 months). EGFR gene amplification was detected in four patients (8.5%), all of whom responded well. Compared to patients with lower levels of transforming growth factor-alpha (TGF-α), those with high levels showed better response and longer PFS (6.0 vs 2.7 months, p=0.001) and OS (12.9 vs 7.0 months, p=0.001). C+XP was well tolerated and effective for advanced gastric or esophagogastric junction adenocarcinoma as first-line therapy. Severity of skin rash and TGF-α level correlated with efficacy, and EGFR overexpression might predict cetuximab efficacy.
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Affiliation(s)
- Xiaotian Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, 100142, China,
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Al-Batran SE, Werner D. Recent advances and future trends in the targeted therapy of metastatic gastric cancer. Expert Rev Gastroenterol Hepatol 2014; 8:555-69. [PMID: 24665840 DOI: 10.1586/17474124.2014.902304] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The better understanding of the molecular mechanisms behind gastric cancer has led to the development of new therapeutic strategies that are likely to improve patient outcomes in the near future. Recently, targeting the HER2 and the VEGF pathways with trastuzumab and ramucirumab, respectively, have been found to improve survival, while directed therapies against a number of other pathways are under clinical evaluation. These include the hepatocyte growth factor and its receptor c-MET, the insulin-like growth factor 1, the fibroblast growth factor, the mammalian target of rapamycin (mTOR), the epidermal growth factor receptor, and other pathways, as well as relevant immunotherapeutic strategies. This article reviews recent advances and future trends of these concepts for gastric cancer and adenocarcinoma of the gastroesophageal junction.
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Affiliation(s)
- Salah-Eddin Al-Batran
- Krankenhaus Nordwest, UCT-University Cancer Center Frankfurt, Frankfurt am Main, Germany
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Garrido M, Fonseca PJ, Vieitez JM, Frunza M, Lacave AJ. Challenges in first line chemotherapy and targeted therapy in advanced gastric cancer. Expert Rev Anticancer Ther 2014; 14:887-900. [PMID: 24953238 DOI: 10.1586/14737140.2014.915194] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Chemotherapy prolongs survival in advanced gastric cancer (AGC). The challenges involved in this procedure are providing a framework to aid in determining the best single or combined chemotherapy protocols for targeted agents in front-line therapy for patients in a clinical setting. A review of Phase II-III studies published or referenced in major oncology congress publications from 1970 to 2013 was performed. Cisplatin and fluoropyrimidine remain the reference regimen. Fluoropyrimidine combined with oxaliplatin or irinotecan may also be employed in special situations. There are no comparative studies of the same regimens with or without anthacyclines; thus, the effectiveness of anthacyclines remains under debate. The introduction of trastuzumab in the front-line therapy of HER2-positive patients and ramucirumab in refractory patients ushered in an age of targeted therapy for this disease.
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Affiliation(s)
- Marcelo Garrido
- Hemato-Oncology Department, Pontifical Catholic University of Chile, Diagonal paraguay 319, Santiago de chile, Chile
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Moorcraft SY, Chau I. Investigational therapies targeting the ErbB family in oesophagogastric cancer. Expert Opin Investig Drugs 2014; 23:1349-63. [PMID: 24949530 DOI: 10.1517/13543784.2014.930126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The prognosis for patients with oesophagogastric (OG) cancer remains poor, with a median survival of approximately 9 - 11 months for patients with metastatic disease. However, a more personalised approach to treatment, using drugs tailored to the molecular characteristics of patients' tumours, has the potential to improve patient outcomes. Drugs targeting the ErbB family of receptors have been developed, but these have had varying degrees of success in clinical practice. AREAS COVERED The authors provide an overview of the ErbB receptor family with regard to OG cancers. Furthermore, they evaluate the evidence from preclinical and clinical trials of therapeutics targeting this family, including monoclonal antibodies, tyrosine kinase inhibitors and novel agents. EXPERT OPINION Drugs targeting the ErbB family have been evaluated in OG cancer, with a notable success story in the case of trastuzumab, although there have been disappointing failures with anti-EGFR therapy. The response to targeted treatment remains variable and further biomarker research is essential to identify patients most likely to benefit from these therapies. The treatment of OG cancer remains challenging, but new anti-HER2 therapies and combination therapies hold promise for the future.
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Affiliation(s)
- Sing Yu Moorcraft
- The Royal Marsden NHS Foundation Trust, Gastrointestinal Unit, Department of Medicine , Sutton SM2 5PT , UK +44 020 8642 6011 ; +44 020 8643 9414 ;
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Aprile G, Giampieri R, Bonotto M, Bittoni A, Ongaro E, Cardellino GG, Graziano F, Giuliani F, Fasola G, Cascinu S, Scartozzi M. The challenge of targeted therapies for gastric cancer patients: the beginning of a long journey. Expert Opin Investig Drugs 2014; 23:925-42. [PMID: 24806575 DOI: 10.1517/13543784.2014.912631] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced disease remains dismal. Collaborative, high-quality research and advances in high-throughput technologies have contributed to elucidate molecular pathways underpinning disease progression and have stimulated many clinical studies testing target therapies in the advanced disease setting. Although progress has been made thanks to trastuzumab in HER2 positive tumours, antiangiogenic drugs have produced conflicting results and EGFR-inhibitors have failed to show major improvements. AREAS COVERED While commenting on the results of many key Phase III randomized trials, the Authors discuss the most promising classes of novel targeted agents and present the current challenges toward a customized treatment. EXPERT OPINION Palliative chemotherapy became the worldwide standard of care for patients with advanced gastric cancers, producing significant life prolongation and improvement of life quality. Nevertheless, long-term outcomes of those patients remain poor. Because of the encouraging advancement in novel targeted therapies, such a disappointing scenario is now evolving. While results serve as a springboard for future research, more comprehensive efforts are needed to clarify the biological mechanisms underpinning cancer progression and help clinicians to develop new effective treatments.
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Affiliation(s)
- Giuseppe Aprile
- University and General Hospital, Department of Medical Oncology , Piazzale S Maria della Misericordia 1, 33100, Udine , Italy +39 432 559308 ; +39 432 559305 ;
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Morishita A, Gong J, Masaki T. Targeting receptor tyrosine kinases in gastric cancer. World J Gastroenterol 2014; 20:4536-4545. [PMID: 24782606 PMCID: PMC4000490 DOI: 10.3748/wjg.v20.i16.4536] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 12/19/2013] [Accepted: 03/19/2014] [Indexed: 02/07/2023] Open
Abstract
Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials. One group of representative targeted oncogenic kinases, the receptor tyrosine kinases (RTKs), has been associated with gastric cancer development. Trastuzumab, an inhibitor of ERBB2, has been approved for the treatment of gastric cancer, although other receptor tyrosine kinases, such as epidermal growth factor receptor, vascular endothelial growth factor, platelet-derived growth factor receptor, c-Met, IGF-1R and fibroblast growth factor receptor 2, are also activated in gastric cancer. The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients. On the other hand, the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients; however, a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial. Other clinical trials, especially phase III trials that have tested drugs targeting RTKs, such as cetuximab, panitumumab, gefitinib, erlotinib, figitumumab, sorafenib, sunitinib and lapatinib, have shown that these drugs have modest effects against gastric cancer. This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies.
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Adua D, Di Fabio F, Rojas Llimpe FL, Pini S, Pinto C. Long-term survival in an advanced gastric cancer patient treated with cetuximab in association with FOLFIRI: a case report. J Gastrointest Oncol 2014; 5:E13-7. [PMID: 24490046 PMCID: PMC3904018 DOI: 10.3978/j.issn.2078-6891.2013.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Accepted: 07/30/2013] [Indexed: 01/20/2023] Open
Abstract
In December 2004, a 52-year-old woman with metastatic gastric cancer was enrolled in the phase II clinical trial FOLCETUX, receiving cetuximab at an initial dose of 400 mg/m(2) i.v. followed by weekly doses of 250 mg/m(2), irinotecan 180 mg/m(2) i.v. on day 1, LFA 100 mg/m(2) i.v. followed by 5-FU 400 mg/m(2) i.v. bolus and 600 mg/m(2) i.v. 22-h continuous infusion on days 1 and 2 every two weeks, to a total of 17 cycles. CT and PET-CT performed after six weeks treatment failed to show any residual disease, with complete radiological response in accord to RECIST criteria and complete metabolic response. A total of 24 maintenance administrations with cetuximab alone (250 mg/m(2) weekly) were performed, as foreseen by the protocol in responders. In November 2012 a clinical, radiological (CT) and metabolic (PET-CT) patient examination proved negative for recurrent disease, signifying 95 months' progression free survival.
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Affiliation(s)
- Daniela Adua
- Medical Oncology, S. Orsola-Malpighi Hospital, Bologna, Italy
| | | | | | - Sara Pini
- Medical Oncology, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Carmine Pinto
- Medical Oncology, S. Orsola-Malpighi Hospital, Bologna, Italy
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Durães C, Almeida GM, Seruca R, Oliveira C, Carneiro F. Biomarkers for gastric cancer: prognostic, predictive or targets of therapy? Virchows Arch 2014; 464:367-78. [DOI: 10.1007/s00428-013-1533-y] [Citation(s) in RCA: 124] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 11/12/2013] [Accepted: 12/23/2013] [Indexed: 12/12/2022]
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45
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Kasper S, Schuler M. Targeted therapies in gastroesophageal cancer. Eur J Cancer 2014; 50:1247-58. [PMID: 24495747 DOI: 10.1016/j.ejca.2014.01.009] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 01/07/2014] [Accepted: 01/08/2014] [Indexed: 02/07/2023]
Abstract
Gastroesophageal cancers comprising gastric cancer (GC), and cancers of the distal oesophagus and gastroesophageal junction (GEJ) are a global health threat. In Western populations the incidence of GC is declining which has been attributed to effective strategies of eradicating Helicobacter pylori infection. To the contrary, GEJ cancers are on the rise, with obesity and reflux disease being viewed as major risk factors. During the past decade perioperative chemotherapy, pre- or postoperative radio-chemotherapy, and, in Asian populations, adjuvant chemotherapy have been shown to improve the outcome of patients with advanced GC and GEJ cancers suited for surgery. Less progress has been made in the treatment of metastatic disease. The introduction of trastuzumab in combination with platinum/fluoropyrimidine-based chemotherapy for patients with HER2-positive disease has marked a turning point. Recently, several novel agents targeting growth factor receptors, angiogenic pathways, adhesion molecules and mediators of intracellular signal transduction have been clinically explored. Here we summarise the current status and future developments of molecularly targeted therapies in GC and GEJ cancer.
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Affiliation(s)
- Stefan Kasper
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Martin Schuler
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
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46
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Mohamed A, El-Rayes B, Khuri FR, Saba NF. Targeted therapies in metastatic esophageal cancer: advances over the past decade. Crit Rev Oncol Hematol 2014; 91:186-96. [PMID: 24582516 DOI: 10.1016/j.critrevonc.2014.01.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 01/14/2014] [Accepted: 01/17/2014] [Indexed: 12/29/2022] Open
Abstract
Esophageal cancer is one of the most aggressive malignancies of the upper aerodigestive tract. Despite advances in surgical techniques and multi-modality therapies, the 5-year survival rate remains poor (14%). Over the past decade, efforts have been focused on the field of drug development with the advancement of novel molecularly targeted therapeutic agents. These agents target a variety of cancer relevant pathways such as vascular endothelial growth factor (VEGF) or its receptor, the cyclooxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), and mammalian target of rapamycin (mTOR) pathways. The number of approved targeted agents remains few, with HER-2 inhibitors leading the list for treatment of HER-2 expressing metastatic adenocarcinomas. Novel agents have not yet been widely explored in esophageal cancer. In this review, we will provide a concise and systematic overview of the development of novel targeted therapies currently under investigation for the treatment of metastatic esophageal disease.
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Affiliation(s)
- Amr Mohamed
- Department of Medicine, Morehouse School of Medicine, Atlanta, GA, USA
| | - Bassel El-Rayes
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA
| | - Fadlo R Khuri
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA
| | - Nabil F Saba
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
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Zhang L, Zhao G, Hou Y, Zhang J, Hu J, Zhang K. The experimental study on the treatment of cytokine-induced killer cells combined with EGFR monoclonal antibody against gastric cancer. Cancer Biother Radiopharm 2014; 29:99-107. [PMID: 24443838 DOI: 10.1089/cbr.2012.1381] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIMS To investigate the antitumor activity of cytokine-induced killer (CIK) cells combined with epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) against gastric cancer cell line SGC7901. MATERIALS AND METHODS Immunocytochemistry assay was performed to detect the expression of EGFR in SGC7901 cell lines. The cytotoxicity activity of CIK cells combined with EGFR mAb was analyzed by the (51)Cr release assay. Then, the comparison of the cytotoxicity activity between CIK cells combined with EGFR mAb and CIK cells combined with CD3 mAb and CIK cells was conducted. Antitumor activity of CIK cells combined with EGFR mAb in vivo was analyzed by tumor growth assay and tumor reduction assay. RESULTS The cell lysis rate of CIK cells combined with EGFR mAb was higher than those of CIK cells combined with CD3 mAb and CIK cells only (p<0.05). The lysis rates of the latter two groups were not different. The antitumor activity of CIK cells combined with EGFR mAb was higher than those of other groups in vivo (p<0.05). CONCLUSION It was suggested in the current study that EGFR mAb could enhance the antitumor ability of CIK cells to bind and kill the gastric cancer cells in vitro and in vivo.
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Affiliation(s)
- Lin Zhang
- 1 Department of Gastroenterology, The 309 Hospital of PLA , Beijing, P.R. China
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48
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Qiu MZ, Xu RH. The progress of targeted therapy in advanced gastric cancer. Biomark Res 2013; 1:32. [PMID: 24330856 PMCID: PMC3878836 DOI: 10.1186/2050-7771-1-32] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 12/02/2013] [Indexed: 12/13/2022] Open
Abstract
Although palliative chemotherapy has been shown to prolong survival and improve quality of life, the survival of advanced gastric cancer (AGC) patients remains poor. With the advent of targeted therapy, many molecular targeted agents have been evaluated in clinical studies. Trastuzumab, an anti-HER2 monoclonal antibody, has shown activity against HER2-positive AGC and becomes the first targeted agent approved in AGC. Drugs that target epidermal growth factor receptor, including monoclonal antibody and tyrosine kinase inhibitor, do not bring survival benefit to patients with AGC. Additionally, vascular endothelial growth factor inhibitors are also under investigation. Ramucirumab has shown promising result. Other targeted agents are in preclinical or early clinical development, such as mammalian target of rapamycinm inhibitors and c-MET inhibitors.
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Affiliation(s)
- Miao-zhen Qiu
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou 510060, China
| | - Rui-hua Xu
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou 510060, China
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Zhang L, Yang J, Cai J, Song X, Deng J, Huang X, Chen D, Yang M, Wery JP, Li S, Wu A, Li Z, Li Z, Liu Y, Chen Y, Li Q, Ji J. A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy. Sci Rep 2013; 3:2992. [PMID: 24141978 PMCID: PMC3801116 DOI: 10.1038/srep02992] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 09/27/2013] [Indexed: 12/18/2022] Open
Abstract
A preclinical trial identified 4 of 20 (20%) gastric cancer (GC) patient-derived xenografts responded to cetuximab. Genome-wide profiling and additional investigations revealed that high EGFR mRNA expression and immunohistochemistry score (3+) are associated with tumor growth inhibition. Furthermore, EGFR amplification were observed in 2/4 (50%) responders with average copy number 5.8 and >15 respectively. Our data suggest that a GC subtype with EGFR amplification and overexpression benefit from cetuximab treatment.
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Affiliation(s)
- Lianhai Zhang
- 1] Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery [2]
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Serum epidermal growth factor is associated with prognosis and hormone receptor status in patients with HER2-positive metastatic breast cancer treated with first-line trastuzumab plus taxane chemotherapy. Cancer Chemother Pharmacol 2013; 72:1023-9. [DOI: 10.1007/s00280-013-2268-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 08/09/2013] [Indexed: 11/26/2022]
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