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Bach Y, Sharma D, Aoyama H, Ma LX, Barron CC, Wang X, Akhtar S, Yang Y, St Bernard A, McLaughlin R, Megid TBC, Farooq AR, Chen EX, Jang RWJ, Elimova E. Ramucirumab and paclitaxel in second or greater lines of therapy in patients with HER2-positive gastroesophageal cancer: a single center study. Oncologist 2025; 30:oyaf037. [PMID: 40152313 PMCID: PMC11950916 DOI: 10.1093/oncolo/oyaf037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 02/04/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) overexpression is present in approximately 20-25 of patients with advanced gastroesophageal adenocarcinoma (GEA). Upon progression on 1st line therapy, ramucirumab and paclitaxel (rampac) is given in ≥2 line setting regardless of HER2 status. We aim to assess whether ramucirumab is associated with better survival in HER2 positive(+) pts compared to those with HER2(-) disease. METHODS We reviewed all consecutive adult patients with metastatic/unresectable GEA who were treated with rampac for ≥2nd line therapy at Princess Margaret Cancer Centre from 2010 to 2021. Progression free survival (PFS) and overall survival (OS) were defined as time from starting rampac to progression or death and estimated using the Kaplan-Meier method. RESULTS There were 126 patients who received rampac following progression of 1st line chemotherapy, 96(76%) were male. The age at time of presentation and starting rampac was 59.0 ± 10.3 years and 59.9 ± 10.3 years, respectively. At the time of diagnosis, 32(25%) patients were HER2+. The majority of patients (n = 99;78%) received rampac in the 2L line setting compared to 28(22%) patients who received it in the 3rd/4th line setting. The median PFS and OS for HER2 + pts were 3.6 months and 9.4 months, respectively, which were similar to HER2- patients (median PFS = 3.6 months; median OS = 8.2 months). There was no statistically significant association between HER2 positivity and PFS (adjusted hazards ratio (HR) = 0.76, 95% confidence interval (CI) 0.48-1.22, P = .26), nor OS (adjusted HR = 0.88, 95% CI, 0.55-1.41, P = .59). CONCLUSION Rampac remains a valid treatment option for patients who are unable to participate in trials or do not have access to further HER2-directed therapy beyond first line.
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Affiliation(s)
- Yvonne Bach
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Divya Sharma
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Hiroko Aoyama
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Lucy X Ma
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Carly C Barron
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Xin Wang
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Sokaina Akhtar
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Yahan Yang
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Alana St Bernard
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Ronan McLaughlin
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Thais B C Megid
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Abdul R Farooq
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Eric X Chen
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Raymond W J Jang
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
| | - Elena Elimova
- Princess Margaret Cancer Centre, 700 University Avenue, Toronto, ON, Canada M5G 1X6
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Lu H, Zhang B, Xie Y, Zhao W, Han W, Zhou L, Wang Z. Sitravatinib is a potential EGFR inhibitor and induce a new death phenotype in Glioblastoma. Invest New Drugs 2023; 41:564-578. [PMID: 37322389 DOI: 10.1007/s10637-023-01373-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 05/11/2023] [Indexed: 06/17/2023]
Abstract
Glioblastoma (GBM) is a highly lethal neurological tumor that presents significant challenge for clinicians due to its heterogeneity and high mortality rate. Despite extensive research, there is currently no effective drug treatment available for GBM. Research evidence has consistently demonstrated that the epidermal growth factor receptor (EGFR) promotes tumor progression and is associated with poor prognosis in several types of cancer. In glioma, EGFR abnormal amplification is reported in approximately 40% of GBM patients, with overexpression observed in 60% of cases, and deletion or mutation in 24% to 67% of patients. In our study, Sitravatinib, a potential EGFR inhibitor, was identified through molecular docking screening based on protein structure. The targeting of EGFR and the tumor inhibitory effect of Sitravatinib on glioma were verified through cellular and in vivo experiments, respectively. Our study also revealed that Sitravatinib effectively inhibited GBM invasive and induced DNA damage and cellular senescence. Furthermore, we observed a novel cell death phenotype induced by Sitravatinib, which differed from previously reported programmed death patterns such as apoptosis, pyroptosis, ferroptosis, and necrosis.
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Affiliation(s)
- Hanwen Lu
- The Department of Neuroscience, Institute of Neurosurgery, School of Medicine, Xiamen University, Xiamen City, China
- Department of Neurosurgery, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, Xiamen City, China
| | - Bingchang Zhang
- The Department of Neuroscience, Institute of Neurosurgery, School of Medicine, Xiamen University, Xiamen City, China
- Department of Neurosurgery, The First Affiliated Hospital of Xiamen University, Xiamen City, China
| | - Yuanyuan Xie
- The Department of Neuroscience, Institute of Neurosurgery, School of Medicine, Xiamen University, Xiamen City, China
- Department of Neurosurgery, The First Affiliated Hospital of Xiamen University, Xiamen City, China
| | - Wenpeng Zhao
- The Department of Neuroscience, Institute of Neurosurgery, School of Medicine, Xiamen University, Xiamen City, China
- Department of Neurosurgery, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, Xiamen City, China
| | - Wanhong Han
- The Department of Neuroscience, Institute of Neurosurgery, School of Medicine, Xiamen University, Xiamen City, China
- Department of Neurosurgery, The First Affiliated Hospital of Xiamen University, Xiamen City, China
| | - Liwei Zhou
- The Department of Neuroscience, Institute of Neurosurgery, School of Medicine, Xiamen University, Xiamen City, China
- Department of Neurosurgery, The First Affiliated Hospital of Xiamen University, Xiamen City, China
| | - Zhanxiang Wang
- The Department of Neuroscience, Institute of Neurosurgery, School of Medicine, Xiamen University, Xiamen City, China.
- Department of Neurosurgery, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, Xiamen City, China.
- Department of Neurosurgery, The First Affiliated Hospital of Xiamen University, Xiamen City, China.
- Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen City, China.
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Zhang G, Dong J, Lu L, Liu Y, Hu D, Wu Y, Zhao A, Xu H. Acacetin exerts antitumor effects on gastric cancer by targeting EGFR. Front Pharmacol 2023; 14:1121643. [PMID: 37266143 PMCID: PMC10231641 DOI: 10.3389/fphar.2023.1121643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 05/09/2023] [Indexed: 06/03/2023] Open
Abstract
Background: Gastric cancer (GC) is a common malignant tumor with a poor prognosis. Combination treatments may prolong the survival of patients with GC. Acacetin, which is a flavonoid, exerts potent inhibitory effects on several types of cancer cells; however, the mechanisms of action remain poorly understood. Methods: Network pharmacology and RNA sequencing were used to predict the targets of acacetin, which were then verified by drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and molecular docking. The biological functions of acacetin in MKN45 and MGC803 cells were investigated using TUNEL assays, crystal staining and colony formation assays. The pathways affected by acacetin were verified through reverse experiments. The in vivo antitumor efficacy of acacetin was assessed in a subcutaneous xenotransplanted tumor model. Results: In this study, we identified EGFR from more than a dozen predicted targets as a protein that directly binds to acacetin. Moreover, acacetin affected the level of phosphorylated EGFR. In vitro, acacetin promoted the apoptosis of GC cells. Importantly, EGFR agonists reversed the inhibitory effects of acacetin on the STAT3 and ERK pathways. In vivo, acacetin decreased the protein levels of pEGFR in tumors, resulting in increased GC xenograft tumor regression without obvious toxicity. Conclusion: Our findings highlight EGFR as one of the direct targets of acacetin in GC cells. Acacetin inhibited the phosphatase activity of EGFR in vitro and in vivo, which played a role in the antitumor effects of acacetin. These studies provide new evidence for the use of acacetin as a potential reagent for the treatment of GC.
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Affiliation(s)
- Guangtao Zhang
- Longhua Hospital, Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontier Research Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation;, Shanghai, China
| | - Jiahuan Dong
- Longhua Hospital, Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lu Lu
- Longhua Hospital, Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontier Research Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation;, Shanghai, China
| | - Yujing Liu
- Longhua Hospital, Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontier Research Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation;, Shanghai, China
| | - Dan Hu
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai, China
| | - Yuanmin Wu
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai, China
| | - Aiguang Zhao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hanchen Xu
- Longhua Hospital, Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontier Research Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation;, Shanghai, China
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Haque E, Esmail A, Muhsen I, Salah H, Abdelrahim M. Recent Trends and Advancements in the Diagnosis and Management of Gastric Cancer. Cancers (Basel) 2022; 14:5615. [PMID: 36428707 PMCID: PMC9688354 DOI: 10.3390/cancers14225615] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/10/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022] Open
Abstract
Gastric cancer is an enigmatic malignancy that has recently been shown to be increasing in incidence globally. There has been recent progress in emerging technologies for the diagnosis and treatment of the disease. Improvements in non-invasive diagnostic techniques with serological tests and biomarkers have led to decreased use of invasive procedures such as endoscopy. A multidisciplinary approach is used to treat gastric cancer, with recent significant advancements in systemic therapies used in combination with cytotoxic chemotherapies. New therapeutic targets have been identified and clinical trials are taking place to assess their efficacy and safety. In this review, we provide an overview of the current and emerging treatment strategies and diagnostic techniques for gastric cancer.
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Affiliation(s)
- Emaan Haque
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Abdullah Esmail
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA
| | - Ibrahim Muhsen
- Section of Hematology and Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Haneen Salah
- Department of Pathology, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA
- Cockrell Center for Advanced Therapeutic Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA
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Wang S, Chen Y, Zhang H, Liang Z, Bu J. The Value of Predicting Human Epidermal Growth Factor Receptor 2 Status in Adenocarcinoma of the Esophagogastric Junction on CT-Based Radiomics Nomogram. Front Oncol 2021; 11:707686. [PMID: 34722254 PMCID: PMC8552039 DOI: 10.3389/fonc.2021.707686] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 09/29/2021] [Indexed: 01/08/2023] Open
Abstract
Purpose We developed and validated a CT-based radiomics nomogram to predict HER2 status in patients with adenocarcinoma of esophagogastric junction (AEG). Method A total of 101 patients with HER2-positive (n=46) and HER2-negative (n=55) esophagogastric junction adenocarcinoma (AEG) were retrospectively analyzed. They were then randomly divided into a training cohort (n=70) and a verification cohort (n=31). The radiomics features were obtained from the portal phase of the CT enhanced scan. We used the least absolute shrinkage and selection operator (LASSO) logistic regression method to select the best radiomics features in the training cohort, combined them linearly, and used the radiomics signature formula to calculate the radiomics score (Rad-score) of each AEG patient. A multivariable logistic regression method was applied to develop a prediction model that incorporated the radiomics signature and independent risk predictors. The prediction performance of the nomogram was evaluated using the training and validation cohorts. Result In the training (P<0.001) and verification groups (P<0.001), the radiomics signature combined with seven radiomics features was significantly correlated with HER2 status. The nomogram composed of CT-reported T stage and radiomics signature showed very good predictive performance for HER2 status. The area under the curve (AUC) of the training cohort was 0.946 (95% CI: 0.919–0.973), and that of the validation group was 0.903 (95% CI: 0.847–0.959). The calibration curve of the radiomics nomogram showed a good degree of calibration. Decision-curve analysis revealed that the radiomics nomogram was useful. Conclusion The nomogram CT-based radiomics signature combined with CT-reported T stage can better predict the HER2 status of AEG before surgery. It can be used as a non-invasive prediction tool for HER2 status and is expected to guide clinical treatment decisions in clinical practice, and it can assist in the formulation of individualized treatment plans.
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Affiliation(s)
- Shuxing Wang
- Department of Radiology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangdong, China
| | - Yiqing Chen
- Department of Radiology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangdong, China
| | - Han Zhang
- Department of Radiology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangdong, China
| | - Zhiping Liang
- Department of Radiology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangdong, China
| | - Jun Bu
- Department of Radiology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangdong, China
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Corso S, Pietrantonio F, Apicella M, Migliore C, Conticelli D, Petrelli A, D'Errico L, Durando S, Moya-Rull D, Bellomo SE, Ughetto S, Degiuli M, Reddavid R, Fumagalli U, De Pascale S, Sgroi G, Rausa E, Baiocchi GL, Molfino S, De Manzoni G, Bencivenga M, Siena S, Sartore-Bianchi A, Morano F, Corallo S, Prisciandaro M, Di Bartolomeo M, Gloghini A, Marsoni S, Sottile A, Sapino A, Marchiò C, Dahle-Smith A, Miedzybrodzka Z, Lee J, Ali SM, Ross JS, Alexander BM, Miller VA, Petty R, Schrock AB, Giordano S. Optimized EGFR Blockade Strategies in EGFR Addicted Gastroesophageal Adenocarcinomas. Clin Cancer Res 2021; 27:3126-3140. [PMID: 33542076 DOI: 10.1158/1078-0432.ccr-20-0121] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 12/04/2020] [Accepted: 02/01/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents. EXPERIMENTAL DESIGN We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX). RESULTS The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition. CONCLUSIONS This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors.See related commentary by Openshaw et al., p. 2964.
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Affiliation(s)
- Simona Corso
- Department of Oncology, University of Torino, Candiolo, Torino, Italy.
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Maria Apicella
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy
| | - Cristina Migliore
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy
| | - Daniela Conticelli
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy
| | | | - Laura D'Errico
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy
| | | | | | - Sara E Bellomo
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy
| | - Stefano Ughetto
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy
| | - Maurizio Degiuli
- Department of Oncology, University of Torino, Orbassano, Torino, Italy
| | - Rossella Reddavid
- Department of Oncology, University of Torino, Orbassano, Torino, Italy
| | | | | | - Giovanni Sgroi
- Surgical Oncology Unit, Department of Surgical Science, ASST Bergamo Ovest, Treviglio, Bergamo, Italy
| | - Emanuele Rausa
- Surgical Oncology Unit, Department of Surgical Science, ASST Bergamo Ovest, Treviglio, Bergamo, Italy
| | - Gian Luca Baiocchi
- Department of Clinical and Experimental Sciences, Surgical Clinic, University of Brescia, Brescia, Italy
| | - Sarah Molfino
- Department of Clinical and Experimental Sciences, Surgical Clinic, University of Brescia, Brescia, Italy
| | - Giovanni De Manzoni
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Section of Surgery, University of Verona, Verona, Italy
| | - Maria Bencivenga
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Section of Surgery, University of Verona, Verona, Italy
| | - Salvatore Siena
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Andrea Sartore-Bianchi
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Federica Morano
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Salvatore Corallo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Michele Prisciandaro
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Di Bartolomeo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Annunziata Gloghini
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Silvia Marsoni
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy
| | | | - Anna Sapino
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy
- Department of Medical Sciences, University of Torino, Torino, Italy
| | - Caterina Marchiò
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy
- Department of Medical Sciences, University of Torino, Torino, Italy
| | - Asa Dahle-Smith
- Tayside Cancer Centre, Ninewells Hospital, Dundee, Scotland, United Kingdom
| | | | - Jessica Lee
- Foundation Medicine, Inc., Cambridge, Massachusetts
| | - Siraj M Ali
- Foundation Medicine, Inc., Cambridge, Massachusetts
| | - Jeffrey S Ross
- Foundation Medicine, Inc., Cambridge, Massachusetts
- Department of Pathology, Upstate Medical University, Syracuse, New York
| | | | | | - Russell Petty
- Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, Scotland, United Kingdom
| | | | - Silvia Giordano
- Department of Oncology, University of Torino, Candiolo, Torino, Italy.
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy
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Sun W, Jiang C, Ji Y, Xiao C, Song H. Long Noncoding RNAs: New Regulators of Resistance to Systemic Therapies for Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8853269. [PMID: 33506041 PMCID: PMC7808844 DOI: 10.1155/2021/8853269] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/07/2020] [Accepted: 12/19/2020] [Indexed: 02/07/2023]
Abstract
Gastric cancer (GC) is the second leading cause of cancer mortality and the fourth most commonly diagnosed malignant disease, with approximately 951,000 new cases diagnosed and approximately 723,000 cases of mortality each year. The highest mortality rate of GC is in East Asia, and the lowest is in North America. A large number of studies have demonstrated that GC patients are characterized by higher morbidity, metastasis rates, and mortality and lower early diagnosis rates, radical resection rates, and 5-year survival rates. All cases of GC can be divided into two important stages, namely, early- and advanced-stage GC, and the stage mainly determines the treatment strategy for and the therapeutic effect in GC patients. Patients with early-stage GC undergo radical surgery followed by chemotherapy, and the 5-year survival rate can be as high as 90%. However, patients with advanced-stage GC cannot undergo radical surgery because they are at risk for metastasis; therefore, they can choose only radiotherapy or chemotherapy and have a poor prognosis. Based on the lack of specific clinical manifestations and detection methods, most GC patients (>70%) are diagnosed in the advanced stage; therefore, continued efforts toward developing treatments have been focused on advanced-stage GC patients and include molecular targeted therapy, immunotherapy, and small molecular therapy. Nevertheless, in recent years, accumulating evidence has indicated that small molecules, especially long noncoding RNAs (lncRNAs), are involved in the occurrence, development, and progression of GC, and their abundantly dysregulated expression has been identified in GC tissues and cell lines. Therefore, lncRNAs are considered easily detectable molecules and ideal biomarkers or target-specific agents for the future diagnosis or treatment of GC. In this review, we primarily discuss the status of GC, the role of lncRNAs in GC, and the emerging systemic treatments for GC.
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Affiliation(s)
- Weihong Sun
- Department of Internal Medicine-Oncology Affiliated Qingdao Central Hospital, Qingdao University, 127 Siliu South Road, Qingdao 266042, China
- Department of Internal Medicine-Oncology Qingdao Tumor Hospital, 127 Siliu South Road, Qingdao 266042, China
| | - Changqing Jiang
- Department of Pathology Qingdao Municipal Hospital, Donghai Middle Road, Qingdao 266071, China
| | - Ying Ji
- Department of Internal Medicine-Oncology Affiliated Qingdao Central Hospital, Qingdao University, 127 Siliu South Road, Qingdao 266042, China
- Department of Internal Medicine-Oncology Qingdao Tumor Hospital, 127 Siliu South Road, Qingdao 266042, China
| | - Chao Xiao
- Department of Internal Medicine-Oncology Affiliated Qingdao Central Hospital, Qingdao University, 127 Siliu South Road, Qingdao 266042, China
- Department of Internal Medicine-Oncology Qingdao Tumor Hospital, 127 Siliu South Road, Qingdao 266042, China
| | - Haiping Song
- Department of Internal Medicine-Oncology Affiliated Qingdao Central Hospital, Qingdao University, 127 Siliu South Road, Qingdao 266042, China
- Department of Internal Medicine-Oncology Qingdao Tumor Hospital, 127 Siliu South Road, Qingdao 266042, China
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Sun LF, Yang K, Wang YG, Liu YX, Hou PX, Lu ZH, Chen XL, Zhang WH, Zhou ZG, Mo XM, Hu JK. The Role of HER2 in Self-Renewal, Invasion, and Tumorigenicity of Gastric Cancer Stem Cells. Front Oncol 2020; 10:1608. [PMID: 32974199 PMCID: PMC7472958 DOI: 10.3389/fonc.2020.01608] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 07/24/2020] [Indexed: 02/05/2023] Open
Abstract
Background Deregulation of HER2 expression could affect the biological characteristics of gastric cancer cells and treatment option for gastric cancer patients. This research aims to investigate the impact of HER2 on biological characteristics of gastric cancer stem cells (GCSCs) and prognosis of gastric cancer patients. Methods HER2 knockdown in GCSCs were constructed by lentivirus transfection. Alterations of proliferation, self-renewal, invasion, migration, colony formation, and tumorigenicity of GCSCs were examined. The changes of gene expressions after HER2 interference in GCSCs were detected by gene microarray. The impact of concentration of serum HER2 and expression of HER2 in tumor tissues on survival of 213 gastric cancer patients was also analyzed. Results Down-regulation of HER2 decreased the self-renewal, colony formation, migration, invasion, proliferation, and chemotherapy resistance of GCSCs. However, the tumorigenicity of GCSCs in vivo was increased after down-regulation of HER2. The results of gene microarray showed that HER2 gene might regulate the signal transduction of mTOR, Jak-STAT, and other signal pathways and affect the biological characteristics of GCSCs. Furthermore, survival analyses indicated that patients with high concentration of HER2 in serum had a favorable overall survival. However, there was no significant correlation between expression of HER2 in tumor tissue and overall survival. Conclusion Interference of HER2 in GCSCs decreased the capacity of self-renewal, proliferation, colony formation, chemotherapy resistance, invasion, and migration but might increase the tumorigenicity in vivo. Patients with high concentration of HER2 in serum seemed to have a favorable prognosis.
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Affiliation(s)
- Li-Fei Sun
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Kun Yang
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Yi-Gao Wang
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yu-Xin Liu
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Pei-Xian Hou
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Zheng-Hao Lu
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Xiao-Long Chen
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Wei-Han Zhang
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Zong-Guang Zhou
- Department of Gastrointestinal Surgery and Laboratory of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Xian-Ming Mo
- Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Jian-Kun Hu
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
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9
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Franchi M, Tritto R, Torroni L, Reno C, La Vecchia C, Corrao G. Effectiveness and Healthcare Cost of Adding Trastuzumab to Standard Chemotherapy for First-Line Treatment of Metastatic Gastric Cancer: A Population-Based Cohort Study. Cancers (Basel) 2020; 12:cancers12061691. [PMID: 32630517 PMCID: PMC7352495 DOI: 10.3390/cancers12061691] [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: 04/25/2020] [Revised: 06/17/2020] [Accepted: 06/23/2020] [Indexed: 02/07/2023] Open
Abstract
A randomized clinical trial showed that trastuzumab, added to traditional chemotherapy, significantly improved overall survival in human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic gastric cancer patients. This population-based study aimed at evaluating both the clinical and economic impact of trastuzumab in a real-world setting. By using the healthcare utilization databases of Lombardy, Italy, a cohort of patients newly diagnosed with metastatic gastric cancer during the period 2011–2016 was selected. Among these, patients initially treated with either trastuzumab-based chemotherapy or standard chemotherapy alone were followed up until death, migration in other regions or June 2018. Overall survival and average cumulative costs were estimated and compared between the two treatment arms. Among the 1198 metastatic gastric cancer patients who started therapy within six months after metastasis detection, 87 were initially treated with trastuzumab-based chemotherapy and 1111 with standard chemotherapy. Median overall survival and restricted mean survival were 10.2 and 7.4 months, and 14.9 and 11.4 months, respectively, in the two treatment arms. The adjusted hazard ratio of death was 0.73 (95% CI 0.57–0.93). The average per capita cumulative healthcare costs were, respectively, EUR 39,337 and 26,504, corresponding to an incremental cost-effectiveness ratio of EUR 43,998 for each year of survival gained. Our study shows that adding trastuzumab to conventional chemotherapy is effective and cost-effective.
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Affiliation(s)
- Matteo Franchi
- National Centre for Healthcare Research and Pharmacoepidemiology, 20126 Milan, Italy; (R.T.); (G.C.)
- Laboratory of Healthcare Research & Pharmacoepidemiology, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, 20126 Milan, Italy
- Correspondence: ; Tel.: +39-02-6448-5859
| | - Roberta Tritto
- National Centre for Healthcare Research and Pharmacoepidemiology, 20126 Milan, Italy; (R.T.); (G.C.)
- Laboratory of Healthcare Research & Pharmacoepidemiology, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, 20126 Milan, Italy
| | - Lorena Torroni
- Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, Università degli studi di Verona, 37134 Verona, Italy;
| | - Chiara Reno
- Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy;
| | - Carlo La Vecchia
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milano, Italy;
| | - Giovanni Corrao
- National Centre for Healthcare Research and Pharmacoepidemiology, 20126 Milan, Italy; (R.T.); (G.C.)
- Laboratory of Healthcare Research & Pharmacoepidemiology, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, 20126 Milan, Italy
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10
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Zhou C, Zhong X, Song Y, Shi J, Wu Z, Guo Z, Sun J, Wang Z. Prognostic Biomarkers for Gastric Cancer: An Umbrella Review of the Evidence. Front Oncol 2019; 9:1321. [PMID: 31850212 PMCID: PMC6895018 DOI: 10.3389/fonc.2019.01321] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 11/12/2019] [Indexed: 12/14/2022] Open
Abstract
Introduction: Biomarkers are biological molecules entirely or partially participating in cancerous processes that function as measurable indicators of abnormal changes in the human body microenvironment. Aiming to provide an overview of associations between prognostic biomarkers and gastric cancer (GC), we performed this umbrella review analyzing currently available meta-analyses and grading the evidence depending on the credibility of their associations. Methods: A systematic literature search was conducted by two independent investigators of the PubMed, Embase, Web of Science, and Cochrane Databases to identify meta-analyses investigating associations between prognostic biomarkers and GC. The strength of evidence for prognostic biomarkers for GC were categorized into four grades: strong, highly suggestive, suggestive, and weak. Results: Among 120 associations between prognostic biomarkers and GC survival outcomes, only one association, namely the association between platelet count and GC OS, was supported by strong evidence. Associations between FITC, CEA, NLR, foxp3+ Treg lymphocytes (both 1- and 3-year OS), CA 19-9, or VEGF and GC OS were supported by highly suggestive evidence. Four associations were considered suggestive and the remaining 108 associations were supported by weak or not suggestive evidence. Discussion: The association between platelet count and GC OS was supported by strong evidence. Associations between FITC, CEA, NLR, foxp3+ Treg lymphocytes (both 1- and 3-year OS), CA 19-9, or VEGF and GC OS were supported by highly suggestive evidence, however, the results should be interpreted cautiously due to inadequate methodological quality as deemed by AMSTAR 2.0.
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Affiliation(s)
- Cen Zhou
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xi Zhong
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jinxin Shi
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhonghua Wu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhexu Guo
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jie Sun
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
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11
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Arienti C, Pignatta S, Tesei A. Epidermal Growth Factor Receptor Family and its Role in Gastric Cancer. Front Oncol 2019; 9:1308. [PMID: 31850207 PMCID: PMC6901979 DOI: 10.3389/fonc.2019.01308] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 11/11/2019] [Indexed: 12/24/2022] Open
Abstract
Despite the gradual decrease in incidence, gastric cancer is still the third leading cause of cancer death worldwide. Although chemotherapy enhances overall survival and quality of life in advanced disease, the median overall survival is < 12 months. In recent years, the human epidermal growth factor receptor (ErbB) family has been extensively investigated in gastric cancer. The ErbB family is composed of four closely-related members: ErbB-1 (HER1 or epidermal growth factor receptor, EGFR), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4), all of which play a critical role in regulating cell growth, proliferation and migration of tumors. It is well known that gastric cancer overexpresses HER in a heterogeneous pattern, especially EGFR, and HER2. HER3 is another important member of the ErbB family that preferentially activates the phosphatidylinositol 3-kinase (PI3K) pathway. Furthermore, its heterodimerization with HER2 seems fundamental for steering HER2-overexpressing breast cancer tumor growth. Less is known about the impact of HER4 on gastric cancer. Improved survival from the use of trastuzumab has paved the way for ErbB receptor family-targeted treatments in gastric cancer. However, unlike trastuzumab, ErbB receptor-targeted drugs have not consistently maintained the encouraging results obtained in preclinical and early clinical trials. This may be attributable to the intrinsic heterogeneity of gastric cancer and/or to the lack of standardized test quality for established biomarkers used to evaluate these biological targets. This review presents an overview of the most recent clinical studies on agents targeting the ErbB family in gastric cancer.
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Affiliation(s)
| | | | - Anna Tesei
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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12
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HER2, NF- κB, and SATB1 Expression Patterns in Gastric Cancer and Their Correlation with Clinical and Pathological Parameters. DISEASE MARKERS 2019; 2019:6315936. [PMID: 31737131 PMCID: PMC6815548 DOI: 10.1155/2019/6315936] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 05/15/2019] [Accepted: 09/07/2019] [Indexed: 02/07/2023]
Abstract
Gastric cancer (GC) is currently recognized as one of the most common and fatal tumor worldwide. The identification of novel biomarkers in relation to clinical information as well as extending the knowledge on a multiple crosstalk between various oncogenic pathways implicated in GC carcinogenesis seems pivotal to limit the disease-associated mortality. Therefore, we assessed the expression of HER2, NF-κB, and SATB1 in a total of 104 gastric adenocarcinomas and 30 normal gastric samples and correlated the expression patterns with each other and with some clinicopathological variables. Protein expression was examined by immunohistochemistry (IHC) on tissue microarrays (TMAs), and fluorescence in situ hybridization (FISH) was employed to detect HER2 amplification. In the studied group, HER2 and SATB1 were found to be overexpressed in gastric cancer tissue in comparison to normal gastric mucosa. The expression status of the former protein was seen to differ according to some clinicopathological features, but without statistical significance, whereas the expression of the latter was not importantly associated with any of them. In turn, the NF-κB protein level was significantly related to the presence of lymph node metastasis. HER2 expression was not significantly correlated with that of other proteins, but a positive correlation was found between the expression of SATB1 and NF-κB. Further studies with a larger group of patients combined with in vitro mechanistic experiments are required to fully elucidate the role and relationship of HER2, NF-κB, and SATB1 expression in gastric cancer progression. However, to the best of our knowledge, this study is the first look at a simultaneous evaluation of these three markers in the samples of gastric cancer patients.
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13
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Assessment of EGFR and ERBB2 (HER2) in Gastric and Gastroesophageal Carcinomas: EGFR Amplification is Associated With a Worse Prognosis in Early Stage and Well to Moderately Differentiated Carcinoma. Appl Immunohistochem Mol Morphol 2019; 26:374-382. [PMID: 27753660 DOI: 10.1097/pai.0000000000000437] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epidermal growth factor receptor 1 (EGFR) and erb-b2 receptor tyrosine kinase 2 (ERBB2/HER2) are frequently dysregulated in human cancers. We analyzed EGFR and ERBB2 status in 105 gastric and gastroesophageal junction carcinoma and their clinicopathologic features. For EGFR, 92 (88%) tumors were scored as 0, 2 (2%) as 1+, 7 (7%) as 2+, and 4 (3%) as 3+ by immunohistochemistry (IHC) and 4 (4%) tumors showed EGFR amplification by fluorescence in situ hybridization (FISH). For ERBB2, 90 (86%) tumors were scored as 0, 4 (4%) as 1+, 6 (6%) as 2+, and 5 (5%) as 3+ by IHC and 12 (12%) showed ERBB2 amplification by FISH. The concordance rate between IHC and FISH of EGFR was 98.1% (P<0.001) and of ERBB2 was 93.3% (P<0.001). Most tumors with ERBB2 amplification were tubular adenocarcinoma (N=11, P=0.02) and Lauren intestinal type (N=12, P=0.016). There was no statistically significant difference between EGFR amplification and tumor classification. EGFR amplification had significant impact on overall survival in certain subgroups: early stages (stages I and II) (P<0.001), well to moderately differentiated tumors (P=0.001), and fewer regional lymph node metastasis (pN1) (P=0.001). ERBB2 status had little predictive value on overall survival. In conclusion, this study showed ERBB2 amplification was significantly observed in tubular adenocarcinoma and Lauren intestinal-type carcinoma. The IHC scoring criteria for ERBB2 can be applied to EGFR. EGFR amplification had associated with poor prognosis in early, well to moderately differentiated carcinoma.
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14
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Coccolini F, Fugazzola P, Ansaloni L, Sartelli M, Cicuttin E, Leandro G, De' Angelis GL, Gaiani F, Di Mario F, Tomasoni M, Catena F. Advanced gastric cancer: the value of systemic and intraperitoneal chemotherapy. ACTA BIO-MEDICA : ATENEI PARMENSIS 2018; 89:104-109. [PMID: 30561427 PMCID: PMC6502214 DOI: 10.23750/abm.v89i8-s.7904] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Indexed: 12/20/2022]
Abstract
Several possibilities in treating advanced gastric cancer exist. Radical surgery associated with chemotherapy represents the cornerstone. Which one is more effective among neoadjuvant, adjuvant or perioperative chemotherapy is still a matter of debate. Several innovative results showed the necessity to keep increasingly into consideration the intraperitoneal administration of chemotherapies. Moreover, classical drugs and their ways of administration should be combined with the new ones to improve results. Lastly the prevention of recurrence should be considered: one possibility is to administer intraperitoneal chemotherapy earlier in the therapeutic algorithm. (www.actabiomedica.it)
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Affiliation(s)
- Federico Coccolini
- Emergency, General and Trauma Surgery dept., Bufalini hospital, Cesena, Italy.
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15
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Giampieri R, Del Prete M, Cantini L, Baleani MG, Bittoni A, Maccaroni E, Berardi R. Optimal management of resected gastric cancer. Cancer Manag Res 2018; 10:1605-1618. [PMID: 29950898 PMCID: PMC6016582 DOI: 10.2147/cmar.s151552] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Although advances in medical treatment for gastric cancer (GC) have been made, surgery remains the mainstay of cure for patients with localized disease. Improvement in surgical modalities leads to increased chance of cure for resected patients, but a non-negligible number of patients eventually relapse. On this basis, it has been hypothesized that the addition of complementary systemic or local treatments (such as chemotherapy and radiotherapy) could help in improving patients' survival by reducing the risk of recurrence. Several studies have tried to identify the best approach in localized GC: some of them have assessed the role of perioperative chemotherapy [CT] with different drug combinations, while others have focused on the benefit obtained by addition of radiotherapy, whose role is still under investigation. In particular, the role of chemoradiotherapy, both in adjuvant and neoadjuvant settings, is still uncertain. In the last few years, several clinicopathological and molecular factors have been investigated and identified as potential prognostic markers in GC. Many of these factors could have influenced the outcome of patients receiving combined treatments in the abovementioned studies. Patients have not been generally distinguished by the site of disease (esophageal, gastric and junctional cancers) and surgical approach, making data difficult to be interpreted. The purpose of this review was to shed light on these highly controversial topics.
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Affiliation(s)
- Riccardo Giampieri
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Michela Del Prete
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Luca Cantini
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Maria Giuditta Baleani
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Alessandro Bittoni
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Elena Maccaroni
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Rossana Berardi
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
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16
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Xie S, Zhang H, Wang X, Ge Q, Hu J. The relative efficacy and safety of targeted agents used in combination with chemotherapy in treating patients with untreated advanced gastric cancer: a network meta-analysis. Oncotarget 2018; 8:26959-26968. [PMID: 28460479 PMCID: PMC5432310 DOI: 10.18632/oncotarget.15923] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 02/15/2017] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer is one of the leading mortal causes. Targeted therapy is a new type of cancer treatment, which precisely identifies and attacks cancer cells and significantly reduces side effects. In this network meta-analysis, we focused on the efficacy and safety of 12 targeted agents on gastric cancer among a total of 8,405 patients from 24 trials. Hazard ratio (HR) with 95% credible interval (CrI) were calculated for primary outcomes, including overall survival (OS) and progression-free survival (PFS), while odds ratio (OR) with 95% CrI were calculated for secondary outcomes. Surface under the cumulative ranking curve (SUCRA) were calculated to illustrate the rank probability of various agents for different outcomes. Compared with other analyzed treatments, ramucirumab is outstanding in survival outcomes. However, higher risk of hematological events should be noted during its application. Lapatinib is also efficacious in progression reduction, while it is always combined with severe gastrointestinal events. Trastuzumab is proposed for its high efficacy in improving survival rate and safety, which is proper for most patients. In conclusion, trastuzumab was recommended as the optimal targeted agent combined with chemotherapy for gastric cancer patients.
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Affiliation(s)
- Shuping Xie
- Department of Gastroenterology, Huaihe Hospital of Henan University, Kaifeng, Henan, 475000, China
| | - Huixiang Zhang
- Department of Radiotherapy, Huaihe Hospital of Henan University, Kaifeng, Henan, 475000, China
| | - Xueyan Wang
- Department of Gastroenterology, Huaihe Hospital of Henan University, Kaifeng, Henan, 475000, China
| | - Quanxing Ge
- Department of Gastroenterology, Huaihe Hospital of Henan University, Kaifeng, Henan, 475000, China
| | - Junhong Hu
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, Henan, 475000, China
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17
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Szász AM, Lánczky A, Nagy Á, Förster S, Hark K, Green JE, Boussioutas A, Busuttil R, Szabó A, Győrffy B. Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget 2018; 7:49322-49333. [PMID: 27384994 PMCID: PMC5226511 DOI: 10.18632/oncotarget.10337] [Citation(s) in RCA: 753] [Impact Index Per Article: 107.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 06/13/2016] [Indexed: 02/07/2023] Open
Abstract
Introduction Multiple gene expression based prognostic biomarkers have been repeatedly identified in gastric carcinoma. However, without confirmation in an independent validation study, their clinical utility is limited. Our goal was to establish a robust database enabling the swift validation of previous and future gastric cancer survival biomarker candidates. Results The entire database incorporates 1,065 gastric carcinoma samples, gene expression data. Out of 29 established markers, higher expression of BECN1 (HR = 0.68, p = 1.5E-05), CASP3 (HR = 0.5, p = 6E-14), COX2 (HR = 0.72, p = 0.0013), CTGF (HR = 0.72, p = 0.00051), CTNNB1 (HR = 0.47, p = 4.3E-15), MET (HR = 0.63, p = 1.3E-05), and SIRT1 (HR = 0.64, p = 2.2E-07) correlated to longer OS. Higher expression of BIRC5 (HR = 1.45, p = 1E-04), CNTN1 (HR = 1.44, p = 3.5E- 05), EGFR (HR = 1.86, p = 8.5E-11), ERCC1 (HR = 1.36, p = 0.0012), HER2 (HR = 1.41, p = 0.00011), MMP2 (HR = 1.78, p = 2.6E-09), PFKB4 (HR = 1.56, p = 3.2E-07), SPHK1 (HR = 1.61, p = 3.1E-06), SP1 (HR = 1.45, p = 1.6E-05), TIMP1 (HR = 1.92, p = 2.2E- 10) and VEGF (HR = 1.53, p = 5.7E-06) were predictive for poor OS. MATERIALS AND METHODS We integrated samples of three major cancer research centers (Berlin, Bethesda and Melbourne datasets) and publicly available datasets with available follow-up data to form a single integrated database. Subsequently, we performed a literature search for prognostic markers in gastric carcinomas (PubMed, 2012–2015) and re-validated their findings predicting first progression (FP) and overall survival (OS) using uni- and multivariate Cox proportional hazards regression analysis. Conclusions The major advantage of our analysis is that we evaluated all genes in the same set of patients thereby making direct comparison of the markers feasible. The best performing genes include BIRC5, CASP3, CTNNB1, TIMP-1, MMP-2, SIRT, and VEGF.
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Affiliation(s)
- A Marcell Szász
- MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.,2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - András Lánczky
- MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary
| | - Ádám Nagy
- MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary
| | - Susann Förster
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Kim Hark
- Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Jeffrey E Green
- Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Alex Boussioutas
- Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.,Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia
| | - Rita Busuttil
- Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.,Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia
| | - András Szabó
- 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Balázs Győrffy
- MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.,2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
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18
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Hedner C, Borg D, Nodin B, Karnevi E, Jirström K, Eberhard J. Expression and prognostic significance of human epidermal growth factor receptors 1, 2 and 3 in oesophageal and gastric adenocarcinomas preneoadjuvant and postneoadjuvant treatment. J Clin Pathol 2017; 71:451-462. [PMID: 29138285 DOI: 10.1136/jclinpath-2017-204774] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 10/23/2017] [Accepted: 10/25/2017] [Indexed: 12/11/2022]
Abstract
AIMS Neoadjuvant treatment has now become the standard of care for oesophageal and gastric cancer. The aim of this study was to investigate the influence of neoadjuvant therapy on the expression of human epidermal growth factor receptor 1 (HER1/EGFR), HER2 and HER3, in oesophageal and gastric adenocarcinoma. METHODS Immunohistochemical expression of EGFR, HER2 and HER3 was examined and compared in pretreatment biopsies, post-treatment surgical resection specimens and metastases in a retrospective cohort of 166 patients with adenocarcinoma of the oesophagus or stomach. The relationship between expression of the investigative markers and histopathological response to neoadjuvant treatment, overall survival (OS) and recurrence free survival (RFS) was analysed. RESULTS Conversion of protein expression between pretreatment biopsy and post-treatment surgical resection was seen in 4.6% of the cases for EGFR, 5.9% for HER2% and 19.4% for HER3. Histopathological response to neoadjuvant treatment was significantly and stepwise associated with OS and RFS . High HER3 protein expression in post-treatment surgical resection specimens was significantly associated with a prolonged OS in univariable analysis (HR=0.39; 95% CI 0.17 to 0.93), but did not remain significant in multivariable analysis. Expression of EGFR and HER2 in post-treatment surgical resection specimens was not prognostic. No correlation between pretreatment HER-protein expression and histopathological response was seen. CONCLUSIONS The results from this study underscore the need for further studies on the influence of neoadjuvant treatment on biomarker expression, as this may influence treatment strategy as well as prognosis. Histopathological response is validated as a useful prognostic factor.
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Affiliation(s)
- Charlotta Hedner
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, Lund, Sweden
| | - David Borg
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, Lund, Sweden
| | - Björn Nodin
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, Lund, Sweden
| | - Emelie Karnevi
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, Lund, Sweden
| | - Karin Jirström
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, Lund, Sweden
| | - Jakob Eberhard
- Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, Lund, Sweden
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19
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Kumarasinghe MP, Morey A, Bilous M, Farshid G, Francis G, Lampe G, McCue G, Von Neumann-Cosel V, Fox SB. HER2 testing in advanced gastric and gastro-oesophageal cancer: analysis of an Australia-wide testing program. Pathology 2017; 49:575-581. [PMID: 28823752 DOI: 10.1016/j.pathol.2017.05.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 05/15/2017] [Accepted: 05/21/2017] [Indexed: 01/29/2023]
Abstract
This Australian human epidermal growth factor receptor 2 (HER2) testing program aimed to analyse >800 cases tested in a coordinated setting to further evaluate the criteria to establish HER2 status in advanced gastric and gastro-oesophageal junction (GOJ) cancer. Heterogeneity, and minimum number of biopsy fragments for reliable HER2 assessment were also examined in a subset of samples. Five laboratories tested 891 samples referred to determine HER2 status for potential anti-HER2 treatment. Cancer site, specimen type (endoscopic biopsy/resection/metastases), immunohistochemistry (IHC) score, HER2 gene and CEP17 copy number (CN) and HER2:CEP17 ratios were recorded. Samples were derived from stomach (53.1%), GOJ (28.2%) or metastases (18.5%). IHC for HER2 and dual probe HER2:CEP17 in situ hybridisation (ISH) were performed in parallel. A stringent definition (SD) of HER2 positivity was used (IHC2+/3+ plus CN>6 and ratio>2) and compared with other published criteria. HER2 positive rate was 13.9% (114/820) by SD, and 12.9-16.0% using other definitions. There was higher concordance between IHC and HER2 CN by ISH than with ratio. The HER2 positive rate was significantly higher in GOJ samples than others (p = 0.03) and in endoscopic biopsies than resections (p = 0.047). In a subset of 98 positive cases, 39 (39.8%) showed heterogeneity, and in 282 endoscopic biopsies positivity rate plateaued at five tumour fragments, suggesting this is the minimum number of biopsies that should be examined.
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Affiliation(s)
- M Priyanthi Kumarasinghe
- PathWest, QEII Medical Centre and School of Pathology & Laboratory Medicine, University of Western Australia, Perth, WA, Australia.
| | | | - Michael Bilous
- Australian Clinical Labs, Norwest Private Hospital, Bella Vista, NSW, Australia
| | - Gelareh Farshid
- Discipline of Medicine, Adelaide University and Directorate of Surgical Pathology, SA Pathology, Adelaide, SA, Australia
| | | | - Guy Lampe
- Pathology Queensland, Brisbane, Qld, Australia
| | | | | | - Stephen B Fox
- Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic, Australia
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20
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Zhang Z, Tang H, Lin J, Hu Y, Luo G, Luo Z, Cheng C, Wang P. Clinicopathologic and prognostic significance of human epidermal growth factor receptor in patients with gastric cancer: An updated meta-analysis. Oncotarget 2017; 8:17202-17215. [PMID: 28199988 PMCID: PMC5370033 DOI: 10.18632/oncotarget.15231] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 01/06/2017] [Indexed: 12/12/2022] Open
Abstract
Purpose The aim of this update meta-analysis was to clarify the clinicopathologic and prognostic significance of human epidermal growth factor receptor(EGFR) expression in gastric cancer patients. Experimental Design Several electronic databases were searched from January 1970 to May 2016. The odds ratio (OR) was calculated to assess the association between EGFR expression and pathological parameters. The hazard ratio (HR) and 95% CI were calculated to explore the relationship between EGFR expression and overall survival. Results Finally 7229 patients with gastric cancer from 25 eligible studies were included in the present meta analysis. High EGFR expression was found to be significantly related with tumor differentiation (OR=1.96, 95%CI: 1.14-3.34, Z=2.43, P=0.015), lymph node metastasis (OR=2.20, 95% CI: 1.63-2.96, Z=5.17, P=0.001), and tumor stage (OR=2.13, 95% CI: 1.35-3.36, Z=3.25, P=0.001). However, high EGFR expression was not significantly associated with invasion depth (OR=2.09, 95% CI: 0.4-11.05, Z=0.87, P=0.385). The pooled HR suggested that high EGFR expression was significantly correlated with overall survival (HR=1.19, 95% CI 1.04-1.37, Z=2.44, P=0.015). Conclusions The present meta-analysis demonstrated that high EGFR expression significantly predicts poor prognosis, suggesting that high EGFR expression may serve as a predictive biomarker for poor prognosis in patients with gastric cancer.
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Affiliation(s)
- Zhiqiao Zhang
- Department of Infectious Disease, The First People's Hospital of Shunde, Shunde, Guangdong, China.,Department of Internal Medicine, The Chencun Hospital Affiliated to The First People's Hospital of Shunde, Shunde, Guangdong, China
| | - Hongfeng Tang
- Department of Science and Education, The First People's Hospital of Shunde, Shunde, Guangdong, China
| | - Jixin Lin
- Department of Internal Medicine, The Chencun Hospital Affiliated to The First People's Hospital of Shunde, Shunde, Guangdong, China
| | - Yunzhao Hu
- Department of Infectious Disease, The First People's Hospital of Shunde, Shunde, Guangdong, China.,Department of Internal Medicine, The Chencun Hospital Affiliated to The First People's Hospital of Shunde, Shunde, Guangdong, China
| | - Guanying Luo
- Department of Infectious Disease, The First People's Hospital of Shunde, Shunde, Guangdong, China.,Department of Internal Medicine, The Chencun Hospital Affiliated to The First People's Hospital of Shunde, Shunde, Guangdong, China
| | - Zhaowen Luo
- Department of Internal Medicine, The Chencun Hospital Affiliated to The First People's Hospital of Shunde, Shunde, Guangdong, China
| | - Canchang Cheng
- Department of Infectious Disease, The First People's Hospital of Shunde, Shunde, Guangdong, China.,Department of Internal Medicine, The Chencun Hospital Affiliated to The First People's Hospital of Shunde, Shunde, Guangdong, China
| | - Peng Wang
- Department of Infectious Disease, The First People's Hospital of Shunde, Shunde, Guangdong, China.,Department of Internal Medicine, The Chencun Hospital Affiliated to The First People's Hospital of Shunde, Shunde, Guangdong, China
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21
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Wang Y, He L, Cheng Y. An independent survival prognostic role for human epidermal growth factor receptor 2 in gastric cancer: evidence from a meta-analysis. Clin Transl Oncol 2017; 20:212-220. [DOI: 10.1007/s12094-017-1711-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 06/23/2017] [Indexed: 12/16/2022]
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22
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Yu L, Gao C, Feng B, Wang L, Tian X, Wang H, Ma D. Distinct prognostic values of YAP1 in gastric cancer. Tumour Biol 2017; 39:1010428317695926. [PMID: 28381174 DOI: 10.1177/1010428317695926] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The Hippo pathway regulates intrinsic organ sizes by regulating apoptosis and cell proliferation. YAP1 (yes-associated protein 1) is a transcriptional effector of the Hippo pathway. YAP1 expression is reported to be associated with gastric cancer carcinogenesis and malignancy. In this study, we compared the expression of YAP1 in gastric cancer and normal stomach tissues. Tissue microarray analysis was performed in 156 gastric cancer samples, 8 adjacent normal stomach tissues, and 4 normal stomach tissues. We also analyzed the association between YAP1 protein expression and clinicopathological features, such as age, gender, histological differentiation, and clinical stages. We used the ONCOMINE database and the Kaplan-Meier plotter to analyze YAP1 expression status in different clinicopathological parameters of gastric cancer. We also used the Kaplan-Meier plotter to summarize the survival information of YAP1 from a total of 631 gastric cancer patients. YAP1 expression was found to be elevated in gastric cancer tissues compared to normal stomach tissues. YAP1 messenger RNA was found to be upregulated in gastric intestinal-type adenocarcinoma and gastric mixed adenocarcinoma compared to gastric mucosa. YAP1 high expression was found to be correlated to worse overall survival for all gastric cancer patients followed for 20 years. These results indicate that YAP1 can be used to predict the prognosis of gastric cancer. And YAP1 maybe a potential drug target for gastric cancer patients.
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Affiliation(s)
- Lan Yu
- 1 Key Laboratory of Cancer Invasion and Metastasis of the Ministry of Education, Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun Gao
- 1 Key Laboratory of Cancer Invasion and Metastasis of the Ministry of Education, Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bei Feng
- 1 Key Laboratory of Cancer Invasion and Metastasis of the Ministry of Education, Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liming Wang
- 1 Key Laboratory of Cancer Invasion and Metastasis of the Ministry of Education, Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xun Tian
- 1 Key Laboratory of Cancer Invasion and Metastasis of the Ministry of Education, Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Wang
- 2 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ding Ma
- 2 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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23
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Chiavenna SM, Jaworski JP, Vendrell A. State of the art in anti-cancer mAbs. J Biomed Sci 2017; 24:15. [PMID: 28219375 PMCID: PMC5319201 DOI: 10.1186/s12929-016-0311-y] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 12/13/2016] [Indexed: 12/31/2022] Open
Abstract
Following Milstein’s discovery, the monoclonal antibodies (mAbs) became a basic tool for biomedical science. In cancer field, since the first mAb was approved by the FDA a great improvement took place making of them a therapeutic option for many cancer types in the current clinical practice. Today, mAbs are being developed to target different molecules with different mechanisms of action and its target potential is unlimited. However, this huge and fast growing new field needs to be organized to better understand the treatment options we have to confront different cancer diseases. Current cancer targeted immunotherapies aim to achieve different goals like the regulation of osteoclast function, the delivery of cytotoxic drugs into tumor cells and the blockade of oncogenic pathways, neo-angiogenesis and immune checkpoints. Here, we reviewed the most relevant therapeutic mAbs for solid tumors available in current clinical practice.
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Affiliation(s)
- S M Chiavenna
- Ferrer Advanced Biotherapeutics, Ferrer Internacional, Barcelona, Spain.
| | - J P Jaworski
- Institute of Virology, CICVyA, INTA - CONICET, Castelar, Buenos Aires, Argentina
| | - A Vendrell
- Faculty of Medicine, CEFYBO - CONICET/University of Buenos Aires, C.A.B.A., Argentina
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24
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Neuzillet C, Rousseau B, Kocher H, Bourget P, Tournigand C. Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers Part 1: GI carcinomas. Pharmacol Ther 2017; 174:145-172. [PMID: 28223233 DOI: 10.1016/j.pharmthera.2017.02.028] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the molecular biology of cancer cell has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents being more specific to cancer cells were expected to be less toxic than cytotoxic agents. Targeted agents have provided clinical benefit in many GI cancer types. For example, antiangiogenics and anti-EGFR therapies have significantly improved survival of patients affected by metastatic colorectal cancer and have deeply changed the therapeutic strategy in this disease. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms (e.g., RAS mutation for anti-EGFR therapies), or to an activity restricted to some tumour settings (e.g., lack of activity in other cancer types, or on the microscopic residual disease in adjuvant setting). Many studies are negative in overall population but positive in some specific patient subgroups (e.g., trastuzumab in HER2-positive gastric cancer), illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this first part, we will focus on adenocarcinomas and squamous cell carcinomas, for which targeted therapies are mostly used in combination with chemotherapy.
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Affiliation(s)
- Cindy Neuzillet
- INSERM UMR1149, Bichat-Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 46 rue Henri Huchard, 75018 Paris, and 100 boulevard du Général Leclerc, 92110 Clichy, France; Department of Medical Oncology, Henri Mondor University Hospital, AP-HP, Paris Est Créteil University (UPEC), 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London, E1 1BB, United Kingdom.
| | - Benoît Rousseau
- Department of Medical Oncology, Henri Mondor University Hospital, AP-HP, Paris Est Créteil University (UPEC), 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
| | - Hemant Kocher
- Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London, E1 1BB, United Kingdom
| | - Philippe Bourget
- Department of Clinical Pharmacy, Necker-Enfants Malades University Hospital, 149 Rue de Sèvres, 75015 Paris, France
| | - Christophe Tournigand
- Department of Medical Oncology, Henri Mondor University Hospital, AP-HP, Paris Est Créteil University (UPEC), 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
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25
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Fusco N, Bosari S. HER2 aberrations and heterogeneity in cancers of the digestive system: Implications for pathologists and gastroenterologists. World J Gastroenterol 2016; 22:7926-7937. [PMID: 27672288 PMCID: PMC5028807 DOI: 10.3748/wjg.v22.i35.7926] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 08/01/2016] [Accepted: 08/10/2016] [Indexed: 02/06/2023] Open
Abstract
Management of cancers of the digestive system has progressed rapidly into the molecular era. Despite the significant recent achievements in the diagnosis and treatment of these patients, the number of deaths for these tumors has currently plateaued. Many investigations have assessed the role of HER2 in tumors of the digestive system in both prognostic and therapeutic settings, with heterogeneous results. Novel testing and treatment guidelines are emerging, in particular in gastric and colorectal cancers. However, further advances are needed. In this review we provide a comprehensive overview of the current state-of-knowledge of HER2 alterations in the most common tumors of the digestive system and discuss the operational implications of HER2 testing.
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26
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Concordance of HER2 expression in paired primary and metastatic sites of gastric and gastro-oesophageal junction cancers. Pathology 2016; 47:641-6. [PMID: 26517644 DOI: 10.1097/pat.0000000000000323] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
HER2 is amplified/overexpressed in a subset of gastric and gastro-oesophageal junction cancers. Addition of anti-HER2 therapy has been shown to provide survival benefit in this setting. However, there are limited data assessing the concordance of HER2 status between primary and metastatic sites.A total of 113 samples from 43 paired primary and metastatic tumours were tested for HER2 status, by immunohistochemistry (IHC) for protein expression and silver in situ hybridisation (SISH) for gene amplification.Primary sites tested included endoscopic biopsies (n = 30) and resections (n = 24). Metastatic samples included lymph nodes (n = 29), peritoneal effusions (n = 21) and miscellaneous sites (n = 9). The overall HER2+ rate was 11%. Of 41 (95%; 95% CI 88.5-100%) concordant cases, 38 were HER2- and three were HER2+. There were two (5%) discordant cases, one of which showed heterogeneity of HER2 expression.This series confirms a high concordance rate of 95%, supporting that testing of primary tumours and metastases is equally valid and providing clinical rationale for the addition of anti-HER2 therapy in HER2+ disseminated disease.
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27
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Chen XZ, Zhang WH, Chen HN, Liu JP, He D, Liu Y, Liu K, Chen XL, Mo XM, Zhou ZG, Hu JK. Associations between serum CA724 and HER2 overexpression among stage II-III resectable gastric cancer patients: an observational study. Oncotarget 2016; 7:23647-57. [PMID: 27027339 PMCID: PMC5029653 DOI: 10.18632/oncotarget.8145] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 02/28/2016] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Associations between serum tumor biomarkers and human epidermal growth factor receptor 2 (HER2) overexpression among locally advanced gastric cancer patients were yet to be determined and therefore warranted investigation. RESULTS A total of 318 patients were analyzed. The odds ratios of CA724 were 4.79 (95% CI 1.55-14.79) and 6.29 (1.40-28.19) in comparing the HER2 (2+/3+) and HER2 (3+) with the negative group, respectively (p < 0.05). A combination of the four biomarkers yielded slightly but not significantly greater areas under the curve (AUC = 0.83; 0.71-0.94) than that of serum CA724 alone (0.80; 0.68-0.91); however, an index generated from the combination had better diagnostic performance with 85.7% sensitivity, 80.4% specificity and 97.8% negative predictive value to predict the strong overexpression of HER2 (3+). CA199, CEA or CA125 alone was not associated with HER2 overexpression. Leave-one-out cross-validation found a consistent association between serum CA724 and HER2 (2+/3+) overexpression. METHODS Patients undergoing radical gastrectomy from 8/2012 to 12/2013 and with pathological stage II-III gastric cancer were retrospectively analyzed. HER2 expression of the surgical samples was estimated using immunohistochemistry; serum CA724, CA199, CEA and CA125 were preoperatively tested. Internal validation was performed using the leave-one-out approach. CONCLUSIONS Serum CA724 is significantly associated with the overexpression of HER2 among locally advanced gastric cancer patients. The combination of CA724, CA199, CEA and CA125 is better than serum CA724 alone in predicting HER2 overexpression. External validation and further investigation of the biological mechanisms of these associations are required.
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Affiliation(s)
- Xin-Zu Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wei-Han Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hai-Ning Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jian-Ping Liu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Du He
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Liu
- West China School of Public Health, Sichuan University, Chengdu, China
| | - Kai Liu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao-Long Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xian-Ming Mo
- Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zong-Guang Zhou
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jian-Kun Hu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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28
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Zhai JS, Song JG, Zhu CH, Wu K, Yao Y, Li N. Expression of APPL1 is correlated with clinicopathologic characteristics and poor prognosis in patients with gastric cancer. ACTA ACUST UNITED AC 2016; 23:e95-e101. [PMID: 27122990 DOI: 10.3747/co.23.2775] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Although appl1 is overexpressed in many cancers, its status in gastric cancer (gc) is not known. In the present study, we used relevant pathologic and clinical data to investigate appl1 expression in patients with gc. METHODS In 47 gc and 27 non-gc surgical specimens, immunohistochemistry was used to detect the expression of appl1, and reverse-transcriptase polymerase chain reaction (rt-pcr) was used to detect messenger rna (mrna). A scatterplot visualized the relationship between survival time and mrna expression in gc patients. The log-rank test and other survival statistics were used to determine the association of appl1 expression with the pathologic features of the cancer and clinical outcomes. RESULTS In gc, appl1 was expressed in 28 of 47 specimens (59.6%), and in non-gc, it was expressed in 7 of 23 specimens (30.4%, p < 0.05). The expression of mrna in gc was 0.82 [95% confidence interval (ci): 0.78 to 0.86], and in non-gc, it was 0.73 (95% ci: 0.69 to 0.77; p < 0.05). Immunohistochemistry demonstrated that, in gc, appl1 expression was correlated with depth of infiltration (p = 0.005), lymph node metastasis (p = 0.017), and TNM stage (p = 0.022), but not with pathologic type (p = 0.41). Testing by rt-pcr demonstrated that, in gc, appl1 mrna expression was correlated with depth of infiltration (p = 0.042), lymph node metastasis (p = 0.031), and TNM stage (p = 0.04), but again, not with pathologic type (p = 0.98). The correlation coefficient between survival time and mrna expression was -0.83 (p < 0.01). Overexpression of appl1 protein (hazard ratio: 3.88; 95% ci: 1.07 to 14.09) and mrna (hazard ratio: 4.23; 95% ci: 3.09 to 15.11) was a risk factor for death in patients with gc. CONCLUSIONS Expression of appl1 is increased in gc. Overexpression is prognostic for a lethal outcome.
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Affiliation(s)
- J S Zhai
- Postgraduate Team, Chinese pla General Hospital, Medical School of Chinese pla, Beijing, P.R.C.;; Department of Gastroenterology, Chinese pla 309 Hospital, Beijing, P.R.C
| | - J G Song
- Department of Gastroenterology, Chinese pla 309 Hospital, Beijing, P.R.C
| | - C H Zhu
- Department of Gastroenterology, Chinese pla 309 Hospital, Beijing, P.R.C
| | - K Wu
- Department of Gastroenterology, Chinese pla 309 Hospital, Beijing, P.R.C
| | - Y Yao
- Department of Gastroenterology, Chinese pla 309 Hospital, Beijing, P.R.C
| | - N Li
- Postgraduate Team, Chinese pla General Hospital, Medical School of Chinese pla, Beijing, P.R.C.;; Department of Gastroenterology, Chinese pla 309 Hospital, Beijing, P.R.C
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Duan LX, Zhao AG, Zheng J. Individualized molecular targeted therapy for gastric cancer based on human epidermal growth factor receptor 2 gene detection. Shijie Huaren Xiaohua Zazhi 2016; 24:1031-1039. [DOI: 10.11569/wcjd.v24.i7.1031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Compared with traditional chemotherapy drugs, molecular targeted drugs have the advantages of high specificity and fewer side effects. Human epidermal growth factor receptor 2 (HER2) has been a focus of research in recent years, although the relationship between HER2 and prognosis of gastric cancer remains controversial. With the advent of trastuzumab, lapatinib, pertuzumab and other anti-HER2 drugs, many clinical studies have achieved good results; however, there are still some patients with unsatisfactory results due to the occurrence of drug resistance. Finding solutions to overcome drug resistance can increase the efficacy, and individualized molecular targeted therapy can better benefit gastric cancer patients.
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Concordance rate between HER2 immunohistochemistry and in situ hybridization in gastric carcinoma: systematic review and meta-analysis. Int J Biol Markers 2016; 31:e1-10. [PMID: 26349670 DOI: 10.5301/jbm.5000171] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2015] [Indexed: 12/17/2022]
Abstract
PURPOSE The aim of this study was to investigate the diagnostic accuracy of HER2 immunohistochemistry (IHC) in gastric carcinoma (GC) through a systematic review, meta-analysis and diagnostic test accuracy review. METHOD The current study included 12,679 GC cases and 181 subsets in 45 eligible studies. We performed concordance analysis between HER2 IHC and in situ hybridization (ISH) in GC. Diagnostic test accuracy was analyzed and the area under the curve (AUC) on the summary receiver operating characteristic (SROC) curve was calculated. RESULTS HER2 amplification rates were 3.0%, 31.8%, and 93.0% in the IHC score 0/1+, 2+, and 3+ groups, respectively. The concordance rates between IHC and ISH were 0.969 (95% confidence interval [CI] 0.962-0.975), 0.393 (95% CI 0.331-0.458) and 0.915 (95% CI 0.882-0.939) in the HER2 IHC score 0/1+, 2+, and 3+ groups, respectively. For all the HER2 IHC score groups, the positive rates were higher in the silver ISH (SISH) subgroup than in the fluorescence ISH (FISH) and chromogenic ISH (CISH) subgroups. In diagnostic test accuracy review, the pooled sensitivity and specificity were 0.86 (95% CI 0.84-0.87) and 0.91 (95% CI 0.90-0.91). The AUC on SROC curve was 0.958. However, there was no significant difference in the values of AUC between the ISH methods. CONCLUSIONS Our results showed that HER2 IHC was well concordant with ISH in HER2 IHC score 0/1+ or 3+. Although this meta-analysis showed higher diagnostic accuracy of HER2 IHC, more detailed criteria for HER2 IHC score 2+ cases will be required to predict HER2 status.
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Expression and Prognostic Significance of Human Epidermal Growth Factor Receptors 1 and 3 in Gastric and Esophageal Adenocarcinoma. PLoS One 2016; 11:e0148101. [PMID: 26844548 PMCID: PMC4742525 DOI: 10.1371/journal.pone.0148101] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 01/13/2016] [Indexed: 01/08/2023] Open
Abstract
Background Gastric and esophageal adenocarcinomas are major global cancer burdens. These cancer forms are characterized by a poor prognosis and a modest response to chemo- radio- and targeted treatment. Hence there is an obvious need for further enhanced diagnostic and treatment strategies. The aim of this study was to examine the expression and prognostic impact of human epidermal growth factor receptor 1 (HER1/EGFR) and 3 (HER3), as well as the occurrence of EGFR and KRAS mutations in gastric and esophageal adenocarcinoma. Methods Immunohistochemical expression of EGFR and HER3 was analysed in all primary tumours and a subset of lymph node metastases in a consecutive cohort of 174 patients with adenocarcinoma of the stomach, cardia and esophagus. The anti-HER3 antibody used was validated by siRNA-mediated knockdown, immunohistochemistry and quantitative real-time PCR. EGFR and KRAS mutation status was analysed by pyrosequencing tecchnology. Results and Discussion High EGFR expression was an independent risk factor for shorter overall survival (OS), whereas high HER3 expression was associated with a borderline significant trend towards a longer OS. KRAS mutations were present in only 4% of the tumours and had no prognostic impact. All tumours were EGFR wild-type. These findings contribute to the ongoing efforts to decide on the potential clinical value of different HERs and druggable mutations in gastric and esophageal adenocarcinomas, and attention is drawn to the need for more standardised investigational methods.
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Ji K, Zhang L, Zhang M, Chu Q, Li X, Wang W. Prognostic Value and Clinicopathological Significance of p-stat3 Among Gastric Carcinoma Patients: A Systematic Review and Meta-Analysis. Medicine (Baltimore) 2016; 95:e2641. [PMID: 26844481 PMCID: PMC4748898 DOI: 10.1097/md.0000000000002641] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
The overexpression of phosphorylated signal transducer and activator of transcription 3 (p-stat3) was detected in a variety of human tumors. The published studies on p-stat3 expression among gastric carcinoma patients remain controversial.In order to clarify the prognosis value of p-stat3 with overall survival and its association with clinicopathological characteristics in gastric carcinoma, we performed a systematic review and meta-analysis.Eligible studies were retrieved by searching PubMed, Embase, Cochrane library, and Chinese biomedical literature service system databases.Studies described the association between p-stat3 expression and clinicopathological characteristics and overall survival in gastric carcinoma patients; p-stat3 expression was detected by immunohistochemistry (IHC).Odds ratio (OR) and hazard ratio (HR) were considered as a measure of evaluating the association in meta-analysis; I was used to assess the heterogeneity across studies; publication bias was assessed with funnel plot, Egger test, and Begg test.Twenty-three studies including 2872 patients which evaluated the p-stat3 expression by IHC in gastric carcinoma were included. The pooled HR (HR = 2.02, 95% CI: 1.49-2.73, P < 0.00001) indicated that the increased p-stat3 expression was significantly associated with poor overall survival. In addition, when we investigated the association between p-stat3 overexpression and clinicopathological characteristics of gastric carcinoma, we found that the increased p-stat3 expression was significantly associated with tumor differentiation (poorly vs well-moderately: OR = 3.70, 95% CI: 1.98-6.93, P < 0.0001) and lymph node metastasis (present vs absent: OR = 2.40, 95% CI: 1.28-4.50, P = 0.007).The different type of primary antibody was used; the assessment methods of p-stat3 positive expression were defined differently; the locations of p-stat3 expression were different; the method of extrapolating HR from Kaplan-Meier survival curves did seem to be less reliable than when HR was extracted directly from literatures; sample sizes, the age of patients, and the follow-up durations are different.In conclusion, our meta-analysis indicates that the increased p-stat3 expression may be not only predict poor prognosis, but also be associated with worse tumor differentiation and lymph node metastasis in patients with gastric carcinoma.
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Affiliation(s)
- Kun Ji
- From the Department of Pathophysiology, Shenyang Medical College, Shenyang (KJ, LZ); Grade 2012 Clinical Medicine, Shenyang Medical College, Shenyang (MZ, QC); Department of Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun (XL); and Department of Neurosurgery, The Second Clinical Medical School of Inner Mongolia University for the Nationalities (Inner Mongolia General Forestry Hospital), Inner Mongolia, China (WW)
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Jácome AA, Coutinho AK, Lima EM, Andrade AC, Santos JSD. Personalized medicine in gastric cancer: Where are we and where are we going? World J Gastroenterol 2016; 22:1160-71. [PMID: 26811654 PMCID: PMC4716027 DOI: 10.3748/wjg.v22.i3.1160] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 09/22/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
Despite improvements in adjuvant therapies for gastric cancer in recent years, the disease is characterized by high recurrence rates and a dismal prognosis. The major improvement in the treatment of recurrent or metastatic gastric cancer in recent years has been the incorporation of trastuzumab, a monoclonal antibody that inhibits human epidermal growth factor receptor 2 (HER2) heterodimerization, after the demonstrated predictive value of the overexpression and/or amplification of this receptor. Beyond HER2, other genetic abnormalities have been identified, and these mutations may be targetable by tyrosine kinase inhibitors or monoclonal antibodies. The demonstration of four distinct molecular subtypes of gastric cancer by the Cancer Genome Atlas study highlight the enormous heterogeneity of the disease and its complex interplay between genetic and epigenetic alterations and provide a roadmap to implement genome-guided personalized therapy in gastric cancer. In the present review, we aim to discuss, from a clinical point of view, the genomic landscape of gastric cancer described in recent studies, the therapeutic insights derived from these findings, and the clinical trials that have been conducted and those in progress that take into account tailored therapies for gastric cancer.
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Coccolini F, Montori G, Ceresoli M, Cima S, Valli MC, Nita GE, Heyer A, Catena F, Ansaloni L. Advanced gastric cancer: What we know and what we still have to learn. World J Gastroenterol 2016; 22:1139-1159. [PMID: 26811653 PMCID: PMC4716026 DOI: 10.3748/wjg.v22.i3.1139] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 09/25/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is a common neoplastic disease and, more precisely, is the third leading cause of cancer death in the world, with differences amongst geographic areas. The definition of advanced gastric cancer is still debated. Different stadiating systems lead to slightly different stadiation of the disease, thus leading to variations between the single countries in the treatment and outcomes. In the present review all the possibilities of treatment for advanced gastric cancer have been analyzed. Surgery, the cornerstone of treatment for advanced gastric cancer, is analyzed first, followed by an investigation of the different forms and drugs of chemotherapy and radiotherapy. New frontiers in treatment suggest the growing consideration for intraperitoneal administration of chemotherapeutics and combination of traditional drugs with new ones. Moreover, the necessity to prevent the relapse of the disease leads to the consideration of administering intraperitoneal chemotherapy earlier in the therapeutical algorithm.
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Wang YW, Zhu ML, Wang RF, Xue WJ, Zhu XR, Wang LF, Zheng LZ. Predictable factors for lymph node metastasis in early gastric cancer analysis of clinicopathologic factors and biological markers. Tumour Biol 2016; 37:8567-78. [PMID: 26733174 DOI: 10.1007/s13277-015-4721-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 12/21/2015] [Indexed: 12/29/2022] Open
Abstract
Predicting lymph node metastasis (LNM) accurately is very important to decide treatment strategies preoperatively. The aim of this study was to explore risk factors that predict the presence of LNM in early gastric cancer (EGC). A total of 230 patients with EGC who underwent curative gastrectomy with lymph adenectomy at Xinhua Hospital from January 2006 to July 2014 were retrospectively reviewed. We studied the relationship between clinicopathological factors, biological markers (p53, ki67, nm23, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), E-cadherin (E-cad), beta-catenin (b-catenin), glutathione S-transferase (GST), and topoisomerase II (Topo II)), and LNM of EGC patients by chi-square test and logistic regression analysis. Meta-analyses were further conducted to review the effects of the proteins (P53, ki67, E-cad, and b-catenin) on LNM in ECG patients. LNM was detected in 42 (18.3 %) of 230 patients. Incidences of LNM was distinct in different tumor size (p = 0.044), depth of submucosal invasion (p < 0.0001), and P53 overexpression (p = 0.004). Multivariate analysis further indentified that large tumor size (≥20 mm, odds ratio (OR) = 2.168, p = 0.041), submucosa (OR = 4.000, p = 0.0005), and P53 overexpression (OR = 3.010, p = 0.022) were independent risk factors of LNM in EGC patients. The meta-analysis revealed a significantly statistical association of P53, ki67, and b-catenin with an increased risk of LNM in EGC patients (P53, OR = 1.81, p = 0.017; ki67, OR = 2.53, p = 0.0003; b-catenin, OR = 0.53, p = 0.01). Tumor size (≥20 mm), the depth of invasion (submucosa), and P53 overexpression may be helpful predictors of LNM in EGC patients. Furthermore, the results of meta-analysis revealed that P53, ki67 overexpression, and abnormal expression of b-catenin may be associated with LNM in EGC. The results need further validation in single large studies.
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Affiliation(s)
- Yi-Wei Wang
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Mei-Ling Zhu
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Rui-Fen Wang
- Department of Pathology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Wen-Ji Xue
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Xue-Ru Zhu
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China
| | - Li-Feng Wang
- Department of Pathology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China.
| | - Lei-Zhen Zheng
- Department of Oncology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, NO.1665, Kong Jiang Road, Shanghai, 200092, People's Republic of China.
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Impact of c-erbB-2 protein on 5-year survival rate of gastric cancer patients after surgery: a cohort study and meta-analysis. TUMORI JOURNAL 2015; 103:249-254. [PMID: 26549693 DOI: 10.5301/tj.5000444] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2015] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To explore the association of c-erbB-2 protein expression with clinicopathological characteristics and prognosis of gastric cancer (GC) after surgery. METHODS A total of 133 patients undergoing surgical resection for GC between March 2006 and January 2009 in the Second Affiliated Hospital of Wenzhou Medical University were included in this study. c-erbB-2 protein expression was determined by immunohistochemistry. Afterwards, a meta-analysis was performed to further confirm the association between c-erbB-2 protein expression and GC by employing stringent inclusion and exclusion criteria. All data analyses were conducted with STATA 12.0 and SPSS 19.0. RESULTS There was no significant difference in c-erbB-2 expression among patients with various parameters including age, gender and histological types (all p>0.05). Among 133 GC patients, 32 patients presented c-erbB-2-positive expression and 101 presented c-erbB-2-negative expression (24.1% vs. 75.9%). The c-erbB-2-positive expression rate was significantly higher in GC tissues of patients with lymph node metastasis than those without. Similarly, a significant increase in c-erbB-2 expression was observed in well/moderately differentiated GC tissues compared with poorly differentiated GC. Patients with negative c-erbB-2 expression had a higher 5-year survival rate than those with positive c-erbB-2 expression, which was consistent with the results of the meta-analysis (OR = 0.54, 95% CI 0.37-0.80, p = 0.002). CONCLUSIONS Our study demonstrated that high expression of c-erbB-2 protein was strongly associated with lymph node metastasis, histological differentiation and 5-year survival rate in GC patients after surgery.
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Murphy AG, Lynch D, Kelly RJ. State of the art management of metastatic gastroesophageal cancer. ANNALS OF TRANSLATIONAL MEDICINE 2015; 3:236. [PMID: 26539453 DOI: 10.3978/j.issn.2305-5839.2015.09.19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The anatomical locations of upper gastrointestinal (GI) tumors have changed remarkably in the western world and reflect the increasing impact of obesity and gastroesophageal (GE) reflux rather than infectious etiologies. Incidence rates of GE tumors are rising rapidly and survival rates for patients with metastatic disease remain poor. Traditionally, cytotoxic chemotherapy has had some survival advantages but increasingly complex combination regimens are limited by toxicities. The advent of molecularly targeted therapy has provided additional options for patients with advanced disease including trastuzumab and ramucirumab. There has also been detailed molecular characterization of upper GI tumors which hopefully will result in improved tailoring of clinical trial design accounting for the heterogeneity inherent in GE tumors. While numerous targeted therapies are currently being studied in clinical trials, there is much excitement regarding the role of immunotherapy in GE cancers. Although further investigation is warranted, it represents a promising avenue for patients with advanced GE tumors.
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Affiliation(s)
- Adrian G Murphy
- 1 Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA ; 2 Faculty of Education & Health Services, University of Limerick, Limerick, Ireland
| | - David Lynch
- 1 Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA ; 2 Faculty of Education & Health Services, University of Limerick, Limerick, Ireland
| | - Ronan J Kelly
- 1 Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA ; 2 Faculty of Education & Health Services, University of Limerick, Limerick, Ireland
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HER2 Status in Premalignant, Early, and Advanced Neoplastic Lesions of the Stomach. DISEASE MARKERS 2015; 2015:234851. [PMID: 26494937 PMCID: PMC4606090 DOI: 10.1155/2015/234851] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 07/30/2015] [Indexed: 02/06/2023]
Abstract
Objectives. HER2 expression in gastric cancer (GC) has received attention as
a potential target for therapy with Trastuzumab. We reviewed the current knowledge on HER2
status in premalignant gastric lesions and in early (EGC) and advanced (AGC) GC to discuss
the possible pathogenetic and prognostic roles of HER2 overexpression in GC. Results.
HER2 overexpression was documented in gastric low-grade (LG) and high-grade intraepithelial neoplasia
(HG-IEN), with higher frequency in gastric type dysplasia. HER2 overexpression was significantly
associated with disease recurrence and poor prognosis in EGC representing an independent risk
factor for lymph node metastases. HER2 overexpression was more frequent in AGC characterized
by high grade, advanced stage, and high Ki-67 labeling index. The discordance in HER2
status was evidenced between primitive GC and synchronous or metachronous
metastases. Conclusions. HER2 overexpression in premalignant gastric
lesions suggests its potential involvement in the early steps of gastric carcinogenesis.
The assessment of HER2 status in EGC may be helpful for the identification of patients
who are at low risk for developing nodal metastases. Finally, the possible discordance in
HER2 status between primary GC and its synchronous metastases support routine assessment
of HER2 both in the primary GC and in its metastatic lesions.
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Jiang W, Jin Z, Zhou F, Cui J, Wang L, Wang L. High co-expression of Sp1 and HER-2 is correlated with poor prognosis of gastric cancer patients. Surg Oncol 2015; 24:220-5. [PMID: 26096373 DOI: 10.1016/j.suronc.2015.05.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Revised: 04/09/2015] [Accepted: 05/19/2015] [Indexed: 10/23/2022]
Abstract
The aim of this study was to investigate co-expression of HER-2 and Sp1 in gastric cancer (GC) so as to determine whether these two proteins may be correlated with poor prognosis of GC patients. We examined the HER-2 overexpression and amplification and expression levels of Sp1 in 227 GC patients using immune-histochemical staining and fluorescence in situ hybridization. Data on clinicopathological features and relevant prognostic factors in these patients were analyzed. Of the 227 gastric cancer samples, 11.89% were positive for HER-2 overexpression/amplification under the new scoring system, and the frequency of negative, weak positive and strong positive expression of Sp1 was 14.98%, 48.01% and 37.0% respectively. No statistically positive correlation was observed between the expression levels of HER-2 and Sp1 in GC tissues. HER-2 overexpression was closely correlated to the Lauren type, degree of differentiation, tumor size and lymph node metastasis, and Sp1 as well (P < 0.05). Overexpression of HER-2 and Sp1 predicted poor survival in univariate analysis as well as in a Cox proportional hazards model.
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Affiliation(s)
- Weihua Jiang
- Department of Oncology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai 200080, People's Republic of China
| | - Ziliang Jin
- Department of Oncology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai 200080, People's Republic of China
| | - Fei Zhou
- Department of Oncology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai 200080, People's Republic of China
| | - Jiujie Cui
- Department of Oncology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai 200080, People's Republic of China
| | - Lei Wang
- Department of Oncology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai 200080, People's Republic of China
| | - Liwei Wang
- Department of Oncology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai 200080, People's Republic of China.
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Jun KH, Lee JE, Kim SH, Jung JH, Choi HJ, Kim YI, Chin HM, Yang SH. Clinicopathological significance of N-cadherin and VEGF in advanced gastric cancer brain metastasis and the effects of metformin in preclinical models. Oncol Rep 2015; 34:2047-53. [PMID: 26260219 DOI: 10.3892/or.2015.4191] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 06/26/2015] [Indexed: 11/05/2022] Open
Abstract
Gastric cancer is the second most common cause of cancer-related death worldwide. Although brain metastasis is a rare complication of gastric cancer, no standard therapy for gastric cancer brain metastasis has been established. We attempted to identify biological markers that predict brain metastasis, and investigated how to modulate such markers. A case-control study of patients newly diagnosed with gastric cancer who had developed brain metastasis during follow-up, was conducted. These patients were compared with patients who had advanced gastric cancer but no evidence of brain metastasis. Immunohistochemistry was used to analyze the expression of E-cadherin, N-cadherin, MSS1, claudin-3, claudin-4, Glut1, clusterin, ITGB4, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and p53. The expression of VEGF tended to be higher in the case group (33.3 vs. 0%, p=0.055). Median survival was significantly correlated with vascular invasion (12 vs. 33 months, p=0.008) and N-cadherin expression (36 vs. 12 months, p=0.027). We also investigated the effects of metformin in tumor-bearing mouse models. VEGF expression was decreased and E-cadherin increased in the metformin‑treated group when compared with the control group. The expression of the mesenchymal marker MMP9 was decreased in the metformin-treated group. Brain metastasis of advanced gastric cancer was associated with the expression of VEGF. Metformin treatment may be useful for modulating the metastatic capacity by reducing VEGF expression and blocking epithelial-to-mesenchymal transition.
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Affiliation(s)
- Kyong-Hwa Jun
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea
| | - Jung Eun Lee
- Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea
| | - Se Hoon Kim
- Department of Pathology, Yonsei University of College of Medicine, Seoul, Republic of Korea
| | - Ji-Han Jung
- Department of Hospital Pathology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea
| | - Hyun-Joo Choi
- Department of Hospital Pathology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea
| | - Young Il Kim
- Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea
| | - Hyung-Min Chin
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea
| | - Seung-Ho Yang
- Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea
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Seo JY, Jin EH, Jo HJ, Yoon H, Shin CM, Park YS, Kim N, Jung HC, Lee DH. Clinicopathologic and molecular features associated with patient age in gastric cancer. World J Gastroenterol 2015; 21:6905-6913. [PMID: 26078567 PMCID: PMC4462731 DOI: 10.3748/wjg.v21.i22.6905] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 01/10/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare characteristics and prognosis of gastric cancer based on age.
METHODS: A retrospective study was conducted on clinical and molecular data from patients (n = 1658) with confirmed cases of gastric cancer in Seoul National University Bundang Hospital (Seoul, South Korea) from 2003 to 2010 after exclusion of patients diagnosed with lymphoma, gastrointestinal stromal tumor, and metastatic cancer in the stomach. DNA was isolated from tumor and adjacent normal tissue, and a set of five markers was amplified by polymerase chain reaction to assess microsatellite instability (MSI). MSI was categorized as high, low, or stable if ≥ 2, 1, or 0 markers, respectively, had changed. Immunohistochemistry was performed on tissue sections to detect levels of expression of p53, human epidermal growth factor receptor (HER)-2, and epidermal growth factor receptor. Statistical analysis of clinical and molecular data was performed to assess prognosis based on the stratification of patients by age (≤ 45 and > 45 years).
RESULTS: Among the 1658 gastric cancer patients, the number of patients with an age ≤ 45 years was 202 (12.2%; 38.9 ± 0.4 years) and the number of patients > 45 years was 1456 (87.8%; 64.1 ± 0.3 years). Analyses revealed that females were predominant in the younger group (P < 0.001). Gastric cancers in the younger patients exhibited more aggressive features and were at a more advanced stage than those in older patients. Precancerous lesions, such as atrophic gastritis and intestinal metaplasia, were observed less frequently in the older than in the younger group (P < 0.001). Molecular characteristics, including overexpression of p53 (P < 0.001), overexpression of HER-2 (P = 0.006), and MSI (P = 0.006), were less frequent in gastric cancer of younger patients. Cancer related mortality was higher in younger patients (P = 0.048), but this difference was not significant after adjusting for the stage of cancer.
CONCLUSION: Gastric cancer is distinguishable between younger and older patients based on both clinicopathologic and molecular features, but stage is the most important predictor of prognosis.
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Single nucleotide polymorphisms in AREG and EREG are prognostic biomarkers in locally advanced gastric cancer patients after surgery with curative intent. Pharmacogenet Genomics 2015; 24:539-47. [PMID: 25203737 DOI: 10.1097/fpc.0000000000000087] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Amphiregulin (AREG) and epiregulin (EREG) are important ligands to the epithelial growth factor receptor, which is involved in the regulation of progression and stemness in gastric cancer (GC). This study investigated whether frequent single nucleotide polymorphisms (SNPs) in genes of AREG and EREG are associated with recurrence-free survival and overall survival in patients with locally advanced GC. METHODS SNPs with a minor allele frequency of at least 10% were analyzed using direct DNA sequencing in two independent study populations. RESULTS The minor allele of AREG rs1615111 was associated with a significantly higher 3-year recurrence rate and lower 3-year survival rate [hazard ratio (HR)=2.21 and 2.35, respectively] compared with patients homozygous for the dominant allele G. The value for overall survival could be validated with a HR of 2.54 (P=0.018) in an independent cohort. Patients homozygous for the minor allele A of EREG rs12641042 had a significantly higher 3-year survival rate than patients with allele C (HR 0.48; P=0.034), but significance was lost in multivariable analysis (P=0.066). The value of rs12641042 could not be validated (P=0.98). Exploratory multivariable subgroup analysis showed the strongest prognostic value for rs1615111 in tumors with a diffuse histology (Pfor interaction=0.004). CONCLUSION AREG rs1615111, located in the AREG genomic region, can significantly define different prognostic cohorts in locally advanced GC. This value is most evident in GC patients with diffuse histology, which might be relevant as none of the trials testing epithelial growth factor receptor inhibitors has been enriched for diffuse histology or a molecularly defined population.
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Gao W, Xu J, Wang F, Zhang L, Peng R, Shu Y, Wu J, Tang Q, Zhu Y. Plasma membrane proteomic analysis of human Gastric Cancer tissues: revealing flotillin 1 as a marker for Gastric Cancer. BMC Cancer 2015; 15:367. [PMID: 25948494 PMCID: PMC4525731 DOI: 10.1186/s12885-015-1343-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Accepted: 04/22/2015] [Indexed: 02/07/2023] Open
Abstract
Background Gastric cancer remains the second leading cause of cancer-related deaths in the world. Successful early gastric cancer detection is hampered by lack of highly sensitive and specific biomarkers. Plasma membrane proteins participate and/or have a central role in the metastatic process of cancer cells and are potentially useful for cancer therapy due to easy accessibility of the targets. Methods In the present research, TMT method followed by mass spectrometry analysis was used to compare the relative expression levels of plasma membrane proteins between noncancer and gastric cancer tissues. Results Of a total data set that included 501 identified proteins, about 35% of the identified proteins were found to be plasma membrane and associated proteins. Among them, 82 proteins were at least 1.5-fold up- or down-regulated in gastric cancer compared with the adherent normal tissues. Conclusions A number of markers (e.g. annexin A6, caveolin 1, epidermal growth factor receptor, integrin beta 4) were previously reported as biomarkers of GC. Additionally, several potential biomarkers participated in endocytosis pathway and integrin signaling pathways were firstly identified as differentially expressed proteins in GC samples. Our findings also supported the notion that flotillin 1 is a potential biomarker that could be exploited for molecular imaging-based detection of gastric cancer. Together, the results show that subcellular proteomics of tumor tissue is a feasible and promising avenue for exploring oncogenesis. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1343-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wen Gao
- Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 GuangZhou Road, Nanjing, 210029, China. .,Department of Oncology, The first affiliated hospital of Nanjing medical university, 300 GuangZhou Road, Nanjing, 210029, China.
| | - Jing Xu
- Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 GuangZhou Road, Nanjing, 210029, China. .,Department of Oncology, The first affiliated hospital of Nanjing medical university, 300 GuangZhou Road, Nanjing, 210029, China.
| | - Fuqiang Wang
- Analysis Center of Nanjing Medical University, 104 Hanzhong Road, 210009, Nanjing, China.
| | - Long Zhang
- Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 GuangZhou Road, Nanjing, 210029, China.
| | - Rui Peng
- Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 GuangZhou Road, Nanjing, 210029, China.
| | - Yongqian Shu
- Department of Oncology, The first affiliated hospital of Nanjing medical university, 300 GuangZhou Road, Nanjing, 210029, China.
| | - Jindao Wu
- Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 GuangZhou Road, Nanjing, 210029, China.
| | - Qiyun Tang
- Department of Gastroenterology, The first affiliated hospital of Nanjing medical university, 300 GuangZhou Road, Nanjing, 210029, China.
| | - Yunxia Zhu
- Analysis Center of Nanjing Medical University, 104 Hanzhong Road, 210009, Nanjing, China.
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Thiel A, Ristimäki A. Targeted therapy in gastric cancer. APMIS 2015; 123:365-72. [PMID: 25706252 DOI: 10.1111/apm.12359] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 11/27/2014] [Indexed: 12/20/2022]
Abstract
Gastric cancer is often diagnosed at an advanced stage. Although chemotherapy prolongs survival and improves quality of life, the survival of gastric cancer patients with advanced disease is short. Thanks to recent insights into the molecular pathways involved in gastric carcinogenesis, new targeted treatment options have become available for gastric cancer patients. Trastuzumab, an antibody targeted to HER-2, was shown to improve survival of advanced gastric cancer patients harboring HER-2 overexpression due to gene amplification in their tumor cells, and is currently also explored in adjuvant and neoadjuvant settings. Another agent with promising results in clinical trials is ramucirumab, an antibody targeting VEGFR-2. No clear survival benefit, however, were experienced with agents targeting EGFR (cetuximab, panitumumab), VEGF-A (bevacizumab), or mTOR (everolimus). Drugs targeting c-MET/HGF are currently under investigation in biomarker-selected cohorts, with promising results in early clinical trials. This review will summarize the current status of targeted treatment options in gastric cancer.
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Affiliation(s)
- Alexandra Thiel
- Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland; Genome-Scale Biology, Research Programs Unit, University of Helsinki, Helsinki, Finland
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Nagaraja V, Eslick GD. HER2 expression in gastric and oesophageal cancer: a meta-analytic review. J Gastrointest Oncol 2015; 6:143-54. [PMID: 25830034 DOI: 10.3978/j.issn.2078-6891.2014.107] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 12/08/2014] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Since the advent and the success of adjuvant medical therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the form of trastuzumab there has been increasing interest in the development of similar therapies in other solid organ malignancies including gastric cancer and oesophageal cancer. Over the years, multiple observational studies have been inconsistent. Several meta-analyses have been published looking at the association between HER2 and gastric cancer and oesophageal cancer. This review aims to summarize the meta-analytic evidence for the association between HER2 in gastric and oesophageal cancer. METHODS A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane Library, Google Scholar, Science Direct, and Web of Science. RESULTS Of the articles selected, only nine studies met full criteria. Six of them reviewed the role of HER2 in gastric cancer and the remaining three reviewed its role in oesophageal cancer. CONCLUSIONS The current evidence regarding the role of HER2 is unclear. However, it clearly plays a key role in the pathogenesis of gastric and oesophageal carcinomas. Targeted therapy towards this subgroup (despite variable frequency and association with survival) would offer a mortality benefit and improve survival.
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Affiliation(s)
- Vinayak Nagaraja
- The Whiteley-Martin Research Centre, Discipline of Surgery, The Sydney Medical School Nepean, Penrith, NSW 2751, Australia
| | - Guy D Eslick
- The Whiteley-Martin Research Centre, Discipline of Surgery, The Sydney Medical School Nepean, Penrith, NSW 2751, Australia
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Martin V, Cappuzzo F, Mazzucchelli L, Frattini M. HER2 in solid tumors: more than 10 years under the microscope; where are we now? Future Oncol 2015; 10:1469-86. [PMID: 25052756 DOI: 10.2217/fon.14.19] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
HER2 is a well-recognized mediator of the cancerogenic process. It is dysregulated in a wide range of solid tumors, mainly via protein overexpression and/or gene amplification, thus making HER2 an attractive target for tailored treatment. The anti-HER2 therapy trastuzumab was approved for the treatment of HER2-positive metastatic breast cancer patients more than 10 years ago. Since then, trastuzumab and other HER2-inhibitors have been entered into clinical practice for the treatment of breast cancer and, more recently, have been approved to treat HER2-positive metastatic gastric cancers. Currently, HER2-targeted therapies are under evaluation in other tumor types. Due to the relevance of proper patient selection, the accurate assessment of HER2 status is fundamental. This review will discuss the established knowledge and novel insights into the HER2 story, mainly focusing on breast, gastric and colorectal cancers, as well as providing a brief overview of salivary gland, bladder, ovarian and lung tumors.
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Affiliation(s)
- Vittoria Martin
- Institute of Pathology, Via in Selva 24, 6600 Locarno, Switzerland
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Li Y, Wang X, Vural S, Mishra NK, Cowan KH, Guda C. Exome analysis reveals differentially mutated gene signatures of stage, grade and subtype in breast cancers. PLoS One 2015; 10:e0119383. [PMID: 25803781 PMCID: PMC4372331 DOI: 10.1371/journal.pone.0119383] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 01/30/2015] [Indexed: 12/17/2022] Open
Abstract
Breast cancers exhibit highly heterogeneous molecular profiles. Although gene expression profiles have been used to predict the risks and prognostic outcomes of breast cancers, the high variability of gene expression limits its clinical application. In contrast, genetic mutation profiles would be more advantageous than gene expression profiles because genetic mutations can be stably detected and the mutational heterogeneity widely exists in breast cancer genomes. We analyzed 98 breast cancer whole exome samples that were sorted into three subtypes, two grades and two stages. The sum deleterious effect of all mutations in each gene was scored to identify differentially mutated genes (DMGs) for this case-control study. DMGs were corroborated using extensive published knowledge. Functional consequences of deleterious SNVs on protein structure and function were also investigated. Genes such as ERBB2, ESP8, PPP2R4, KIAA0922, SP4, CENPJ, PRCP and SELP that have been experimentally or clinically verified to be tightly associated with breast cancer prognosis are among the DMGs identified in this study. We also identified some genes such as ARL6IP5, RAET1E, and ANO7 that could be crucial for breast cancer development and prognosis. Further, SNVs such as rs1058808, rs2480452, rs61751507, rs79167802, rs11540666, and rs2229437 that potentially influence protein functions are observed at significantly different frequencies in different comparison groups. Protein structure modeling revealed that many non-synonymous SNVs have a deleterious effect on protein stability, structure and function. Mutational profiling at gene- and SNV-level revealed differential patterns within each breast cancer comparison group, and the gene signatures correlate with expected prognostic characteristics of breast cancer classes. Some of the genes and SNVs identified in this study show high promise and are worthy of further investigation by experimental studies.
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Affiliation(s)
- You Li
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Xiaosheng Wang
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Suleyman Vural
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Nitish K. Mishra
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Kenneth H. Cowan
- Fred and Pamela Buffett Cancer Center, Nebraska Medical Center, Omaha, Nebraska, United States of America
- Eppley Institute for Cancer Research, Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Chittibabu Guda
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- Fred and Pamela Buffett Cancer Center, Nebraska Medical Center, Omaha, Nebraska, United States of America
- Eppley Institute for Cancer Research, Nebraska Medical Center, Omaha, Nebraska, United States of America
- Bioinformatics and Systems Biology Core, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- * E-mail:
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Murphy A, Kelly RJ. From molecular classification to targeted therapeutics: the changing face of systemic therapy in metastatic gastroesophageal cancer. Gastroenterol Res Pract 2015; 2015:896560. [PMID: 25784931 PMCID: PMC4346691 DOI: 10.1155/2015/896560] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 01/15/2015] [Indexed: 01/14/2023] Open
Abstract
Histological classification of adenocarcinoma or squamous cell carcinoma for esophageal cancer or using the Lauren classification for intestinal and diffuse type gastric cancer has limited clinical utility in the management of advanced disease. Germline mutations in E-cadherin (CDH1) or mismatch repair genes (Lynch syndrome) were identified many years ago but given their rarity, the identification of these molecular alterations does not substantially impact treatment in the advanced setting. Recent molecular profiling studies of upper GI tumors have added to our knowledge of the underlying biology but have not led to an alternative classification system which can guide clinician's therapeutic decisions. Recently the Cancer Genome Atlas Research Network has proposed four subtypes of gastric cancer dividing tumors into those positive for Epstein-Barr virus, microsatellite unstable tumors, genomically stable tumors, and tumors with chromosomal instability. Unfortunately to date, many phase III clinical trials involving molecularly targeted agents have failed to meet their survival endpoints due to their use in unselected populations. Future clinical trials should utilize molecular profiling of individual tumors in order to determine the optimal use of targeted therapies in preselected patients.
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Affiliation(s)
- Adrian Murphy
- Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
| | - Ronan J. Kelly
- Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
- Gastroesophageal Cancer Therapeutics Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Room G93, Baltimore, MD 21231, USA
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Liu Y, Gao JB, Yue SW, Liu J, Gao XZ, Zheng Y, Zhang YL. Correlation between CT contrast enhancement ratio and CT perfusion parameters and expression of HER2 in gastric cancer. Shijie Huaren Xiaohua Zazhi 2015; 23:426-431. [DOI: 10.11569/wcjd.v23.i3.426] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the correlation between the computed tomography (CT) contrast enhancement ratio (CER) in arterial phase and venous phase, CT perfusion parameters and expression of human epidermal growth factor receptor 2 (HER2) in pathologically proven gastric cancer.
METHODS: A retrospective analysis of triple-phase CER was performed on 105 patients who underwent MSCT. A retrospective analysis of CT perfusion parameters including maximal arterial flow (AF), blood volume (BV), blood flow (BF) and clearance (CL) was performed on 50 patients who underwent 320-detector-row CT perfusion. The expression of HER2 was detected by immunohistochemistry in all the patients. The differences in CER and CT perfusion parameters between the HER2-negative and HER2-positive groups were analyzed.
RESULTS: The triple-phase CER values in the HER2-negative group were 0.65±0.35, 1.18±0.53 and 2.62±1.41, respectively; the corresponding values in the HER2-positive group were 0.78±0.44, 1.47±0.61 and 2.37±1.36. CER in the venous phase was significantly higher in the HER2-positive group than in the HER2-negative group ((P = 0.010), although CER values in the arterial phase and arterial-venous phase were not significantly different ((P = 0.094, 0.597). The perfusion parameters in the HER2-negative group were as follows: AF = 117.15 mL/(100 mL·min) ± 31.56 mL/(100 mL·min), BV = 20.69 mL/100 Ml ± 13.41 mL/100 mL, BF = 6.42 mL/(100 mL·min) ± 4.25 mL/(100 mL·min), and CL = 4.46 1/s ± 2.25 1/s; the corresponding values in the HER2-positive group were 119.08 mL/(100 mL·min) ± 41.97 mL/(100 mL·min), 20.07 mL/100 mL ± 14.46 mL/100 mL, 6.39 mL/(100 mL·min) ± 3.68 mL/(100 mL·min), and 5.63 1/s ± 2.90 1/s. There was no significant difference in AF, BV, BF or CL between the two groups ((P = 0.888, 0.886, 0.979 and 0.123, respectively).
CONCLUSION: The CER in venous phase is significantly higher in the HER2-positive group than in the HER2-negative group, but there is no significant difference in the CT perfusion parameters.
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Jin EH, Lee DH, Jung SA, Shim KN, Seo JY, Kim N, Shin CM, Yoon H, Jung HC. Clinicopathologic factors and molecular markers related to lymph node metastasis in early gastric cancer. World J Gastroenterol 2015; 21:571-577. [PMID: 25593477 PMCID: PMC4294168 DOI: 10.3748/wjg.v21.i2.571] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 07/09/2014] [Accepted: 07/25/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze predictive factors for lymph node metastasis in early gastric cancer.
METHODS: We analyzed 1104 patients with early gastric cancer (EGC) who underwent a gastrectomy with lymph-node dissection from May 2003 through July 2011. The clinicopathologic factors and molecular markers were assessed as predictors for lymph node metastasis. Molecular markers such as microsatellite instability, human mutL homolog 1, p53, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) were included. The χ2 test and logistic regression analysis were used to determine clinicopathologic parameters.
RESULTS: Lymph node metastasis was observed in 104 (9.4%) of 1104 patients. Among 104 cases of lymph node positive patients, 24 patients (3.8%) were mucosal cancers and 80 patients (16.7%) were submucosal. According to histologic evaluation, the number of lymph node metastasis found was 4 (1.7%) for well differentiated tubular adenocarcinoma, 45 (11.3%) for moderately differentiated tubular adenocarcinoma, 36 (14.8%) for poorly differentiated tubular adenocarcinoma, and 19 (8.4%) for signet ring cell carcinoma. Of 690 EGC cases, 77 cases (11.2%) showed EGFR overexpression. HER2 overexpression was present in 110 cases (27.1%) of 406 EGC patients. With multivariate analysis, female gender (OR = 2.281, P = 0.009), presence of lymphovascular invasion (OR = 10.950, P < 0.0001), diameter (≥ 20 mm, OR = 3.173, P = 0.01), and EGFR overexpression (OR = 2.185, P = 0.044) were independent risk factors for lymph node involvement.
CONCLUSION: Female gender, tumor size, lymphovascular invasion and EGFR overexpression were predictive risk factors for lymph node metastasis in EGC.
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