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Xu Q, Yin Z, Li Y, Zhu X, Lou H, Ni J. Prognostic value of HER2 expression in cervical adenocarcinoma: A retrospective cohort study. Oncol Lett 2025; 29:217. [PMID: 40093868 PMCID: PMC11907399 DOI: 10.3892/ol.2025.14963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 01/30/2025] [Indexed: 03/19/2025] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is an important therapeutic target in various types of cancer, although the prognostic value and therapeutic potential of HER2 in cervical adenocarcinoma are still underexplored. The present study aimed to examine the association between HER2 expression levels and prognosis in cervical adenocarcinoma, offering new insights into targeted therapies for HER2-expressing cervical adenocarcinoma. A total of 179 patients with cervical cancer who received surgery were included, and HER2 status in surgical specimens of the included patients were assessed using two classification methods: Immunohistochemistry (IHC) alone and traditional combined IHC/fluorescence in situ hybridization (FISH). IHC alone was used to categorize patients into the HER2 zero expression (IHC 0) and HER2 expression (IHC 1+, 2+ and 3+) groups, while traditional combined IHC/FISH classified the HER2 expression as negative (IHC 0 and 1+ or IHC 2+/FISH-) or positive (IHC 3+ or IHC 2+/FISH+). Kaplan-Meier survival analysis and log-rank tests were used to assess the patients' survival prognosis. A Cox proportional hazards regression model was used to identify independent prognostic factors. The HER2 expression rate was 44.1% (79/179) according to IHC alone, while 5.0% (9/179) were classified as HER2-positive according to the traditional method. HER2 expression was significantly associated with advanced International Federation of Gynecology and Obstetrics stages, higher rates of lymph node metastasis, vascular or perineural invasion, elevated cancer antigen 125 levels and increased recurrence rate (P<0.05). Moreover, HER2 expression was significantly associated with shorter progression-free survival (PFS) time [51.02±2.75 vs. 56.01±2.22 months; hazard ratio (HR), 0.559; 95% confidence interval (CI), 0.313-0.998; P=0.049]. Additionally, programmed death-ligand 1 expression levels were significantly higher in HER2-expressing patients who died (P=0.039). When HER2 status was assessed using the traditional combined IHC/FISH method, HER2 positivity was significantly associated with poorer PFS time (36.44±7.85 vs. 55.17±1.78 months; HR, 0.125; 95% CI, 0.03033-0.5156; P=0.004). In conclusion, classification of HER2 status in patients with cervical adenocarcinoma using IHC alone may provide a promising method for predicting patient outcomes and optimizing therapeutic strategies to improve treatment efficacy.
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Affiliation(s)
- Qing Xu
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Zhuomin Yin
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Yueqi Li
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Xiu Zhu
- Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Hanmei Lou
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Juan Ni
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
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Wang X, Hui H, Han J, Guo T, Wang Y, Meng L, Chen C, He J, Guo X, Zhong F, Du H, Tian J, Xing X, Du Y, Ji J. A CLDN18.2-Targeted Nanoplatform Manipulates Magnetic Hyperthermia Spatiotemporally for Synergistic Immunotherapy in Gastric Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413913. [PMID: 40019387 PMCID: PMC12021038 DOI: 10.1002/advs.202413913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 01/06/2025] [Indexed: 03/01/2025]
Abstract
Precision treatment of gastric cancer requires specific biomarkers, and CLDN18.2 emerges as a promising target for patients' stratification and therapeutic guidance. In 563 cases, 54.4% of patients are identified as CLDN18.2-positive, with CLDN18.2 expression negatively correlated with immune-related factors like PD-L1, indicating a "cold" tumor microenvironment. Here, a novel CLDN18.2 monoclonal antibody 1D5 is created with superior high specificity and affinity, and the antibody-dependent fluorescence-magnetic nanoparticle is developed for specific detection and magnetic hyperthermia (MHT). Under the assistance of sensitive fluorescence and deep-penetrating magnetic particle imaging for tracing and timing the optimal nanoparticle dosage, MHT induces robust immunogenic response via DNA mismatch repair and tumor-associated antigen release. It recruits CD11c+ dendritic cells, compensates PD-1 in CD8+ T cells, and enhances CD86+ macrophage polarization. The combination of anti-PD-1 therapy increased TNF-α and IFN-γ secretion and further boosted the cytotoxic efficacy of CD8+ T cells. Excellent therapeutic efficacy is found simultaneously on cell-derived allografts and patient-derived xenografts based on this spatiotemporally manipulated strategy, presenting a therapeutic option for enhancing responsiveness to immunotherapy for CLDN18.2-positive individuals.
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Affiliation(s)
- Xueying Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Gastrointestinal Cancer Translational ResearchPeking University Cancer Hospital & InstituteBeijing100142China
- CAS Key Laboratory of Molecular ImagingInstitute of AutomationChinese Academy of SciencesBeijing100190China
| | - Hui Hui
- CAS Key Laboratory of Molecular ImagingInstitute of AutomationChinese Academy of SciencesBeijing100190China
- University of Chinese Academy of SciencesBeijing100080China
| | - Jing Han
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Gastrointestinal Cancer Translational ResearchPeking University Cancer Hospital & InstituteBeijing100142China
- CAS Key Laboratory of Molecular ImagingInstitute of AutomationChinese Academy of SciencesBeijing100190China
| | - Ting Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Gastrointestinal Cancer Translational ResearchPeking University Cancer Hospital & InstituteBeijing100142China
| | - Yiding Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Gastrointestinal Cancer Translational ResearchPeking University Cancer Hospital & InstituteBeijing100142China
| | - Lin Meng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Department of Biochemistry and Molecular BiologyPeking University Cancer Hospital & InstituteBeijing100142China
| | - Cong Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Gastrointestinal Cancer Translational ResearchPeking University Cancer Hospital & InstituteBeijing100142China
| | - Jie He
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Gastrointestinal Cancer Translational ResearchPeking University Cancer Hospital & InstituteBeijing100142China
- School of Engineering Medicine & School of Biological Science and Medical EngineeringBeihang UniversityBeijing100191China
| | - Xiaoyong Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Gastrointestinal Cancer Translational ResearchPeking University Cancer Hospital & InstituteBeijing100142China
| | - Fuyu Zhong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Gastrointestinal Cancer Translational ResearchPeking University Cancer Hospital & InstituteBeijing100142China
| | - Hong Du
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Gastrointestinal Cancer Translational ResearchPeking University Cancer Hospital & InstituteBeijing100142China
| | - Jie Tian
- School of Engineering Medicine & School of Biological Science and Medical EngineeringBeihang UniversityBeijing100191China
- Key Laboratory of Big Data‐Based Precision Medicine (Beihang University)Ministry of Industry and Information Technology of ChinaBeijing100191China
| | - Xiaofang Xing
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersBeijing Key Laboratory of Carcinogenesis and Translational ResearchGastrointestinal Cancer CentrePeking University Cancer Hospital & InstituteBeijing100142China
| | - Yang Du
- CAS Key Laboratory of Molecular ImagingInstitute of AutomationChinese Academy of SciencesBeijing100190China
- University of Chinese Academy of SciencesBeijing100080China
| | - Jiafu Ji
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal CancersBeijing Key Laboratory of Carcinogenesis and Translational ResearchGastrointestinal Cancer CentrePeking University Cancer Hospital & InstituteBeijing100142China
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Hoyek C, Zheng-Lin B, Jones J, Bekaii-Saab T. Tucatinib in the treatment of HER2-overexpressing gastrointestinal cancers: current insights and future prospects. Expert Opin Investig Drugs 2025; 34:161-168. [PMID: 40019490 DOI: 10.1080/13543784.2025.2472411] [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: 08/14/2024] [Accepted: 02/23/2025] [Indexed: 03/01/2025]
Abstract
INTRODUCTION Over the past 20 years, the treatment landscape of HER2-amplified tumors has considerably evolved. Until now, no approved targeted therapies were available for patients with HER2-amplified metastatic colorectal cancer (mCRC). Tucatinib, a highly selective tyrosine kinase inhibitor, demonstrated significant efficacy in combination with trastuzumab in patients with refractory mCRC, leading to its approval by the Food and Drug Administration (FDA). AREAS COVERED This review dives into the efficacy of tucatinib-based regimens in gastrointestinal malignancies, with a focus on the pivotal MOUNTAINEER trial, which led to the FDA approval of tucatinib plus trastuzumab in chemo-refractory HER2-amplified mCRC. Additionally, ongoing trials are exploring tucatinib in earlier treatment lines and across other gastrointestinal cancers, including biliary tract, gastric, and pancreatic malignancies. The mechanistic basis of dual HER2 inhibition and its implications for clinical practice are discussed. EXPERT COMMENTARY The future of tucatinib-based therapeutic strategies in GI malignancies depends on their integration into different treatment lines. Addressing acquired resistance using liquid biopsy-guided strategies and other TKIs like lapatinib will be paramount to improve outcomes.
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Affiliation(s)
- Celine Hoyek
- Department of Hematology and Oncology, Mayo Clinic, Arizona, AZ, USA
| | - Binbin Zheng-Lin
- Department of Hematology and Oncology, Mayo Clinic, Arizona, AZ, USA
| | - Jeremy Jones
- Department of Hematology and Oncology, Mayo Clinic, Florida, FL, USA
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Korpan M, Puhr HC, Berger JM, Friedrich A, Prager GW, Preusser M, Ilhan-Mutlu A. Current Landscape of Molecular Biomarkers in Gastroesophageal Tumors and Potential Strategies for Co-Expression Patterns. Cancers (Basel) 2025; 17:340. [PMID: 39941712 PMCID: PMC11816248 DOI: 10.3390/cancers17030340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/14/2025] [Accepted: 01/18/2025] [Indexed: 02/16/2025] Open
Abstract
The treatment of metastasized gastroesophageal adenocarcinoma largely depends on molecular profiling based on immunohistochemical procedures. Therefore, the examination of HER2, PD-L1, and dMMR/MSI is recommended by the majority of clinical practice guidelines, as positive expression leads to different treatment approaches. Data from large phase-III trials and consequent approvals in various countries enable physicians to offer their patients several therapy options including immunotherapy, targeted therapy, or both combined with chemotherapy. The introduction of novel therapeutic targets such as CLDN18.2 leads to a more complex decision-making process as a significant number of patients show positive results for the co-expression of other biomarkers besides CLDN18.2. The aim of this review is to summarize the current biomarker landscape of patients with metastatic gastroesophageal tumors, its direct clinical impact on daily decision-making, and to evaluate current findings on biomarker co-expression. Furthermore, possible treatment strategies with multiple biomarker expression are discussed.
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Affiliation(s)
- Martin Korpan
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Hannah Christina Puhr
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Julia M. Berger
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Alexander Friedrich
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Gerald W. Prager
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Matthias Preusser
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Aysegül Ilhan-Mutlu
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
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Rha SY, Zhang Y, Elme A, Pazo Cid R, Alacacioglu A, Ziogas DC, Shitara K, Ranceva A, Nemecek R, Santoro A, Calderon CA, Korphaisarn K, Davis T, Zahlten-Kuemeli A, Conn C, Tan M, Honeycutt H, Wainberg ZA. Prevalence of FGFR2b Protein Overexpression in Advanced Gastric Cancers During Prescreening for the Phase III FORTITUDE-101 Trial. JCO Precis Oncol 2025; 9:e2400710. [PMID: 39854659 PMCID: PMC11781561 DOI: 10.1200/po-24-00710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 11/20/2024] [Accepted: 11/27/2024] [Indexed: 01/26/2025] Open
Abstract
PURPOSE Fibroblast growth factor receptor 2 isoform IIIb (FGFR2b) protein overexpression is an emerging biomarker in gastric cancer and gastroesophageal junction cancer (GC). We assessed FGFR2b protein overexpression prevalence in nearly 3,800 tumor samples as part of the prescreening process for a global phase III study in patients with newly diagnosed advanced or metastatic GC. METHODS As of June 28, 2024, 3,782 tumor samples from prescreened patients from 37 countries for the phase III FORTITUDE-101 trial (ClinicalTrials.gov identifier: NCT05052801) were centrally tested for FGFR2b protein overexpression by immunohistochemistry (IHC) and had evaluable results. FGFR2b positivity was defined as both any % tumor cells (TC) and ≥10% TC exhibiting moderate-to-strong (2+/3+) membranous FGFR2b staining. Prevalence was analyzed across patient and sample characteristics. RESULTS FGFR2b protein overexpression at any % and ≥10%, 2+/3+ TC positivity was 37.8% (1,428/3,782 [95% CI, 36.2 to 39.3]) and 16.2% (612/3,782 [95% CI, 15 to 17.4]), respectively. Of any %, 2+/3+ TC-positive tumors, 42.9% (612/1,428 [95% CI, 40.3 to 45.4]) were FGFR2b ≥10%, 2+/3+ TC positive. FGFR2b prevalence was not notably different within multiple patient and sample characteristics examined (age, sex, collection method [biopsy v resection], collection site, location of primary tumor, and geographic region). CONCLUSION As of the data cutoff date, we report the largest prevalence assessment of FGFR2b protein overexpression in GC with more than one third (37.8%) of patients with GC exhibiting FGFR2b protein overexpression (any % TC, 2+/3+) by a validated IHC assay. Approximately 16% of patients had FGFR2b protein overexpression in ≥10% of TC. FGFR2b prevalence was similar across geographic regions and within defined patient and sample variables regardless of the level of expression.
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Affiliation(s)
- Sun Young Rha
- Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Anneli Elme
- North Estonia Medical Centre Foundation, Tallinn, Estonia
| | | | - Ahmet Alacacioglu
- Izmir Katip Celebi Universitesi Ataturk Egitim ve Arastirma Hastanesi, Menemen, Turkey
| | - Dimitrios C. Ziogas
- First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece
| | - Kohei Shitara
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Japan
| | - Anastasija Ranceva
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania
| | - Radim Nemecek
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute and Masaryk University, Faculty of Medicine, Brno, Czech Republic
| | - Armando Santoro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Medical Oncology and Haematology Unit, IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Rozzano, Milan, Italy
| | | | - Krittiya Korphaisarn
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | | | | | | | | | | | - Zev A. Wainberg
- Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
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Hashemi F, Tajik F, Saeednejad Zanjani L, Dehghan Manshadi M, Safaei S, Babaheidarian P, Fattahi F, Ghods R, Madjd Z. Clinical significance of Talin-1 and HER-2 status in different types of gastric carcinoma. Biomarkers 2024; 29:539-556. [PMID: 39466840 DOI: 10.1080/1354750x.2024.2423270] [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: 07/11/2024] [Accepted: 10/25/2024] [Indexed: 10/30/2024]
Abstract
BACKGROUND Talin-1 (TLN1) is crucial in cell migration, metastasis, and cancer development. This study evaluated Talin-1 expression and its clinical significance in gastric cancer (GC), along with human epidermal growth factor receptor-2 (HER-2) expression and its correlation with Talin-1. METHODS Bioinformatics analysis assessed the potential prognostic value of Talin-1 and HER-2 in GC patients. The study included 223 GC patients (Signet Ring Cells and Intestinal subtypes) and 29 non-malignant tissue samples. Immunohistochemistry (IHC) on tissue microarray slides evaluated Talin-1 and HER-2 expression and clinical significance. Receiver operating characteristic (ROC) curves assessed their diagnostic value. RESULTS Bioinformatics identified Talin-1 as a potential prognostic factor and HER-2 as an oncogene in GC. Talin-1 and HER-2 expression increased in SRC-type GC samples compared to non-malignant tissues. High cytoplasmic Talin-1 expression inversely correlated with tumor expansion and invasion in SRC-type GC. Increased HER-2 expression positively correlated with metastasis. ROC curves showed significant diagnostic values for both proteins. CONCLUSIONS Higher cytoplasmic Talin-1 expression is associated with less invasive tumor behavior, while increased membranous HER-2 expression is associated with metastasis in SRC-type GC. These findings suggest potential use in assessing diagnosis and screening high-risk cancer patients, particularly those with SRC-type GC.
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Affiliation(s)
- Farideh Hashemi
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran Iran
| | - Fatemeh Tajik
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Masoumeh Dehghan Manshadi
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran Iran
| | - Sadegh Safaei
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran Iran
| | | | - Fahimeh Fattahi
- Clinical Research Development Unit of Ayatollah-Khansari Hospital, Arak University of Medical Sciences, Arak, Iran
| | - Roya Ghods
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran Iran
| | - Zahra Madjd
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran Iran
- Department of Pathology, Iran University of Medical Sciences, Tehran, Iran
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Li J, Huang Y, Lao Q. Paclitaxel combined with trastuzumab chemotherapy-related posterior reversible encephalopathy syndrome: A case report and literature review. Radiol Case Rep 2024; 19:2188-2191. [PMID: 38515774 PMCID: PMC10950567 DOI: 10.1016/j.radcr.2024.02.073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 02/18/2024] [Accepted: 02/21/2024] [Indexed: 03/23/2024] Open
Abstract
Posterior reversible encephalopathy syndrome (PRES) in breast carcinoma is a rare disease in clinical practice that is often misdiagnosed and ignored. This study reported a case of a patient admitted to our hospital and discussed the clinical, imaging, and pathogenesis properties of the disease. We retrospectively analyzed the clinical data of this patient and reviewed the relevant literature. Imaging was used to diagnose PRES based on clinical findings, and clinical symptoms improved after discontinuation of the relevant drugs.
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Affiliation(s)
- Jing Li
- Department of Neurology, Guangxi medical university cancer hospital, Nanning, Guangxi, China, 530021
| | - Yanlan Huang
- Department of Neurology, Guangxi medical university cancer hospital, Nanning, Guangxi, China, 530021
| | - Qifang Lao
- Department of Intensive Care Medicine, Guangxi medical university cancer hospital, Nanning, Guangxi, China, 530021
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Shi H, Zhang M, Zhang Y. Construction of a prognostic model for autophagy in Wilm's tumor. Pediatr Surg Int 2024; 40:122. [PMID: 38704513 DOI: 10.1007/s00383-024-05712-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/22/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND Wilm's tumor (WT) is one of the most common childhood urological tumors, ranking second in the incidence of pediatric abdominal tumors. The development of WT is associated with various factors, and the correlation with autophagy is currently unclear. PURPOSE To develop a new prognostic model of autophagy-related genes (ATG) for WT. METHODS Using the Therapeutically applicable research to generate effective treatments (TARGET) database to screen for differentially expressed ATGs in WT and normal tissues. ATGs were screened for prognostic relevance to WT using one-way and multifactorial Cox regression analyses and prognostic models were constructed. The risk score was calculated according to the model, and the predictive ability of the constructed model was analyzed using the ROC (receiver operating characteristic) curve to verify the significance of the model for the prognosis of WT. RESULTS Sixty-eight differentially expressed ATGs were identified by univariate Cox regression analysis, and two critical prognostic ATGs (CXCR4 and ERBB2) were identified by multivariate Cox regression analysis. Patients were divided into high-risk and low-risk groups according to the differential expression of these two ATGs. Kaplan-Meier (KM) curves showed a significant difference in survival time between the two groups. The critical prognostic ATGs were combined with race, age, and stage in a multifactorial regression analysis, and the final prognostic model was produced as a line graph. CONCLUSION The prognostic model of autophagy-related genes composed of the CXCR4 gene and ERBB2 gene has a specific predictive value for the prognosis of WT, and the present study provides a clear basis for future research on biomarkers and therapeutic targets.
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Affiliation(s)
- Haoyu Shi
- Department of Pediatric Surgery, Affiliated Matern and Child Care Hospital of Nantong University, 399 Century Avenue, Chongchuan, Nantong, Jiangsu, China
| | - Min Zhang
- Department of Pediatric Surgery, Affiliated Matern and Child Care Hospital of Nantong University, 399 Century Avenue, Chongchuan, Nantong, Jiangsu, China.
| | - Youbo Zhang
- Department of Pediatric Surgery, Affiliated Matern and Child Care Hospital of Nantong University, 399 Century Avenue, Chongchuan, Nantong, Jiangsu, China
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Nowak KM, Chetty R. Predictive and prognostic biomarkers in gastrointestinal tract tumours. Pathology 2024; 56:205-213. [PMID: 38238239 DOI: 10.1016/j.pathol.2023.12.412] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/28/2023] [Accepted: 12/30/2023] [Indexed: 02/18/2024]
Abstract
Tumours of the gastrointestinal tract represent nearly a quarter of all newly diagnosed tumours diagnosed in 2019. Various treatment modalities for gastrointestinal cancers exist, some of which may be guided by biomarkers. Biomarkers act as gauges of either normal or pathogenic processes or responses to an exposure or intervention. They come in many forms. This review explores established and potential molecular/immunohistochemical (IHC) predictive and prognostic biomarkers of the gastrointestinal tract.
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Affiliation(s)
- Klaudia M Nowak
- Laboratory Medicine Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
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Moradi L, Tajik F, Saeednejad Zanjani L, Panahi M, Gheytanchi E, Biabanaki ZS, Kazemi-Sefat GE, Hashemi F, Dehghan Manshadi M, Madjd Z. Clinical significance of CD166 and HER-2 in different types of gastric cancer. Clin Transl Oncol 2024; 26:664-681. [PMID: 37537510 DOI: 10.1007/s12094-023-03297-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 07/24/2023] [Indexed: 08/05/2023]
Abstract
INTRODUCTION Cluster of differentiation 166 (CD166), a cancer stem cell (CSC) marker, and human epidermal growth factor receptor 2 (HER-2) are expressed in a diversity of malignancies and is associated with tumor progression. Although studies regarding the importance of CSC markers and HER-2 in gastric cancer (GC) have rapidly developed, their clinicopathological, prognosis, and diagnosis value still remain unsatisfying in GC. Therefore, the present study aims to investigate the clinical, prognostic, and diagnostic significance of CD166 and HER-2 in different histological types of GC. MATERIALS AND METHODS Bioinformatic analysis was applied to determine the clinical importance of CD166 and HER-2 expression based on their tissue localization in primary GC tumors and the normal adjacent samples. The expression patterns, clinical significance, prognosis, and diagnosis value of CD166 and HER-2 proteins in tissue microarrays (TMAs) of 206 GC samples, including Signet Ring Cell (SRC) and intestinal types and also 28 adjacent normal tissues were evaluated using immunohistochemistry (IHC). RESULTS The results indicated that the expression of CD166 (membranous and cytoplasmic) and HER-2 were significantly up-regulated in tumor cells compared to adjacent normal tissues (P = 0.010, P < 0.001, and P = 0.011, respectively). A statistically significant association was detected between a high level of membranous expression of CD166 and lymphovascular invasion (P = 0.006); We also observed a statistically significant association between high cytoplasmic expression of CD166 protein and more invasion of the subserosa (P = 0.040) in the SRC type. In contrast, there was no correlation between the expression of HER-2 and clinicopathologic characteristics. Both CD166 and HER-2 showed reasonable accuracy and high specificity as diagnostic markers. CONCLUSION Our results confirmed that increased membranous and cytoplasmic expression of CD166 showed clinical significance in the SRC type and is associated with the progression of the disease and more aggressive tumor behaviors. These findings can be used to assist in designating subgroups of patients that require different follow-up strategies, and also, they might be utilized as the prognostic or diagnostic biomarkers in these types of GC for prospective clinical application.
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Affiliation(s)
- Leila Moradi
- Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Tajik
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Leili Saeednejad Zanjani
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Pathology and Genomic Medicine, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Mahshid Panahi
- Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Elmira Gheytanchi
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Sadat Biabanaki
- Faculty of Biological Sciences, Department of Genetics, Tarbiat Modares University, Tehran, Iran
| | - Golnaz Ensieh Kazemi-Sefat
- Faculty of Advanced Technologies in Medicine, Department of Molecular Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farideh Hashemi
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Faculty of Advanced Technologies in Medicine, Department of Molecular Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Dehghan Manshadi
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Faculty of Advanced Technologies in Medicine, Department of Molecular Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Madjd
- Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran.
- Faculty of Advanced Technologies in Medicine, Department of Molecular Medicine, Iran University of Medical Sciences, Tehran, Iran.
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11
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Shitara K, Yamaguchi K, Muro K, Yasui H, Sakai D, Oshima T, Fujimura M, Sato Y, Yamazaki S, Wakabayashi T, Sugihara M, Kamio T, Shoji H. Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study. Int J Clin Oncol 2024; 29:27-35. [PMID: 37964066 PMCID: PMC10764408 DOI: 10.1007/s10147-023-02422-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 10/02/2023] [Indexed: 11/16/2023]
Abstract
BACKGROUND Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that consists of an anti-human epidermal growth factor receptor 2 (HER2) antibody bound by a cleavable tetrapeptide-based linker to a cytotoxic topoisomerase I inhibitor. Prior to marketing approval in Japan in September 2020, this expanded-access study was conducted to provide T-DXd to previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas. METHODS This multicenter, open-label, expanded-access study was conducted between March 25 and September 25, 2020 at 17 Japanese sites. Previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas received T-DXd 6.4 mg/kg via intravenous infusions at 3-week intervals. Serious adverse events (SAEs), all potential cases of interstitial lung disease (ILD)/pneumonitis, all liver-related events potentially meeting Hy's Law criteria, and all cases of overdose were reported on the case report forms. RESULTS A total of 64 patients were treated with T-DXd. Among the 17 (26.6%) patients with reported SAEs, 10 (15.6%) had SAEs related to T-DXd treatment. Febrile neutropenia was the most common SAE (n = 6). SAEs led to death in six patients; drug-related SAEs (sepsis and febrile neutropenia) led to death in one patient. Drug-related ILD, as determined by the external Adjudication Committee, occurred in three patients (Grade 1, Grade 2, and Grade 3: all n = 1). CONCLUSION This expanded-access study provided T-DXd to a broader population of Japanese patients prior to marketing approval in Japan, bridging the gap between clinical trials and drug approval. No new safety concerns were identified.
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Affiliation(s)
- Kohei Shitara
- National Cancer Center Hospital East, Kashiwa, Chiba, 277-8577, Japan.
| | - Kensei Yamaguchi
- The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan
| | - Kei Muro
- Aichi Cancer Center Hospital, Nagoya, Aichi, 464-8681, Japan
| | - Hisateru Yasui
- Kobe City Medical Center General Hospital, Kobe, Hyogo, 650-0047, Japan
| | - Daisuke Sakai
- Osaka University Hospital, Suita, Osaka, 565-0871, Japan
| | - Takashi Oshima
- Kanagawa Cancer Center, Yokohama, Kanagawa, 241-8515, Japan
| | | | - Yuta Sato
- Daiichi Sankyo Co., Ltd, Chuo-ku, Tokyo, 103-8426, Japan
| | | | | | | | - Takahiro Kamio
- Daiichi Sankyo, Inc, Basking Ridge, New Jersey, 07920, USA
| | - Hirokazu Shoji
- National Cancer Center Hospital, Chuo-ku, Tokyo, 104-0045, Japan
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12
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Skórzewska M, Gęca K, Polkowski WP. A Clinical Viewpoint on the Use of Targeted Therapy in Advanced Gastric Cancer. Cancers (Basel) 2023; 15:5490. [PMID: 38001751 PMCID: PMC10670421 DOI: 10.3390/cancers15225490] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/05/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
The development of therapies for advanced gastric cancer (GC) has made significant progress over the past few years. The identification of new molecules and molecular targets is expanding our understanding of the disease's intricate nature. The end of the classical oncology era, which relied on well-studied chemotherapeutic agents, is giving rise to novel and unexplored challenges, which will cause a significant transformation of the current oncological knowledge in the next few years. The integration of established clinically effective regimens in additional studies will be crucial in managing these innovative aspects of GC. This study aims to present an in-depth and comprehensive review of the clinical advancements in targeted therapy and immunotherapy for advanced GC.
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13
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Pous A, Notario L, Hierro C, Layos L, Bugés C. HER2-Positive Gastric Cancer: The Role of Immunotherapy and Novel Therapeutic Strategies. Int J Mol Sci 2023; 24:11403. [PMID: 37511163 PMCID: PMC10380453 DOI: 10.3390/ijms241411403] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 07/05/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
Gastric cancer is an aggressive disease with increasing global incidence in recent years. Human epidermal growth receptor 2 (HER2) is overexpressed in approximately 10-20% of gastric cancers. The implementation of targeted therapy against HER2 as part of the standard of care treatment in metastatic disease has improved the prognosis of this subset of patients. However, gastric cancer still has high mortality rates and urgently requires new treatment strategies. The combination of immunotherapy with HER2-targeted therapies has shown synergistic effects in preclinical models, this being the rationale behind exploring this combination in clinical trials in locally advanced and metastatic settings. Additionally, the irruption of antibody-drug conjugates and other novel HER2-targeted agents has led to the development of numerous clinical trials showing promising results. This review presents the molecular mechanisms supporting the use of HER2-targeted drugs in combination with immunotherapy and provides an overview of the therapeutic scenario of HER2-positive disease. We focus on the role of immunotherapy but also summarize emerging therapies and combinations under clinical research that may change the standard treatment in HER-2 positive disease in the future.
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Affiliation(s)
- Anna Pous
- Department of Medical Oncology, Institut Català d'Oncologia (ICO) Badalona, 08916 Badalona, Spain
- Badalona Applied Research Group in Oncology (B-ARGO), 08916 Badalona, Spain
| | - Lucía Notario
- Department of Medical Oncology, Institut Català d'Oncologia (ICO) Badalona, 08916 Badalona, Spain
- Badalona Applied Research Group in Oncology (B-ARGO), 08916 Badalona, Spain
| | - Cinta Hierro
- Department of Medical Oncology, Institut Català d'Oncologia (ICO) Badalona, 08916 Badalona, Spain
- Badalona Applied Research Group in Oncology (B-ARGO), 08916 Badalona, Spain
| | - Laura Layos
- Department of Medical Oncology, Institut Català d'Oncologia (ICO) Badalona, 08916 Badalona, Spain
- Badalona Applied Research Group in Oncology (B-ARGO), 08916 Badalona, Spain
| | - Cristina Bugés
- Department of Medical Oncology, Institut Català d'Oncologia (ICO) Badalona, 08916 Badalona, Spain
- Badalona Applied Research Group in Oncology (B-ARGO), 08916 Badalona, Spain
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14
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Yanagimoto Y, Imamura H, Adachi S, Odagiri K, Kawase T, Yamashita M, Takeyama H, Suzuki Y, Ikenaga M, Shimizu J, Tomita N, Dono K. The effect of specimen processing time on HER2 expression in gastric cancer and esophagogastric junction cancer: a single-center retrospective observational study. BMC Cancer 2023; 23:645. [PMID: 37434116 PMCID: PMC10334514 DOI: 10.1186/s12885-023-11148-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 07/04/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND Recent developments in the field of companion diagnosis and molecular-targeting therapeutic agents have helped in developing treatments targeting human epidermal growth factor receptor 2 (HER2) in gastric cancer (GC) and esophagogastric junction cancer (EGJC), and the importance of accurate diagnosis of HER2 expression is increasing. However, the HER2-positivity rate significantly differs among reports in GC and EGJC, and factors that affect HER2-positivity require elucidation. METHODS The present study retrospectively examined factors related to HER2-positivity in a single institution, including age, sex, body mass index, the American Society of Anesthesiologists physical status, tumor information, and surgery information, including time to specimen processing. RESULTS Our study included 165 patients tested for HER2 using GC and EGJC surgery specimens among the 1,320 patients who underwent gastrectomy from January 2007 to June 2022. In total, 35 (21.2%) and 130 (78.8%) patients were HER2-positive and -negative, respectively. Multivariate analysis revealed that intestinal type (odds ratio [OR]: 3.41, 95% confidence interval [CI]: 1.44-8.09, p = 0.005), pM1 (OR: 3.99, 95% CI: 1.51-10.55, p = 0.005), and time to specimen processing of < 120 min (OR: 2.65, 95% CI: 1.01-6.98, p = 0.049) were independent factors that affected HER2-positivity. CONCLUSIONS The outcomes of the present study indicated that intestinal type, pM, and time to specimen processing are important factors affecting HER2-positive rates in GC and EGJC. Therefore, the risk of false-negative HER2 results may be reduced by decreasing the time required to process the resected specimen. Additionally, accurate diagnosis of HER2 expression may increase the opportunity to administer molecular-targeted drugs that can expect therapeutic effects to patients appropriately. TRAIL REGISTRATION Retrospectively registered.
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Affiliation(s)
- Yoshitomo Yanagimoto
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan.
| | - Hiroshi Imamura
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Shiro Adachi
- Department Diagnostic Pathology, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Kazuki Odagiri
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Tomono Kawase
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Masafumi Yamashita
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Hiroshi Takeyama
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Yozo Suzuki
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Masakazu Ikenaga
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Junzo Shimizu
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Naohiro Tomita
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Keizo Dono
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
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15
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Xu B, Chen H, Zhang J, Cong Y, Ning L, Chen L, Zhang Y, Zhang Y, Song Z, Meng Y, He L, Liao WL, Lu Y, Zhao F. A comparative study of gastric adenocarcinoma HER2 IHC phenotype and mass spectrometry-based quantification. Front Oncol 2023; 13:1152895. [PMID: 37350943 PMCID: PMC10283037 DOI: 10.3389/fonc.2023.1152895] [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: 01/28/2023] [Accepted: 04/10/2023] [Indexed: 06/24/2023] Open
Abstract
Introduction Gastric cancer is a highly heterogeneous malignant tumor of the digestive system. Anti-HER2 treatment can inhibit downstream signaling pathways and improve clinical treatment and outcomes in patients with HER2 protein overexpression. Currently, two standard methods for evaluating HER2 expression status are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). However, these low-throughput assays often produce discordant or equivocal results. Methods In this study, we presented a new HER2 protein detection method based on mass spectrometry selected reaction monitoring (MS-SRM) and validated the method. We conducted a retrospective study on 118 formalin-fixed paraffin-embedded (FFPE) tissues from patients with advanced gastric adenocarcinoma in northern China, and we compared the MS-SRM results with those from IHC and correlated them with FISH. Results We established and validated the upper and lower detection limits (300-700 amol/μg) for abnormal HER2 protein expression in advanced gastric cancer. We also found that, among samples with mixed Lauren subtypes, those with a high level of HER2 expression had typical intestinal type features in pathology. Discussion This study demonstrated that the MS-SRM method can overcome the limitations and deficiencies of IHC, directly quantify the expression of HER2 protein in tumor cells and be used as a supplement to IHC. It has the potential to be used as a companion diagnosis for new drugs used to treat advanced gastric cancer. Large-scale clinical validation is required.
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Affiliation(s)
- Bin Xu
- Pathology Department, Fushun Central Hospital, Fushun, Liaoning, China
| | - Hui Chen
- Stomatology Department, Fushun Central Hospital, Fushun, Liaoning, China
| | - Jingjing Zhang
- Technology Department, Tianjin Yunjian Medical Laboratory Co. Ltd., Tianjin, China
| | - Yanghai Cong
- Technology Department, Tianjin Yunjian Medical Laboratory Co. Ltd., Tianjin, China
| | - Li Ning
- Medical Oncology, Fushun Central Hospital, Fushun, Liaoning, China
| | - Limin Chen
- Technology Department, Tianjin Yunjian Medical Laboratory Co. Ltd., Tianjin, China
| | - Yushi Zhang
- Technology Department, Tianjin Yunjian Medical Laboratory Co. Ltd., Tianjin, China
| | - Yong Zhang
- Pathology Department, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China
| | - Zhanchun Song
- Circulation Department, Fushun Central Hospital, Fushun, Liaoning, China
| | - Yuan Meng
- Pathology Department, Fushun Central Hospital, Fushun, Liaoning, China
| | - Lianqi He
- Circulation Department, Fushun Central Hospital, Fushun, Liaoning, China
| | - Wei-li Liao
- Research and Development Department, mProbe Inc., Palo Alto, CA, United States
| | - Ying Lu
- Laboratory Medicine, Fushun Central Hospital, Fushun, Liaoning, China
| | - Fengyi Zhao
- Technology Department, Tianjin Yunjian Medical Laboratory Co. Ltd., Tianjin, China
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16
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Wang S, Zhou X, Niu S, Chen L, Zhang H, Chen H, Zhou F. Assessment of HER2 in Gastric-Type Endocervical Adenocarcinoma and its Prognostic Significance. Mod Pathol 2023; 36:100148. [PMID: 36841435 DOI: 10.1016/j.modpat.2023.100148] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/30/2023] [Accepted: 02/10/2023] [Indexed: 02/27/2023]
Abstract
As the most common type of human papillomavirus-independent endocervical adenocarcinomas (ECAs), gastric-type endocervical adenocarcinomas (GEAs) account for approximately 10% of all ECAs. Although anti-HER2 therapy has been proven effective in many cancers, it has not been used in ECAs, including GEAs, which is at least partly due to the lack of a well-defined guideline. Limited available data regarding HER2 in GEAs and ECAs have considerable variations likely caused by variations in the tumor type selection, testing methods, and scoring criteria. Here, we selected 58 GEA cases to examine the HER2 status using immunohistochemistry and fluorescent in situ hybridization and investigate the prognostic value and their association with other known or potential prognostic factors. When strong complete or lateral/basolateral membranous reactivity in ≥10% tumor cells was used to define HER2 positivity, relatively high prevalence of HER2 overexpression (10/58[17.2%]) and amplification (9/58 [15.5%]), as well as high immunohistochemistry-fluorescent in situ hybridization concordance rate (9/10 [90%]) was found in GEAs. A lateral/basolateral staining pattern ("U-shaped") was observed, at least focally, in most of HER2-positive (3+) and equivocal (2+) tumors. Notably, considerable heterogeneity of HER2 expression was observed in HER2 positive and equivocal cases (80.0% and 83.3%, respectively). HER2 overexpression and amplification were associated with worse progression-free survival (P = .047 and P = .032, respectively). Programmed death-ligand 1 expression was associated with worse progression-free survival (P = .032), whereas mutant-type p53 demonstrated no prognostic significance. Our work laid a solid foundation for the eventual development of a future standard HER2 testing guideline for GEAs.
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Affiliation(s)
- Su Wang
- Department of Pathology, Zhejiang University School of Medicine Women's Hospital, Hangzhou, Zhejiang Province, China
| | - Xin Zhou
- Department of Pathology, Zhejiang University School of Medicine Women's Hospital, Hangzhou, Zhejiang Province, China
| | - Shuang Niu
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas
| | - Lili Chen
- Department of Gynecology, Zhejiang University School of Medicine Women's Hospital, Hangzhou, Zhejiang Province, China
| | - Huijuan Zhang
- Departments of Pathology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Hao Chen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, Parkland Hospital, Dallas, Texas.
| | - Feng Zhou
- Department of Pathology, Zhejiang University School of Medicine Women's Hospital, Hangzhou, Zhejiang Province, China.
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17
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Zhang XN, Gao Y, Zhang XY, Guo NJ, Hou WQ, Wang SW, Zheng YC, Wang N, Liu HM, Wang B. Detailed curriculum vitae of HER2-targeted therapy. Pharmacol Ther 2023; 245:108417. [PMID: 37075933 DOI: 10.1016/j.pharmthera.2023.108417] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 04/10/2023] [Accepted: 04/13/2023] [Indexed: 04/21/2023]
Abstract
With the booming development of precision medicine, molecular targeted therapy has been widely used in clinical oncology treatment due to a smaller number of side effects and its superior accuracy compared to that of traditional strategies. Among them, human epidermal growth factor receptor 2 (HER2)-targeted therapy has attracted considerable attention and has been used in the clinical treatment of breast and gastric cancer. Despite excellent clinical effects, HER2-targeted therapy remains in its infancy due to its resulting inherent and acquired resistance. Here, a comprehensive overview of HER2 in numerous cancers is presented, including its biological role, involved signaling pathways, and the status of HER2-targeted therapy.
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Affiliation(s)
- Xiao-Nan Zhang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Ya Gao
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Xi-Ya Zhang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Ning-Jie Guo
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Wen-Qing Hou
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Shu-Wu Wang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Yi-Chao Zheng
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Ning Wang
- The School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Hong-Min Liu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China.
| | - Bo Wang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China.
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18
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Xu Q, Xu X, Tang H, Yan J, Li J, Bao H, Wu X, Shao Y, Luo C, Wen H, Jin J, Ying J. Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapy. Oncogenesis 2023; 12:21. [PMID: 37072406 PMCID: PMC10113330 DOI: 10.1038/s41389-023-00466-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/20/2023] Open
Abstract
HER2-positive gastric cancer (GC) makes up 15-20% of all GC incidences, and targeted therapy with trastuzumab is the standard of treatment. However, the mechanisms of resistance to trastuzumab are still not fully understood and presents a significant challenge in clinical practice. In this study, whole exome sequencing (WES) was performed on paired tumor tissues before trastuzumab treatment (at baseline) and at progressive disease (PD) in 23 GC patients. Clinicopathological and molecular features that may be associated with primary and/or acquired resistance to trastuzumab were identified. Lauren classification of intestinal type was associated with a more prolonged progression-free survival (PFS) than diffuse type (HR = 0.29, P = 0.019). Patients with low tumor mutation burden (TMB) showed significantly worse PFS, while high chromosome instability (CIN) was correlated with prolonged OS (HR = 0.27; P = 0.044). Patients who responded to treatment had a higher CIN than nonresponders, and a positive trend towards increasing CIN was observed as response improved (P = 0.019). In our cohort, the most common genes to acquire mutations are AURKA, MYC, STK11, and LRP6 with four patients each. We also discovered an association between clonal branching pattern and survival, with an extensive clonal branching pattern being more closely related to a shorter PFS than other branching patterns (HR = 4.71; P = 0.008). We identified potential molecular and clinical factors that provide insight regarding potential association to trastuzumab resistance in advanced HER2-positive GC patients.
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Affiliation(s)
- Qi Xu
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, 310022, Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, China
| | - Xiaoqing Xu
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, 310022, Hangzhou, China
- Department of Medical Oncology, The Second Clinical Medical College of Zhejiang Chinese Medical University, 310053, Hangzhou, China
| | - Haimeng Tang
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., 210031, Nanjing, China
| | - Junrong Yan
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., 210031, Nanjing, China
| | - Jingjing Li
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, 310022, Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, China
| | - Hua Bao
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., 210031, Nanjing, China
| | - Xue Wu
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., 210031, Nanjing, China
| | - Yang Shao
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., 210031, Nanjing, China
- School of Public Health, Nanjing Medical University, 211166, Nanjing, Jiangsu, China
| | - Cong Luo
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, 310022, Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, China
| | - Haimin Wen
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, 310022, Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, China
| | - Jianying Jin
- Department of Medical Oncology, Taizhou Hospital of Zhejiang Province, 317000, Taizhou, China.
| | - Jieer Ying
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, 310022, Hangzhou, China.
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, China.
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, 310022, Hangzhou, China.
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B. AV, Behera MK, Patne SCU, Shukla SK, Dixit VK. Clinicopathological Significance and Prognostic Role of Her2neu Protein Expression in Patients with Carcinoma Stomach: A Prospective Study from Northern India. South Asian J Cancer 2023; 12:135-140. [PMID: 37969677 PMCID: PMC10635765 DOI: 10.1055/s-0042-1759601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023] Open
Abstract
Manas Kumar BeheraBackground and Aims Gastric cancer is the third most common cause of cancer-related mortality worldwide after lungs and colorectum. Although controversial, Her2neu overexpression by immunohistochemistry is usually associated with poor prognosis in patients with carcinoma stomach. We conducted a prospective study to evaluate the prognostic role of Her2neu and its correlation with clinical, pathologic type, and stage of the disease. Methods A prospective study was performed on paraffin blocks of 111 gastric cancer specimens (88 patients were biopsy specimens and 23 were gastrectomy specimens). The paraffin blocks were processed for Her2neu receptor immunohistochemical staining and fluorescence in situ hybridization, and scoring was done. Results Her2neu overexpression was detected in 30 out of 111 (27%) patients. The mean age was 57.68 ± 12.82 years, with males constituting two-thirds of total patients. Tobacco addiction was found in 44% of the patients and smoking in 33% of the patients. Her2neu expression was similar in Lauren's intestinal and diffuse histologic type; however, proximal gastric tumors overexpressed Her2neu as compared with distal tumors. Her2neu 2+ or 3 + (odds ratio: 2.52, 95% CI: 1.61-3.95, p = 0.001) was the only independent predictor of survival in gastric cancer patients. Kaplan-Meir survival analysis showed that the survival of gastric cancer patients with Her2neu overexpression (Her2neu 2+ or 3 + ) was significantly lower than that of those with Her2neu nonexpression ( p = 0.001). Conclusion Her2neu positivity was a significant predictor of mortality in patients with carcinoma stomach, and Her2neu overexpression was associated with a lower overall survival rate compared with Her2neu nonexpression.
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Affiliation(s)
| | - Manas Kumar Behera
- Department of Hepatology, Srirama Chandra Bhanja (SCB) Medical College, Bhubaneswar, Odisha, India
| | - Shashikant C. U. Patne
- Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Sunit Kumar Shukla
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Vinod Kumar Dixit
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
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Subasinghe D, Acott N, Mahesh PKB, Sivaganesh S, Munasinghe S, Kumarasinghe MP, Samarasekera DN, Lokuhetty MDS. Human epidermal growth factor receptor-2 gene expression positivity determined by silver in situ hybridization/immunohistochemistry methods and associated factors in a cohort of Sri Lankan patients with gastric adenocarcinoma: a prospective study. J Int Med Res 2023; 51:3000605231154403. [PMID: 36814374 PMCID: PMC9950620 DOI: 10.1177/03000605231154403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023] Open
Abstract
OBJECTIVE Positive human epidermal growth factor 2 (HER2) expression and its predictive clinicopathological features remain unclear in Sri Lankan gastric cancer (GC) patients. Here, we aimed to determine GC HER2 status predictors by analyzing associations between clinicopathological features and HER2 expression using immunohistochemistry (IHC) and silver in situ hybridization (SISH). METHODS During this 4-year prospective study, clinicopathological data were collected from participants in the National Hospital of Sri Lanka. HER2 IHC and SISH were performed using commercial reagents. Using chi-square tests, associations of HER2-IHC/SISH with clinicopathological features were analyzed. RESULTS Overall, 145 GC patients were included, 69 had gastrectomies and 76 had biopsies. Positive HER2 expression by IHC was associated with age <60 years, high T stage (assessed pathologically in resections and radiologically in biopsies), high nuclear grade, tumor necrosis, mitosis >5/high-power field, with additional perineural invasion and lymphovascular invasion in resections. These features, excluding lymphovascular invasion but including male sex, were associated with HER2 expression by SISH. CONCLUSIONS Age <60 years, high nuclear grade, tumor necrosis, and perineural invasion are associated factors of HER2 status. These could be used to triage GC patients for HER2 status testing in limited resource settings where IHC/SISH analysis is costly.
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Affiliation(s)
- Duminda Subasinghe
- Department of Surgery, Faculty of Medicine, University of
Colombo, University Surgical Unit, The National Hospital of Sri Lanka, Colombo,
Sri Lanka,PathWest Laboratory Medicine, Perth, & School of Pathology
and Laboratory Medicine, University of Western Australia, Perth, Australia,Duminda Subasinghe, Department of Surgery,
Faculty of Medicine, University of Colombo, University Surgical Unit, The
National Hospital of Sri Lanka, Colombo 00800, Sri Lanka.
| | - Nathan Acott
- PathWest Laboratory Medicine, Perth, & School of Pathology
and Laboratory Medicine, University of Western Australia, Perth, Australia
| | | | - Sivasuriya Sivaganesh
- Department of Surgery, Faculty of Medicine, University of
Colombo, University Surgical Unit, The National Hospital of Sri Lanka, Colombo,
Sri Lanka
| | - Sithum Munasinghe
- Translational Health Research Institute, Western Sydney
University, Campbelltown Campus, Campbelltown, New South Wales, Australia
| | - Mariyan Priyanthi Kumarasinghe
- PathWest Laboratory Medicine, Perth, & School of Pathology
and Laboratory Medicine, University of Western Australia, Perth, Australia
| | - Dharmabandu Nandaveva Samarasekera
- Department of Surgery, Faculty of Medicine, University of
Colombo, University Surgical Unit, The National Hospital of Sri Lanka, Colombo,
Sri Lanka
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Ede NJ, Good AJ, Tobias J, Garner-Spitzer E, Zielinski CC, Wiedermann U. Development of the B cell cancer vaccine HER-vaxx for the treatment of her-2 expressing cancers. Front Oncol 2022; 12:939356. [PMID: 36578947 PMCID: PMC9791928 DOI: 10.3389/fonc.2022.939356] [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: 07/22/2022] [Accepted: 11/21/2022] [Indexed: 12/14/2022] Open
Abstract
Her-2/neu is a tumor-associated protein that is overexpressed in a number of malignancies, including advanced cancer of the stomach, and has been proposed as a human cancer vaccine target. Overexpression of Her-2/neu in human breast and gastric carcinomas correlates with a more aggressive course of disease that results in poorer overall survival rates and shorter times to disease progression than in patients with tumors without overexpression of Her-2/neu. Cancer vaccines have the ability to stimulate the native immune system and in particular engineered B cell epitopes can elicit high affinity polyclonal antibodies with similar efficacy to Her-2 monoclonal antibodies such as trastuzumab (Roche). HER-Vaxx is under development as a therapeutic B cell vaccine for the treatment of gastric cancer in patients with Her-2/neu overexpressing metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction, referred to as advanced cancer of the stomach. P467-CRM197, the vaccine's immunogenic component, contains a single peptide antigen composed of 3 individual linear B cell epitope peptide sequences selected from the oncoprotein Her-2/neu that induce the patient's own B cells to produce endogenous anti-Her-2/neu antibodies. This review provides results from comprehensive preclinical studies encompassing primary and secondary pharmacodynamics, biodistribution and safety studies. These studies were performed to support clinical development of HER-Vaxx. Results from the GLP toxicology study in rodents showed that the vaccine did not produce any observable adverse effects suggesting that the doses proposed for the clinical trial should be well tolerated in patients.
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Affiliation(s)
- Nicholas J. Ede
- Immunotherapy R&D Department, Imugene Limited, Sydney, NSW, Australia,*Correspondence: Nicholas J. Ede,
| | - Anthony J. Good
- Immunotherapy R&D Department, Imugene Limited, Sydney, NSW, Australia
| | - Joshua Tobias
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Erika Garner-Spitzer
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Christoph C. Zielinski
- Central European Cancer Center, Wiener Privatklinik, and Central European Cooperative Oncology Group (CECOG), Vienna, Austria
| | - Ursula Wiedermann
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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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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Yang T, Xu R, You J, Li F, Yan B, Cheng JN. Prognostic and clinical significance of HER-2 low expression in early-stage gastric cancer. BMC Cancer 2022; 22:1168. [PMID: 36371187 PMCID: PMC9652852 DOI: 10.1186/s12885-022-10262-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 10/31/2022] [Indexed: 11/15/2022] Open
Abstract
INTRODUCTION Gastric cancer is the most fifth common tumor worldwide. Human epidermal growth factor receptor 2 (HER2) overexpression is associated with poor prognosis and clinical characteristics in gastric cancer. Nevertheless, the biology of HER2-low expression has not reported in gastric cancer. MATERIALS AND METHODS A total of 157 patients with early-stage gastric cancer were retrospectively analyzed. The associations between HER-2 low expression and clinical characteristics were analyzed by Chi-square test. And the prognostic value of HER-2 low expression and clinical characteristics in disease-free survival (DFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression analysis. RESULTS Of 157 patients with early-stage gastric cancer, 31.8% had HER2-low tumors and 50.3% had HER2-negative tumors. HER2-low expression was associated with age, histological differentiation, tumor location and Ki-67 index. However, HER2-low expression was not associated with DFS or OS in early-stage gastric cancer. CONCLUSION HER2-low expression might result in distinct biology, but it was not an independent prognostic factor of DFS or OS in early-stage gastric cancer.
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Affiliation(s)
- Tao Yang
- Department of Oncology, Hainan Hospital of Chinese PLA General Hospital, Sanya, 572013 Hainan China
| | - Rui Xu
- Department of Oncology, Hainan Hospital of Chinese PLA General Hospital, Sanya, 572013 Hainan China
| | - Junhao You
- Department of Oncology, Hainan Hospital of Chinese PLA General Hospital, Sanya, 572013 Hainan China
| | - Fang Li
- Department of Oncology, Hainan Hospital of Chinese PLA General Hospital, Sanya, 572013 Hainan China
| | - Bing Yan
- Department of Oncology, Hainan Hospital of Chinese PLA General Hospital, Sanya, 572013 Hainan China
| | - Jia-nan Cheng
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037 People’s Republic of China
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Chu Y, Li H, Wu D, Guo Q. HER2 protein expression correlates with Lauren classification and P53 in gastric cancer patients. Medicine (Baltimore) 2022; 101:e30647. [PMID: 36123933 PMCID: PMC9478214 DOI: 10.1097/md.0000000000030647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is a key pathological characteristic of gastric cancer (GC). However, the clinical significance of HER2 expression in gastric carcinoma remains controversial. The purpose of this study was to analyze the clinicopathological characteristics of HER2 protein expression, Lauren classification and tumor protein p53 (P53) expression and to evaluate the clinical significance of HER2 protein expression. A total of 176 consecutive patients were prospectively recruited between January 2014 and December 2016 at the Second Affiliated Hospital of Zhejiang University School of Medicine. Histological analysis of the resected tissue was performed for HER2 protein expression using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Additionally, the expression status of HER2 protein and clinicopathological features were analyzed using the chi-squared (χ2) test. Survival analysis was performed using the Kaplan-Meier method, and differences between the survival curves were determined using the log-rank test. All statistical analyses were conducted using SPSS 22.0 statistical software program (IBM Corp., Armonk, NY). A total of 176 patients with GC were enrolled in this study. Intratumoral heterogeneity of HER2 protein overexpression was observed in 42 of 176 cases with IHC grade 2+, accompanied by FISH positivity and IHC grade 3+. HER2 protein expression was correlated with tumor differentiation (P < .001), Lauren classification (P = .001), Borrmann type (P = .003) and P53 expression (P < .001). HER2 protein positivity was associated with significantly higher overall survival (OS) (P = .038). Overexpression of HER2 protein was observed in 23.9% of the cases and was significantly related to the Lauren intestinal subtype and P53 negative expression. HER2 protein overexpression was independently associated with higher OS.
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Affiliation(s)
- Yiming Chu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medicine University, Hangzhou, Zhejiang, China
- Department of Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hongbo Li
- Department of Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Dan Wu
- Department of Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qingqu Guo
- Department of Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- *Correspondence: Qingqu Guo, Department of Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Cancer Institute of Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China (e-mail: )
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Drubay V, Nuytens F, Renaud F, Adenis A, Eveno C, Piessen G. Poorly cohesive cells gastric carcinoma including signet-ring cell cancer: Updated review of definition, classification and therapeutic management. World J Gastrointest Oncol 2022; 14:1406-1428. [PMID: 36160745 PMCID: PMC9412924 DOI: 10.4251/wjgo.v14.i8.1406] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 05/08/2022] [Accepted: 07/17/2022] [Indexed: 02/05/2023] Open
Abstract
While the incidence of gastric cancer (GC) in general has decreased worldwide in recent decades, the incidence of diffuse cancer historically comprising poorly cohesive cells-GC (PCC-GC) and including signet ring cell cancer is rising. Literature concerning PCC-GC is scarce and unclear, mostly due to a large variety of historically used definitions and classifications. Compared to other histological subtypes of GC, PCC-GC is nevertheless characterized by a distinct set of epidemiological, histological and clinical features which require a specific diagnostic and therapeutic approach. The aim of this review was to provide an update on the definition, classification and therapeutic strategies of PCC-GC. We focus on the updated histological definition of PCC-GC, along with its implications on future treatment strategies and study design. Also, specific considerations in the diagnostic management are discussed. Finally, the impact of some recent developments in the therapeutic management of GC in general such as the recently validated taxane-based regimens (5-Fluorouracil, leucovorin, oxaliplatin and docetaxel), the use of hyperthermic intraperitoneal chemotherapy as well as pressurized intraperitoneal aerosol chemotherapy and targeted therapy have been reviewed in depth for their relative importance for PCC-GC in particular.
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Affiliation(s)
- Vincent Drubay
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- Department of Digestive Surgery, Cambrai Hospital Center and Sainte Marie, Group of Hospitals of The Catholic Institute of Lille, Cambrai 59400, France
| | - Frederiek Nuytens
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- Department of Digestive and Hepatobiliary/Pancreatic Surgery, AZ Groeninge Hospital, Kortrijk 8500, Belgium
| | - Florence Renaud
- Department of Pathology, University Lille Hospital, Lille 59000, France
- CNRS, Inserm, UMR9020-U1277-CANTHER-Cancer, University Lille, CHU Lille, Lille 59000, France
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
| | - Antoine Adenis
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
- Department of Medical Oncology, Montpellier Cancer Institute, Monpellier 34000, France
- IRCM, Inserm, University of Monpellier, Monpellier 34000, France
| | - Clarisse Eveno
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- CNRS, Inserm, UMR9020-U1277-CANTHER-Cancer, University Lille, CHU Lille, Lille 59000, France
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
| | - Guillaume Piessen
- Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille 59000, France
- CNRS, Inserm, UMR9020-U1277-CANTHER-Cancer, University Lille, CHU Lille, Lille 59000, France
- FREGAT Network, Claude Huriez University Hospital, Lille 59000, France
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Shi L, Wang Z, Wang L, Jia Y, Li J, Qin Y. A Prognostic Nomogram and Heat Map to Predict Survival in Stage II/III Gastric Cancer Patients After Curative Gastrectomy Followed by Adjuvant Chemotherapy. Cancer Manag Res 2022; 14:287-301. [PMID: 35115828 PMCID: PMC8800584 DOI: 10.2147/cmar.s348890] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 01/12/2022] [Indexed: 02/01/2023] Open
Abstract
Purpose This study aimed to study the prognostic value of clinicopathological data, inflammation and nutritional indicators, and to design an effective prognostic nomogram and heat map to predict cancer-specific survival (CSS) and disease-free survival (DFS) of stage II/III GC patients who underwent curative gastrectomy with adjuvant chemotherapy. Patients and Methods We retrospectively analyzed the data of 611 patients with stage II/III GC after curative gastrectomy followed by adjuvant chemotherapy from 3 GC disease centers. Patients were divided into a training cohort (n = 503) and an external validation cohort (n = 108). Nomograms were established based on independent predictors identified by Cox regression analysis in the training cohort. The consistency index (C-index) and the calibration curve were used to evaluate the discriminative ability and accuracy of the nomogram. Heat maps were constructed with the prognostic factors and the corresponding survival probability. We further divided the patients into low-risk and high-risk groups based on the risk score of the nomogram. Results Through univariate and multivariate survival analysis, the independent risk factors common to CSS and DFS were identified. Then these predictors were incorporated into the nomograms, and the established nomograms used to predict CSS and DFS had high discriminative power in the training cohort. Meanwhile, the calibration curves of CSS and DFS probability also showed good agreement between the prediction based on the nomograms and the actual observation results. The above independent predictors were applied to establish heat maps. Compared with low-risk patients, the high-risk patients calculated according to the nomogram had a shorter survival time and a worse prognosis. Conclusion We established a nomogram and heat map, which could be used to assess the survival rate of stage II/III GC patients who underwent curative gastrectomy with adjuvant chemotherapy. These tools had high prognostic prediction accuracy and provided inspiration for clinical decision-making.
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Affiliation(s)
- Litong Shi
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
| | - Zehua Wang
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
| | - Lei Wang
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
| | - Yongxu Jia
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
| | - Jing Li
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
| | - Yanru Qin
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
- Correspondence: Yanru Qin, Department of Oncology, Zhengzhou University First Affiliated Hospital, No. 1 Jianshe East Road, Erqi District, Zhengzhou, 450052, Henan, People’s Republic of China, Tel +86 13676932999, Email
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Kim HR, Ahn S, Jo H, Kim H, Hong J, Lee J, Lim HY, Kang WK, Kim ST. The Impact of Tumor Mutation Burden on the Effect of Frontline Trastuzumab Plus Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Advanced Gastric Cancers. Front Oncol 2021; 11:792340. [PMID: 34926309 PMCID: PMC8674178 DOI: 10.3389/fonc.2021.792340] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 11/16/2021] [Indexed: 12/09/2022] Open
Abstract
BackgroundTrastuzumab is a HER2-trargeted humanized monoclonal antibody that has been studied as a first-line treatment for patients with HER2-positive advanced gastric cancer (AGC). The effect of anti-HER2 therapy according to tumor mutational burden (TMB) in HER2-positive AGC remains unclear.MethodsWe performed next-generation sequencing (NGS), including TMB analysis, in 31 HER2-positive AGC patients with trastuzumab plus chemotherapy as first-line therapy for recurrent (n=8) or metastatic (n=23) tumors. The TruSight Oncology 500 Assay from Illumina (San Diego, CA, USA) was used to evaluate TMB.ResultsAmong 31 patients, 30 had tumors with immunohistochemistry (IHC) 3+, and one was IHC 2+ and silver in situ hybridization (SISH) positive. The median age was 57.0 years old (range, 35-76), and the majority had tumors with low TMB (87.1%, n=27/31). Only four (12.9%) had tumors with high TMB. Of these four, three achieved complete response (CR) or partial response (PR) to treatment, and the remaining patient was not evaluable for tumor response. Objective response rate (ORR) to trastuzumab plus chemotherapy showed a favorable trend in patients with high TMB (75.0%, n=3/4) compared to patients with low TMB (59.3%, n=16/27) (P=0.546). The median progression-free survival (PFS) was not reached in the TMB-high group but was 8.0 months (95% CI, 7.6-8.5) in the TMB-low group (P=0.019)ConclusionThe status of TMB could be a novel biomarker in predicting the efficacy of trastuzumab plus chemotherapy in HER2-positive AGCs.
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Affiliation(s)
- Hye Ryeon Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
- Department of Internal Medicine, Dong-A University College of Medicine, Busan, South Korea
| | - Soomin Ahn
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hyunji Jo
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hongsik Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Joohyun Hong
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Ho-Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
- *Correspondence: Seung Tae Kim,
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Kim S, Kim YJ, Chung WC. HER-2 positivity is a high risk of recurrence of stage I gastric cancer. Korean J Intern Med 2021; 36:1327-1337. [PMID: 34428882 PMCID: PMC8588971 DOI: 10.3904/kjim.2020.243] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 10/17/2020] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND/AIMS The treatment of gastric cancer remains unsatisfactory. We aimed to investigate the prognostic value of immunohistochemical staining in gastric cancer. METHODS We analyzed 505 (279 early staged, 226 advanced-staged) gastric cancer tissues from patients who underwent radical gastric resection between January 2014 and December 2016. Available surgical specimens immunohistochemically stained for p53, epidermal growth factor receptor (EGFR), human EGFR 2 (HER-2), E-cadherin, and Ki-67 were reviewed. We evaluated the association between positivity to various biomarkers and disease recurrence, disease-free survival, lymph node metastasis, and microscopic lymphovascular invasion. RESULTS The median follow-up duration was 32.5 months (range, 7 to 70). Advanced gastric cancer cases showed high Ki-67 expression; other cases showed unremarkable expression. Concerning disease recurrence, lymphatic invasion, and disease-free interval, all biomarkers had no prognostic effects. HER-2-positive stage I gastric cancer tended to occur in old patients and in the upper one-third of the stomach (p = 0.01). HER-2 positivity was significantly correlated with disease recurrence (p = 0.01), lymphatic invasion (p = 0.03), and vascular invasion (p = 0.03) in stage I cases. CONCLUSION Only HER-2 was associated with the recurrence of stage I gastric cancer. HER-2-positive stage I gastric cancer requires additional therapy despite curative resection.
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Affiliation(s)
- Seonhoo Kim
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Yeon-Ji Kim
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Woo Chul Chung
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
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Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm. Nat Rev Clin Oncol 2021; 18:473-487. [PMID: 33790428 DOI: 10.1038/s41571-021-00492-2] [Citation(s) in RCA: 169] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2021] [Indexed: 02/02/2023]
Abstract
Advances in cancer biology and sequencing technology have enabled the selection of targeted and more effective treatments for individual patients with various types of solid tumour. However, only three molecular biomarkers have thus far been demonstrated to predict a response to targeted therapies in patients with gastric and/or gastro-oesophageal junction (G/GEJ) cancers: HER2 positivity for trastuzumab and trastuzumab deruxtecan, and microsatellite instability (MSI) status and PD-L1 expression for pembrolizumab. Despite this lack of clinically relevant biomarkers, distinct molecular subtypes of G/GEJ cancers have been identified and have informed the development of novel agents, including receptor tyrosine kinase inhibitors and monoclonal antibodies, several of which are currently being tested in ongoing trials. Many of these trials include biomarker stratification, and some include analysis of circulating tumour DNA (ctDNA), which both enables the noninvasive assessment of biomarker expression and provides an indication of the contributions of intratumoural heterogeneity to response and resistance. The results of these studies might help to optimize the selection of patients to receive targeted therapies, thus facilitating precision medicine approaches for patients with G/GEJ cancers. In this Review, we describe the current evidence supporting the use of targeted therapies in patients with G/GEJ cancers and provide guidance on future research directions.
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Kim J, Hong JY, Kim ST, Park SH, Jekal SY, Choi JS, Chang DK, Kang WK, Seo SW, Lee J. Clinical scoring system for the prediction of survival of patients with advanced gastric cancer. ESMO Open 2021; 5:S2059-7029(20)30065-X. [PMID: 32188716 PMCID: PMC7078777 DOI: 10.1136/esmoopen-2020-000670] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 01/28/2020] [Accepted: 01/30/2020] [Indexed: 01/12/2023] Open
Abstract
OBJECTIVE In this study, we established a risk scoring system using easily obtained clinical characteristics at the time of initiating palliative chemotherapy to predict accurate overall survival of patients with advanced gastric cancer after first-line treatment with fluoropyrimidine-platinum combination chemotherapy. METHODS A total of 1733 patients treated at the Samsung Medical Center, Korea were included in the study, and clinicopathological and laboratory data were retrospectively analysed. The dataset was split into a training set (n=1156, 67%) and a validation set (n=577, 33%). Top-ranked variables were identified using the random forest survival algorithm and integrated into a Cox regression model, thereby constructing the scoring system for predicting the overall survival of patients with advanced gastric cancer. RESULTS The following five variables were finally included in the scoring system: serum neutrophil-lymphocyte ratio, alkaline phosphatase level, albumin level, performance status and histologic differentiation. The scoring system determined four distinct risk groups in the validation dataset with median overall survival of 17.1 months (95% CI=14.9 to 20.5 months), 12.9 months (95% CI=11.4 to 14.6 months), 8.1 months (95% CI=5.3 to 12.3 months) and 3.9 months (95% CI=1.5 to 8.2 months), respectively. The area under the curve to estimate the discrimination performance of the scoring system was 66.1 considering 1 year overall survival. CONCLUSIONS We developed a simple and clinically useful predictive scoring model in a homogeneous population with advanced gastric cancer treated with fluoropyrimidine-containing and platinum-containing chemotherapy. However, additional independent validation will be required before the scoring model can be used commonly.
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Affiliation(s)
- Jinchul Kim
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Hematology-Oncology, Inha University College of Medicine and Hospital, Incheon, Republic of Korea
| | - Jung Yong Hong
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seung Tae Kim
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Se Hoon Park
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Se Yong Jekal
- Health Information and Strategy Center, Samsung Medical Center, Seoul, Republic of Korea
| | - Jong Soo Choi
- Health Information and Strategy Center, Samsung Medical Center, Seoul, Republic of Korea
| | - Dong Kyung Chang
- Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won Ki Kang
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung Wook Seo
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jeeyun Lee
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Shao W, Yang Z, Fu Y, Zheng L, Liu F, Chai L, Jia J. The Pyroptosis-Related Signature Predicts Prognosis and Indicates Immune Microenvironment Infiltration in Gastric Cancer. Front Cell Dev Biol 2021; 9:676485. [PMID: 34179006 PMCID: PMC8226259 DOI: 10.3389/fcell.2021.676485] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 05/19/2021] [Indexed: 01/20/2023] Open
Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related deaths and shows high levels of heterogeneity. The development of a specific prognostic model is important if we are to improve treatment strategies. Pyroptosis can arise in response to H. pylori, a primary carcinogen, and also in response to chemotherapy drugs. However, the prognostic evaluation of GC to pyroptosis is insufficient. Consensus clustering by pyroptosis-related regulators was used to classify 618 patients with GC from four GEO cohorts. Following Cox regression with differentially expressed genes, our prognosis model (PS-score) was built by LASSO-Cox analysis. The TCGA-STAD cohort was used as the validation set. ESTIMATE, CIBERSORTx, and EPIC were used to investigate the tumor microenvironment (TME). Immunotherapy cohorts by blocking PD1/PD-L1 were used to investigate the treatment response. The subtyping of GC based on pyroptosis-related regulators was able to classify patients according to different clinical traits and TME. The difference between the two subtypes identified in this study was used to develop a prognosis model which we named “PS-score.” The PS-score could predict the prognosis of patients with GC and his/her overall survival time. A low PS-score implies greater inflammatory cell infiltration and better response of immunotherapy by PD1/PD-L1 blockers. Our findings provide a foundation for future research targeting pyroptosis and its immune microenvironment to improve prognosis and responses to immunotherapy.
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Affiliation(s)
- Wei Shao
- Key Laboratory for Experimental Teratology of The Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zongcheng Yang
- School of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yue Fu
- Key Laboratory for Experimental Teratology of The Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.,School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lixin Zheng
- Key Laboratory for Experimental Teratology of The Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Fen Liu
- Key Laboratory for Experimental Teratology of The Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Li Chai
- Key Laboratory for Experimental Teratology of The Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jihui Jia
- Key Laboratory for Experimental Teratology of The Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong University-Karolinska Institutet Collaborative Laboratory for Cancer Research, Jinan, China
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Yoshikawa GT, Simon N, Nakasone RK, Acoba JD. Disaggregating Data on Pacific Islander Gastric Cancer Patients Reveals Survival Disparity. J Gastrointest Cancer 2021; 53:144-150. [PMID: 33392961 DOI: 10.1007/s12029-020-00579-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE The incidence and prognosis of Pacific Islanders with gastric cancer is not well documented as previous studies have often aggregated this population with Asians. The purpose of our study was to describe patient and tumor characteristics, as well as prognostic factors of Pacific Islanders with gastric cancer. METHODS Patients diagnosed with gastroesophageal junction or gastric adenocarcinoma between 2000 and 2014 were identified in the tumor registry of the largest hospital in Hawaii. Overall survival of Asians, Whites, and Pacific Islanders were calculated using the Kaplan-Meier method and log-rank test. Cox proportional hazards regression models were constructed to assess predictors of survival adjusting for clinical and pathological factors. RESULTS A total of 615 patients were included in the final analysis. Pacific Islanders were found to present at a younger age, were more often uninsured or had Medicaid insurance, and were diagnosed with a higher stage of cancer compared to their Asian and White counterparts. Pacific Islanders were less likely to undergo surgery even after adjusting for stage. Race was a prognostic factor and survival was lowest among Pacific Islanders, but only if the model was unadjusted for treatment. CONCLUSIONS We present an analysis of the largest cohort of Pacific Islander gastric cancer patients. Pacific Islanders have different sociodemographic characteristics and inferior survival compared to Asian patients and should be independently studied.
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Affiliation(s)
- Gene T Yoshikawa
- University of Hawai'i Internal Medicine Residency Program, Honolulu, HI, USA
| | - Nicholas Simon
- John A. Burns School of Medicine, University of Hawai'i at Manoa, Honolulu, HI, USA
| | - Ryon K Nakasone
- Internal Medicine Department, University of Hawai'i, Honolulu, HI, USA
| | - Jared D Acoba
- Internal Medicine Department, University of Hawai'i, Honolulu, HI, USA. .,University of Hawai'i Cancer Center, Honolulu, HI, USA. .,Queen's Medical Center, Honolulu, HI, USA.
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Jeong SH, Park M, Park SY, Park J, Kim TH, Lee YJ, Jung EJ, Ju YT, Jeong CY, Kim JY, Ko GH, Kim M, Nam KT, Goldenring JR. Transcriptome Analysis and the Prognostic Role of NUDC in Diffuse and Intestinal Gastric Cancer. Technol Cancer Res Treat 2021; 20:15330338211019501. [PMID: 34060350 PMCID: PMC8173992 DOI: 10.1177/15330338211019501] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/05/2021] [Accepted: 04/19/2021] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION There have been few studies about gene differences between patients with diffuse-type gastric cancer and those with intestinal-type gastric cancer. The aim of this study was to compare the transcriptomes of signet ring cell gastric cancer (worst prognosis in diffuse-type) and well-differentiated gastric cancer (best prognosis in intestinal-type); NUDC was identified, and its prognostic role was studied. MATERIALS AND METHODS We performed next-generation sequencing with 5 well-differentiated gastric cancers and 3 of signet ring cell gastric cancer surgical samples. We performed gene enrichment and functional annotation analysis using the Database for Annotation, Visualization and Integrated Discovery bioinformatics resources. Immunohistochemistry was used to validate NUDC expression. RESULTS Overall, 900 genes showed significantly higher expression, 644 genes showed lower expression in signet ring cell gastric cancer than in well-differentiated gastric cancers, and there was a large difference in adhesion, vascular development, and cell-to-cell junction components between the 2 subtypes. We performed variant analysis and found 52 variants and 30 cancer driver genes, including NUDC. We analyzed NUDC expression in gastric cancer tissue and its relationship with prognosis. Cox proportional hazard analysis identified T stage, N stage, and NUDC expression as independent risk factors for survival (P < 0.05). The overall survival of the NUDC-positive group was significantly higher (53.2 ± 0.92 months) than that of the NUDC-negative group (44.6 ± 3.7 months) (P = 0.001) in Kaplan-Meier survival analysis. CONCLUSION We found 30 cancer driver gene candidates and found that the NUDC-positive group showed significantly better survival than the NUDC-negative group via variant analysis.
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Affiliation(s)
- Sang-Ho Jeong
- Department of Surgery, School of Medicine, Gyeongsang National University, Jinju, South Korea
- Department of Surgery, Gyeongsang National University, Changwon Hospital, Changwon, South Korea
| | - Miyeong Park
- Department of Anesthesiology, Gyeongsang National University, Changwon Hospital, Changwon, South Korea
| | - Sun Yi Park
- Department of Surgery, School of Medicine, Gyeongsang National University, Jinju, South Korea
| | - Jiho Park
- Department of Surgery, School of Medicine, Gyeongsang National University, Jinju, South Korea
| | - Tae-Han Kim
- Department of Surgery, Gyeongsang National University, Changwon Hospital, Changwon, South Korea
| | - Young-Joon Lee
- Department of Surgery, School of Medicine, Gyeongsang National University, Jinju, South Korea
| | - Eun-Jung Jung
- Department of Surgery, School of Medicine, Gyeongsang National University, Jinju, South Korea
- Department of Surgery, Gyeongsang National University, Changwon Hospital, Changwon, South Korea
| | - Young-tae Ju
- Department of Surgery, School of Medicine, Gyeongsang National University, Jinju, South Korea
| | - Chi-Young Jeong
- Department of Surgery, School of Medicine, Gyeongsang National University, Jinju, South Korea
| | - Ju-Yeon Kim
- Department of Surgery, School of Medicine, Gyeongsang National University, Jinju, South Korea
| | - Gyung Hyuck Ko
- Department of Pathology, School of Medicine, Gyeongsang National University, Jinju, South Korea
| | - Minhye Kim
- Department of Pathology, School of Medicine, Gyeongsang National University, Jinju, South Korea
| | - Ki Taek Nam
- Severance Biomedical Science, Yonsei University College of Medicine, Seodaemun-gu, South Korea
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Ha GY, Yang SH, Kang HJ, Lee HL, Kim J, Kim YJ, Yu HJ, Lee JI, Jin SH. Comparison of survival outcomes according of patients with metastatic gastric cancer receiving trastuzumab with systemic chemotherapy. KOREAN JOURNAL OF CLINICAL ONCOLOGY 2020; 16:63-70. [PMID: 36945715 PMCID: PMC9942733 DOI: 10.14216/kjco.20011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/11/2020] [Accepted: 11/18/2020] [Indexed: 11/07/2022]
Abstract
Purpose Currently, trastuzumab plus chemotherapy is the standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic gastric cancer (mGC) or esophagogastric junction cancer. However, it is not clear whether the prognosis of HER2-positive mGC treated with trastuzumab plus chemotherapy is better than that of HER2-negative mGC treated with chemotherapy as the first-line therapy. Methods We performed a retrospective study comparing the prognosis of mGC according to first-line treatment with trastuzumab plus chemotherapy or chemotherapy only, at the Korea Cancer Center Hospital from 2011 to 2018. The Kaplan-Meier method and Cox proportional hazards model were used for univariate and multivariate survival analyses. Results The median overall survival of trastuzumab group was 26.1 months and that of chemotherapy group was 14.8 months (P=0.047). Trastuzumab group had a longer median progression-free survival than chemotherapy group (23.4 vs. 9.2 months, P=0.026). By univariate analysis, sex, age, World Health Organization (WHO) histology, HER2 status, primary tumor site, extent of disease, number of lesions, number of metastatic, measurability of disease, prior gastrectomy, and chemotherapy group are statistically significant. Using multivariate analysis, number of lesions, number of metastatic, prior gastrectomy, and trastuzumab group (hazard ratio, 0.594; 95% confidence interval, 0.384-0.921; P=0.020) were found to be independent prognostic factors of overall survival. Conclusion The result suggests prognosis of HER2-positive mGC treated by trastuzumab plus chemotherapy could be better than that of HER2-negative mGC treated by chemotherapy only. Well-designed prospective cohort studies are needed to confirm the results of this study. HER2 testing should be performed routinely in all patients newly diagnosed with mGC.
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Affiliation(s)
- Gi-Young Ha
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Sung-Hyun Yang
- Hemato-Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Hye-Jin Kang
- Hemato-Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Hyo-Lak Lee
- Hemato-Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Jin Kim
- Gastroenterology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Yun-Ju Kim
- Gastroenterology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Hang-Jong Yu
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Jong-Inn Lee
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Sung-Ho Jin
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
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Gülten G, Yilmaz B, Demirkan NÇ. Comparing human epidermal growth factor receptor 2 amplification and expression using immunohistochemistry and silver in situ hybridisation in gastric carcinoma and lymph node metastasis. Oncol Lett 2020; 20:1897-1905. [PMID: 32724433 PMCID: PMC7377164 DOI: 10.3892/ol.2020.11731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 05/13/2020] [Indexed: 12/24/2022] Open
Abstract
Detecting the amplification and expression of human epidermal growth factor receptor (HER2) is important for planning trastuzumab treatment for patients with gastric carcinoma. The present study aimed to analyse HER2 amplification and expression in primary gastric adenocarcinoma tumours and metastatic lymph nodes using microarray methods, and to assess the potential contribution of these methods to treatment planning. In total, 60 patients with lymph node metastasis were included in the present study. Microarray blocks were obtained from the tissue blocks of primary tumours and metastatic lymph nodes. HER2 expression and amplification were investigated using immunohistochemical and silver in situ hybridisation (SISH) methods, respectively. Following immunohistochemical evaluation of HER2 in primary tumours, the sensitivity and specificity of the microarray method relative to the single block method were 69 and 100%, respectively. For HER2 detection in microarray block sections from primary tumours, the sensitivity and specificity of the SISH method relative to immunohistochemistry were 56 and 100%, respectively. When using SISH in microarray blocked sections, there was a high degree of concordance (98% concordance rate) between HER2 amplification in the primary tumour and the metastatic lymph node. Furthermore, the sensitivity and specificity of metastatic lymph node results relative to those of the primary tumour were 100 and 98%, respectively. Overall, the single block method was more reliable compared with the microarray method for planning treatment. When microarray blocking was used, a large number of samples must be tested to ensure reliable results. The immunohistochemical method is recommended as the first step as SISH alone increases the risk of false-negative results. Assessing HER2 amplification for treatment planning would be beneficial for primary tumours, as well as metastatic lymph nodes.
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Affiliation(s)
- Gülsün Gülten
- Department of Pathology, Şanlıurfa Training and Research Hospital, 63250 Şanlıurfa, Turkey
| | - Bayram Yilmaz
- Department of Pathology, Hitit University Erol Olçok Training and Research Hospital, 19040 Çorum, Turkey
| | - Neşe Çalli Demirkan
- Department of Pathology, Faculty of Medicine, Pamukkale University, 20160 Denizli, Turkey
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Ahadi M, Moradi A, Musavinejad L, Movafagh A, Moradi A. The Expression of p53, CD44, Ki-67, and HER-2/neu Markers in Gastric Cancer and Its Association with Histopathological Indicators: A Retrospective Study. Asian Pac J Cancer Prev 2020; 21:1607-1614. [PMID: 32592354 PMCID: PMC7568877 DOI: 10.31557/apjcp.2020.21.6.1607] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 06/21/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Gastric cancer is known as one of the most common cancers and causes of deaths. Early and proper diagnosis is one of the most important things for treatment response. Therefore, this study aimed to determine the expression of p53, CD44, Ki-67, and HER-2/neu markers in the gastric cancer and its relationship with histopathological indicators. METHODS This is a descriptive-analytical study, in which 60 patients with cancer who underwent gastrectomy surgery in 2011-2016 in Shohadaye Tajrish Hospital. The participants were investigated for p53, CD44, Ki-67, and HER-2/neu markers' staining plus demographic characteristics, rate of survival, and histopathological features of the tumors. RESULTS The mean age of the participants (44 males and 16 females) was 60.25±1.29 years. The patients' survival rate was 23.82±1.56 months on average. The tumor size was reported as 6.09±2.61 mm and the major tumor type reported was intestinal type (n=40, 66.7%). The level of expression of Ki-67 and CD44 makers was recorded as 33.75 and 24.50%, and p53 and HER-2/neu genes were positive in 25 (41.7%) and 20 (33.3%) patients, respectively. The expression of p53 and CD44 markers had no significant relationship with the demographic characteristics, rate of survival, and histopathological features of the tumor of patients (all p>0.05). The expression of p53 gene was associated with the lower rate of survival (p=0.014), while the expression of HER-2/neu was associated with higher probability of developing intestinal type of stomach adenocarcinoma (p=0.010) and ulcerative macroscopic view (p=0.034). CONCLUSION This study illustrated that p53 and CD44 markers did not have any diagnostic value in predicting the biological behavior of gastric cancer. In fact, incidence of p53 gene was associated with the lower rate of survival, and the expression of HER-2/neu was associated with higher probability of developing the intestinal type of stomach adenocarcinoma and ulcerative macroscopic view.
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Affiliation(s)
- Mahsa Ahadi
- Department of Pathology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Afshin Moradi
- Department of Pathology, Shohada-e-Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Leila Musavinejad
- Department of Pathology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Abolfazl Movafagh
- Department of Medical Genetics, Schoolof Medicine, Shahid Behesti University of Medical Sciences, Tehran, Iran.
| | - Arsham Moradi
- Department of Biology, University of Toronto, Toronto, Canada.
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Dijksterhuis WPM, Verhoeven RHA, Meijer SL, Slingerland M, Haj Mohammad N, de Vos-Geelen J, Beerepoot LV, van Voorthuizen T, Creemers GJ, van Oijen MGH, van Laarhoven HWM. Increased assessment of HER2 in metastatic gastroesophageal cancer patients: a nationwide population-based cohort study. Gastric Cancer 2020; 23:579-590. [PMID: 31927675 PMCID: PMC7305095 DOI: 10.1007/s10120-020-01039-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 01/02/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Addition of trastuzumab to first-line palliative chemotherapy in gastroesophageal cancer patients with HER2 overexpression has shown to improve survival. Real-world data on HER2 assessment and administration of trastuzumab are lacking. The aim of this study was to assess HER2 testing, trastuzumab administration, and overall survival (OS) in a nationwide cohort of metastatic gastroesophageal cancer patients. METHODS Data of patients with synchronous metastatic gastroesophageal adenocarcinoma diagnosed in 2010-2016 that received palliative systemic treatment (n = 2846) were collected from the Netherlands Cancer Registry and Dutch Pathology Registry. The ToGA trial criteria were used to determine HER2 overexpression. Proportions of HER2 tested patients were analyzed between hospital volume categories using Chi-square tests, and over time using trend analysis. OS was tested using the Kaplan Meier method with log rank test. RESULTS HER2 assessment increased annually, from 18% in 2010 to 88% in 2016 (P < 0.01). Median OS increased from 6.9 (2010-2013) to 7.9 months (2014-2016; P < 0.05). Between the hospitals, the proportion of tested patients varied between 29-100%, and was higher in high-volume hospitals (P < 0.01). Overall, 77% of the HER2 positive patients received trastuzumab. Median OS was higher in patients with positive (8.8 months) and negative (7.4 months) HER2 status, compared to non-tested patients (5.6 months; P < 0.05). CONCLUSION Increased determination of HER2 and administration of trastuzumab have changed daily practice management of metastatic gastroesophageal cancer patients receiving palliative systemic therapy, and possibly contributed to their improved survival. Further increase in awareness of HER2 testing and trastuzumab administration may improve quality of care and patient outcomes.
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Affiliation(s)
- Willemieke P. M. Dijksterhuis
- grid.7177.60000000084992262Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands ,grid.470266.10000 0004 0501 9982Department of Research and Development, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands
| | - Rob H. A. Verhoeven
- grid.470266.10000 0004 0501 9982Department of Research and Development, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands
| | - Sybren L. Meijer
- grid.7177.60000000084992262Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Marije Slingerland
- grid.10419.3d0000000089452978Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - Nadia Haj Mohammad
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Judith de Vos-Geelen
- grid.412966.e0000 0004 0480 1382Department of Internal Medicine, Division of Medical Oncology, GROW-School for Oncology and Developmental Biology, Maastricht UMC+, Maastricht, The Netherlands
| | - Laurens V. Beerepoot
- grid.416373.4Department of Medical Oncology, Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands
| | - Theo van Voorthuizen
- grid.415930.aDepartment of Medical Oncology, Rijnstate Hospital, Arnhem, The Netherlands
| | - Geert-Jan Creemers
- grid.413532.20000 0004 0398 8384Department of Medical Oncology, Catharina Hospital, Eindhoven, The Netherlands
| | - Martijn G. H. van Oijen
- grid.7177.60000000084992262Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands ,grid.470266.10000 0004 0501 9982Department of Research and Development, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands
| | - Hanneke W. M. van Laarhoven
- grid.7177.60000000084992262Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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Genc AZ, Koseoglu RD, Arici A, Demir O. HER-2/neu gene analysis on endoscopic biopsy samples and gastric resection materials in gastric carcinomas. RUSSIAN OPEN MEDICAL JOURNAL 2019; 8. [DOI: 10.15275/rusomj.2019.0410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Abstract
Objective ― HER-2/neu assay in gastric cancers is routinely evaluated by immunohistochemistry and fluorescent in situ hybridization methods because the monoclonal antibody trastuzumab developed against HER-2/neu give rise to significant improving on the survival. In the HER-2/neu evaluation, some problems related to the sampling process, analysis method, tumor biology and heterogeinity are encountered. Our aim in the present study was to analyze these evaluation problems on endoscopic biopsy samples and resection materials of our cases with gastric carcinoma. Material and Methods ― The study included 109 gastric cancer cases. The analyses were realized on the resection materials of the 109 cases and the endoscopic mucosa biopsies of 43 out of these 109 cases. Immunohistochemistry was applied on mucosa biopsies and, tumor sections of resections, while fluorescent in situ hybridization was performed on tumor sections of resections (21 cases). The assays results were compared with each other and clinicopathological parameters. Results ― Our rate of HER-2/neu positivity (IHC3+ and IHC2+/FISH+ cases) was 6.42%. The compatibility rate between the rates of overexpression and amplification in resections was 90.5% while the compatibility ratio between the overexpression rates of mucosa samples and resections was 95.4%. The false negativity rate on mucosa biopsies was detected as 4.65%. HER-2/neu status was not correlated with unfavorable clinicopatological features. Conclusion ― Our gene positivity rate was near the lower limit of the range reported in the literature. Our compatibility rate between the results of immunohistochemistry and fluorescent in situ hybridization was over 90%. However our false negativity rate in mucosa biopsy analysis was low according to the literature. In order to preclude false negativity arising from tumor heterogeinity, we think that immunohistochemistry should be applied on the whole section.
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AlMazmomy AM, Al-Hayani MM, Alomari M, Bazi AG. The Use of Epidermal Growth Factor Receptor Type 2-Targeting Tyrosine Kinase Inhibitors in the Management of Epidermal Growth Factor Receptor Type 2-Positive Gastric Cancer: A Narrative Review. Cureus 2019; 11:e6295. [PMID: 31938588 PMCID: PMC6942496 DOI: 10.7759/cureus.6295] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC), including gastroesophageal junction cancer (GEJC), continues to be one of the most frequently diagnosed neoplasms globally. Moreover, GC/GEJC is a principal cause of neoplasm-related fatalities. Early-stage GC/GEJC has a favorable five-year overall survival (OS) rate with surgical resection. However, the vast majority of patients present with advanced inoperable or metastatic disease with a very unfavorable five-year OS rate. Such patients are left with very limited therapeutic options, such as systemic chemotherapy, targeted therapy, and immunotherapy, all of which can be performed as monotherapy or in various combinations. The molecular profiling of GC has revealed several personalized therapeutic vulnerabilities, one of which is the expression of epidermal growth factor receptor type 2 (EGFR2, also known as HER2). HER2 overexpression or amplification is present in a fair subset of patients with GC/GEJC and has been shown to correlate with poor clinicopathological prognostic outcomes. Generally, treatment schemes to tackle HER2 in HER2-positive GC/GEJC comprise the use of anti-HER2 monoclonal antibodies or HER2-targeting tyrosine kinase inhibitors (TKIs). In this study, we engage in a narrative review of the available phase II and III literature on the efficacy and safety of HER2-targeting TKIs in the management of HER2-positive GC/GEJC.
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Affiliation(s)
- Asim M AlMazmomy
- Surgery, College of Medicine King Abdulaziz University, Rabigh, SAU
| | - Majed M Al-Hayani
- Neurology, College of Medicine King Abdulaziz University, Rabigh, SAU
| | - Mohammed Alomari
- Pediatrics, College of Medicine King Abdulaziz University, Rabigh, SAU
| | - Abdulrahman G Bazi
- Internal Medicine, College of Medicine King Abdulaziz University, Rabigh, SAU
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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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Selim JH, Shaheen S, Sheu WC, Hsueh CT. Targeted and novel therapy in advanced gastric cancer. Exp Hematol Oncol 2019; 8:25. [PMID: 31632839 PMCID: PMC6788003 DOI: 10.1186/s40164-019-0149-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 09/28/2019] [Indexed: 12/14/2022] Open
Abstract
The systemic treatment options for advanced gastric cancer (GC) have evolved rapidly in recent years. We have reviewed the recent data of clinical trial incorporating targeted agents, including inhibitors of angiogenesis, human epidermal growth factor receptor 2 (HER2), mesenchymal-epithelial transition, epidermal growth factor receptor, mammalian target of rapamycin, claudin-18.2, programmed death-1 and DNA. Addition of trastuzumab to platinum-based chemotherapy has become standard of care as front-line therapy in advanced GC overexpressing HER2. In the second-line setting, ramucirumab with paclitaxel significantly improves overall survival compared to paclitaxel alone. For patients with refractory disease, apatinib, nivolumab, ramucirumab and TAS-102 have demonstrated single-agent activity with improved overall survival compared to placebo alone. Pembrolizumab has demonstrated more than 50% response rate in microsatellite instability-high tumors, 15% response rate in tumors expressing programmed death ligand 1, and non-inferior outcome in first-line treatment compared to chemotherapy. This review summarizes the current state and progress of research on targeted therapy for advanced GC.
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Affiliation(s)
- Julie H. Selim
- School of Pharmacy, Loma Linda University, Loma Linda, CA 92350 USA
| | - Shagufta Shaheen
- Division of Oncology, Stanford Cancer Center, Stanford, CA 94304 USA
| | - Wei-Chun Sheu
- Department of Internal Medicine, Richmond University Medical Center, Staten Island, NY 10310 USA
| | - Chung-Tsen Hsueh
- Division of Medical Oncology and Hematology, Department of Medicine, Loma Linda University, 11175 Campus Street, CSP 11015, Loma Linda, CA 92354 USA
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Subasinghe D, Acott N, Kumarasinghe MP. A survival guide to HER2 testing in gastric/gastroesophageal junction carcinoma. Gastrointest Endosc 2019; 90:44-54. [PMID: 30928424 DOI: 10.1016/j.gie.2019.03.022] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 03/14/2019] [Indexed: 02/06/2023]
Abstract
Human epidermal growth factor receptor 2 (HER2) status determines gastric/gastroesophageal junction (GEJ) adenocarcinomas that benefit from targeted therapy; hence, HER2 testing has become a routine practice. Accurate HER2 testing is fundamental to select eligible patients who will benefit from HER2-targeted treatment. The reported HER2-positive rate in gastric/GEJ cancers ranges from 4.4% to 53.4%, and HER2-positive tumors are considered to have more-aggressive biologic behavior and tumor recurrence. Main modalities of HER2 testing in clinical practice include immunohistochemistry (IHC) for protein expression and in situ hybridization (ISH) for gene amplification. Many technical pitfalls affect the accuracy of HER2 result. Additionally, several issues in HER2 testing are related to the tumor biology, sample selection, interpretation of IHC and ISH results, and confirming HER2 status. Therefore, gastric/GEJ adenocarcinoma-specific HER2 testing protocols have been developed and standardized to minimize the impact of these preanalytical and analytical factors and to enhance reproducibility of HER2 testing results. This review provides up-to-date practical guidance to clinicians on accurate HER2 testing and interpretation of results in gastric/GEJ adenocarcinoma.
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Affiliation(s)
- Duminda Subasinghe
- Department of Surgery, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka; Digestive Disease Unit, Aintree University Hospital, NHS Foundation Trust, Liverpool, UK; Pathwest Laboratory Medicine, Perth and University of Western Australia, Perth, Australia
| | - Nathan Acott
- Pathwest Laboratory Medicine, Perth and University of Western Australia, Perth, Australia
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Aznab M, Maleksabet D, Khazaei S, Khazaei M, Rezaei M. The Role of Human Epidermal Growth Factor Receptor (HER2/neu) in the Prognosis of Patients with Gastric Cancer. Asian Pac J Cancer Prev 2019; 20:1989-1994. [PMID: 31350955 PMCID: PMC6745225 DOI: 10.31557/apjcp.2019.20.7.1989] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Indexed: 01/17/2023] Open
Abstract
Objective: Gastric cancer is one of the oncological challenges, and tendency toward target therapy in this cancer has been increased. Controversy still exists on prognostic value of HER2/neu expression and its relationship with clinicopathological characteristics and survival of gastric cancer patients. In this regard, the present study examined the status of HER2/neu in patients with gastric cancer and its prognostic effects. Methods: Pathological samples of 97 gastric cancer patients diagnosed over the last 8 or 9 years (from 2008 to the end of 2017) and treated with 5-fluorouracil, Docetaxel, and Cisplatin (TCF) were studied in this investigation. Patients were assigned to two groups according to their HER2/neu status. First group included patients with positive HER2/neu (Score 3) and second group involved patients with negative HER2/neu (Score 0 and 1). Patients were compared in terms of disease stage, survival rate, and mortality. Results: The mean age of patients was 58 years old. There were 75 men and 22 women in this study. In terms of disease stage, 4, 21, 41, and 31 patients were in stage I, II, III, and IV, respectively. Using IHC method, it was found that 27, 23, 25, and 22 patients had HER2/neu expression with score 0, score +1, score 2+ and score+3, respectively. We discovered that expression of positive HER2/neu was associated with male sex. We also observed that survival and mortality rates following treatment initiation were significantly different between HER2/neu positive and negative gastric cancer patients (P<0.01). Conclusion: Evaluation of HER2/neu status in gastric cancer patients showed that HER2/neu 3+ expression could reduce the patients’ survival. Therefore, it is recommended that patients who may benefit from trastuzumab, be treated. A clinical multi-center trial should be also considered for use of this drug in adjuvant cases.
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Affiliation(s)
- Mozaffar Aznab
- Department of Internal Medicine,Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | | | - Sdigheh Khazaei
- Molecular Pathology Research Center, Imam Reza University Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mansour Khazaei
- Taleghani University Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mansour Rezaei
- Department of Biostatistics, Public Health College, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Dai X, Zhang X, Yu J. Clinicopathological features and Borrmann classification associated with HER2-positive in primary gastric cancer. Clin Exp Gastroenterol 2019; 12:287-294. [PMID: 31303779 PMCID: PMC6605773 DOI: 10.2147/ceg.s212895] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 05/27/2019] [Indexed: 12/19/2022] Open
Abstract
PURPOSE Human epidermal growth factor receptor 2 (HER2) assesment is important for patients with advanced gastric cancer (GC) to determine trastuzumab therapy is being considered. A study was performed to evaluate the rate of HER2 positivity in patients with primary gastric cancer and to assess the relationship between HER2-positive and Borrmann classification. PATIENTS AND METHODS Four hundred and sixty-one patients with gastric or gastroesophageal junction cancer were confirmed as having adenocarcinoma between 2005 and 2016. HER2 status was assessed using immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH). Tissues were considered to be HER2-positive when assessment revealed either an IHC score of 3+ or IHC score 2+ accompanied by a positive FISH result. RESULTS The HER2-positive rate was significantly higher in men than in women (19% vs 9%; p=0.006). In our study, HER2-positive gastric tumors with differentiated histology were significantly higher. The proportion of HER2-positive gastric tumors of Borrmann classification III or IV was significantly higher than tumors classified as I or II. CONCLUSIONS HER2-positive gastric cancer tends to be associated with male gender, differentiated histology, and Borrmann tumor classification of III or IV.
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Affiliation(s)
- Xiaomin Dai
- Department of Pathology, Zhejiang Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Xijiong Zhang
- Department of Pathology, The No.1 People’s Hospital of Pinghu, Jiaxing, Zhejiang, People’s Republic of China
| | - Jin Yu
- Department of Pathology, Zhejiang Hospital, Hangzhou, Zhejiang, People’s Republic of China
- Department of Pathology, The No.1 People’s Hospital of Pinghu, Jiaxing, Zhejiang, People’s Republic of China
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Nagaya T, Okuyama S, Ogata F, Maruoka Y, Choyke PL, Kobayashi H. Near infrared photoimmunotherapy using a fiber optic diffuser for treating peritoneal gastric cancer dissemination. Gastric Cancer 2019; 22:463-472. [PMID: 30171392 PMCID: PMC7400986 DOI: 10.1007/s10120-018-0871-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 08/20/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Peritoneal dissemination (PD) of abdominal malignancies is a common form of metastasis and its presence signals a poor prognosis. New treatment is required for patients with PD. Near infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). In this study, we investigate in vitro and in vivo efficacy of trastuzumab (tra)-IR700DX NIR-PIT on a human epidermal growth factor receptor type 2 (HER2)-positive gastric cancer cell line. METHODS NIR-PIT effects were investigated in vitro and in vivo. Disseminated peritoneal implants mice were separated into 5 groups: (1) no treatment; (2) tra-IR700 i.v. only; (3) NIR light only; (4) NIR-PIT; (5) repeated NIR-PIT. The peritoneal cavity was irradiated with NIR light using a fiber optic diffuser delivered through the catheter. RESULTS Specific binding and cell-specific killing was observed after NIR-PIT in vitro. In the in vivo study, fluorescence endoscopy showed high tumor accumulation of tra-IR700 within tumors. Significantly prolonged survival was achieved in the three treatment groups (tra-IR700 i.v. only, NIR-PIT, and repeated NIR-PIT groups) compared with control and NIR light only group (p < 0.05 for tra-IR700 i.v. only, p < 0.01 for NIR-PIT, and p < 0.0001 for repeated NIR-PIT). Moreover, most prolonged survival was shown for the repeated NIR-PIT group (p < 0.0001 vs tra-IR700 i.v. only, p < 0.01 vs NIR-PIT). CONCLUSION NIR-PIT using a fiber optic diffuser to deliver light is a promising candidate for the treatment of disseminated peritoneal metastases and could be readily translated to humans.
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Affiliation(s)
- Tadanobu Nagaya
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, United States of America
| | - Shuhei Okuyama
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, United States of America
| | - Fusa Ogata
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, United States of America
| | - Yasuhiro Maruoka
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, United States of America
| | - Peter L. Choyke
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, United States of America
| | - Hisataka Kobayashi
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, United States of America,Corresponding author: Hisataka Kobayashi, M.D., Ph.D., Phone: 301-435-4086; Fax: 301-402-3191;
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Roy PS, Nyodu T, Hazarika M, Saikia BJ, Bhuyan C, Inamdar A, Nyuthe CW, Borthakur B, Sharma JD. Prevalence of HER2 Expression and Its Correlation with
Clinicopathological Parameters in Gastric or Gastroesophageal
Junction Adenocarcinoma in North-East Indian Population. Asian Pac J Cancer Prev 2019; 20:1139-1145. [PMID: 31030487 PMCID: PMC6948890 DOI: 10.31557/apjcp.2019.20.4.1139] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Objective: Human epidermal growth factor receptor 2 (erbb2/HER2) overexpression, has now been implicated in advanced gastric and gastroesophageal junction cancers. The study was conducted to determine the rate of HER2 positivity in patients with locally advanced or metastatic gastric and gastroesophageal adenocarcinoma in North-East India and to assess the impact of various demographic and clinical parameters on HER2 positivity. Methods: A total of 68 patients of age >18 years of gastric and gastroesophageal adenocarcinoma diagnosed on histopathological examination from September 2016 to February 2018 at Dr B Borooah Cancer Institute, Assam were enrolled for the observational (epidemiological) study. All patients were subjected to the HER2 immunohistochemistry test using a FDA-approved, standardized test kit. HER2 expression was correlated with various demographic and clinicopathological parameters. Results: The overall rate of HER2 positivity in the population studied was 56% (n=38). The rate was non-significantly higher in male, older age group (>60 years) and Hindu population. Similarly, HER2 positivity rate was higher in patients with well differentiated histology and was more common in patients with stage II and III diseases, but neither of the associations is statistically significant. HER2 positivity rate was significantly higher in proximal and in GEJ tumours (56% versus 44%, P=0.002). Conclusion: HER2 overexpression was evident in 56% of the North-East Indian patients with locally advanced and metastatic gastric and gastroesophageal adenocarcinoma. The overexpression correlated significantly with primary tumour site. Routine testing of gastric and gastroesophageal tumours for HER2 expression is recommended to provide a therapeutic advantage in Indian patients.
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Affiliation(s)
- Partha S Roy
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - Tomar Nyodu
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - Munlima Hazarika
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - B J Saikia
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - C Bhuyan
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - Amit Inamdar
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - C W Nyuthe
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - B Borthakur
- Department of Surgical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India
| | - J D Sharma
- Department of Pathology, Dr B Borooah Cancer Institute, Guwahati, Assam, India
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Liu R, Kong Y, Sun P, Li F, Shi X. Correlation between methylation of the caveolin‐1 gene and of caveolin‐1 messenger ribonucleic acid, and protein levels and human epidermal growth factor receptor 2 protein expression in adenocarcinomas of the esophagogastric junction. PRECISION RADIATION ONCOLOGY 2019. [DOI: 10.1002/pro6.61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Affiliation(s)
- Ruizhen Liu
- The First People's Hospital of Wu'an Wu'an Hebei China
| | - Yi Kong
- The First People's Hospital of Wu'an Wu'an Hebei China
| | - Pengbo Sun
- The First People's Hospital of Wu'an Wu'an Hebei China
| | - Faliang Li
- The First People's Hospital of Wu'an Wu'an Hebei China
| | - Xiaopeng Shi
- The First People's Hospital of Wu'an Wu'an Hebei China
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Raj N, Verma D, Kumar A, Rai P, Rao RN. HER2 Oncogene Amplification and Immunohistochemical Profiling in Gastric Adenocarcinoma. Discoveries (Craiova) 2018; 6:e83. [PMID: 32309603 PMCID: PMC7086066 DOI: 10.15190/d.2018.6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background and Objectives: Gastric adenocarcinoma is one of the most common malignant tumors and a major cause of cancer death worldwide, especially in developing countries. Her2/neu gene amplification and protein overexpression in breast cancer is a golden criterion for the targeted therapy with trastuzumab. However, the role of Her2 as a prognostic factor in gastric cancer is still controversial. The purpose of this study was to evaluate the frequency of Her2 oncogene overexpression and concordance between the results for Her2 protein expression and gene amplification. Materials and Methods: A total of 65 retroprospective cases with gastric adenocarcinoma, including biopsy and resected specimens obtained between July 2015 to December 2017, were analyzed. Her2/neu expression was determined by Immuno-histochemistry (IHC). Equivocal and some selected cases were submitted for FISH to detect Her2/neu gene amplification. Results: In the present study, out of 65 patients of gastric adenocarcinoma, there were 50 males and 15 females, with mean age of 54.52 years. The majority of tumors were located within the antropyloric region. We found 27 (41.4%) positivity, scored as IHC 3+ and IHC 2+, and 38 (58.3%) negativity, scored as IHC 1+ and IHC 0. We also evidentiated a significant difference between Her2/neu expression with age (p=0.010) and depth of invasion (p=0.020).Her2/neu gene was amplified only in 13 cases, 4 cases were of Her2/neu (3+) positive, 11 cases (39.3%) Her2/neu (2+) with IHC staining. The concordance rate between the results of IHC and FISH in all 18 cases was 83.3%. Conclusion: IHC detection can be carried out to guide the treatment when FISH detection cannot be performed. Overexpression of Her 2/neu in gastric adenocarcinoma could potentially be used in selecting the patients who can get benefit from the anti-Her2/neu targeted therapy.
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Affiliation(s)
- Nisha Raj
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Divya Verma
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Praveer Rai
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Ram Nawal Rao
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
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Liu S, Mao Q, Xue W, Zhang X, Qi Y, Wang Y, Chen P, Zhou Q. High expression of ALPPL2 is associated with poor prognosis in gastric cancer. Hum Pathol 2018; 86:49-56. [PMID: 30496798 DOI: 10.1016/j.humpath.2018.11.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 11/15/2018] [Accepted: 11/16/2018] [Indexed: 12/11/2022]
Abstract
Alkaline phosphatase placental-like 2 (ALPPL2) is a member of the ALPP alkaline phosphatase family and is reported to be associated with the growth of some tumors. Gastric cancer is one of the most common cancers worldwide. We previously identified a distinct expression pattern of ALPPL2 between gastric cancer and adjacent normal tissues. In this study, we examined the expression of ALPPL2 in gastric adenocarcinoma and its ability to predict prognosis. We used bioinformatics analysis and immunohistochemistry to examine the expression pattern of ALPPL2 and analyzed the associations between ALPPL2 level and perioperative characteristics and the prognosis of gastric adenocarcinoma patients by Kaplan-Meier plotter analysis. Our results indicated that the expression of ALPPL2 was significantly increased in gastric adenocarcinoma (P < .01) and was an independent factor (P < .05) that could provide reliable prognostic information on gastric adenocarcinoma patients. High expression of ALPPL2 was associated with advanced TNM stage (P < .05) and high HER-2 expression (P < .01). Our study suggests that ALPPL2 has the potential to reveal prognostic information on gastric cancer.
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Affiliation(s)
- Shuang Liu
- Department of Clinical Bio-bank, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China; Department of Pathology, Medical School of Nantong University, Nantong, Jiangsu 226001, China
| | - Qinsheng Mao
- Department of General Surgery, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Wanjiang Xue
- Department of General Surgery, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Xiaojing Zhang
- Department of Clinical Bio-bank, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Yue Qi
- Department of Clinical Bio-bank, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Yingjing Wang
- Department of Clinical Bio-bank, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Pei Chen
- Department of Clinical Bio-bank, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Qing Zhou
- Department of Education and Training Office, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
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Ciesielski M, Szajewski M, Pęksa R, Lewandowska MA, Zieliński J, Walczak J, Szefel J, Kruszewski WJ. The relationship between HER2 overexpression and angiogenesis in gastric cancer. Medicine (Baltimore) 2018; 97:e12854. [PMID: 30334990 PMCID: PMC6211927 DOI: 10.1097/md.0000000000012854] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
In gastric cancer, HER2 protein overexpression is considered to be conducive to the higher proliferation activity of the tumor cells. Tumor formation is associated with angiogenesis in order to secure an abundant supply of oxygen and glucose to cancer cells. The aim of the study was to assess if HER2 overexpression is related to higher microvessel density (MVD) in the tumor stroma.The archival samples of primary tumor from 144 consecutive patients that underwent gastric resection for cancer between August 1, 2006 and December 31, 2013 in the Department of Oncological Surgery of Medical University of Gdańsk were analyzed. CD34 was used as a marker of MVD in the tumor stroma. Both CD34 and HER2 protein expressions were tested by immunohistochemistry.The assays were unsuccessful to estimate HER2 in 10 cases and CD34 in 14 cases due to technical reasons. The results were obtained for 128 patients. HER2 0 and HER2 1+ were considered negative, while HER2+ and HER2 3+ were recognized as positive. Mean MVD (mean number of vessels in the visual field) was 32.4 (median 29.5). Microvessel density was insignificantly higher in HER2 positive tumors. The slight difference was also seen between IHC 2+ and 3+ groups. The differences did not reach the level of statistical significance.Statistical analysis performed in our study did not reveal the significant relationship between HER2 overexpression on the tumor cells and MVD in the tumor stroma.
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Affiliation(s)
- Maciej Ciesielski
- Department of Oncological Surgery, Gdynia Oncology Centre, Gdynia
- Division of Propedeutics of Oncology, Medical University Of Gdańsk
| | - Mariusz Szajewski
- Department of Oncological Surgery, Gdynia Oncology Centre, Gdynia
- Division of Propedeutics of Oncology, Medical University Of Gdańsk
| | - Rafał Pęksa
- Department of Pathomorphology, Medical University of Gdańsk, Gdańsk
| | | | - Jacek Zieliński
- Department of Oncological Surgery, Medical University of Gdańsk, Gdańsk, Poland
| | - Jakub Walczak
- Department of Oncological Surgery, Gdynia Oncology Centre, Gdynia
| | - Jarosław Szefel
- Department of Oncological Surgery, Gdynia Oncology Centre, Gdynia
- Division of Propedeutics of Oncology, Medical University Of Gdańsk
| | - Wiesław Janusz Kruszewski
- Department of Oncological Surgery, Gdynia Oncology Centre, Gdynia
- Division of Propedeutics of Oncology, Medical University Of Gdańsk
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