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Hu Y, Wang B, Shi C, Ren P, Zhang C, Wang Z, Zhao J, Zheng J, Wang T, Wei B, Zhang H, Yu R, Shen Y, Ma J, Guo Y. A machine learning approach to risk-stratification of gastric cancer based on tumour-infiltrating immune cell profiles. Ann Med 2025; 57:2489007. [PMID: 40208029 DOI: 10.1080/07853890.2025.2489007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 03/14/2025] [Accepted: 03/25/2025] [Indexed: 04/11/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is a highly heterogeneous disease, and the response of patients to clinical treatment varies substantially. There is no satisfactory strategy for predicting curative effects to date. We aimed to explore a new method for predicting the clinical efficacy of GC treatment based on immune variables detected via flow cytometry. METHODS We collected 394 tumour tissues from GC patients for flow cytometry analysis and gating analysis of tumour-infiltrating immune cells (TIICs). Unsupervised consensus clusters were generated from the cohort to classify patients into different phenogroups, and their clinical characteristics were examined. The derived model was evaluated via principal component analysis and t-distributed stochastic neighbourhood embedding analysis. Kaplan-Meier's curves were used to determine the prognosis during a 920-day-long median follow-up period (interquartile range: 834-1071 days). Adjusted multivariate Cox regression analysis was used to evaluate the association of clusters with disease-free survival (DFS) and recurrence. RESULTS All patients were classified based on their TIIC profiles into the C1 (characterized by low CD45 negative cell, high lymphocyte, high neutrophil and low CD3 + T cell levels), C2 (characterized by high CD8 + CD279+ cell and low CD4+ Th and CD8+ Tc cell numbers) and C3 (characterized by high CD4 + CD25+ and Treg cell levels) phenogroups. Patients from the three clusters had varied pathologies, MMR statuses and TIIC distribution patterns (p < .05). Kaplan-Meier's analysis showed that the prognosis of C3 was inferior compared to C1 and C2 (p = .0025). Adjusted Cox proportional hazard models helped us identify that C1 and C2 exhibited a favourable factor of recurrence after surgery, compared to C3. Kaplan-Meier's analysis showed that C1 and C2 were associated with a better DFS than C3 in some GC patient subgroups. CONCLUSIONS The machine learning model developed was found to be effective model at predicting the prognosis of patients with GC and their TIIC profiles for risk stratification in clinical settings.
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Affiliation(s)
- Yanping Hu
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
| | - Bo Wang
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
| | - Chao Shi
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
| | - Pengfei Ren
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
| | - Chengjuan Zhang
- Center of Repository, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Zhizhong Wang
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
| | - Jiuzhou Zhao
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
| | - Jiawen Zheng
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
| | - Tingjie Wang
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
| | - Bing Wei
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
| | - He Zhang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Rentao Yu
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yihang Shen
- Central Laboratory, Suzhou Ninth People's Hospital, Suzhou, China
| | - Jie Ma
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
| | - Yongjun Guo
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
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Liao Y, Chen X, Hu S, Chen B, Zhuo X, Xu H, Wu X, Zeng X, Zeng H, Zhang D, Zhi Y, Zhao L. Artificial Intelligence for Predicting HER2 Status of Gastric Cancer Based on Whole-Slide Histopathology Images: A Retrospective Multicenter Study. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2408451. [PMID: 39792693 PMCID: PMC11904990 DOI: 10.1002/advs.202408451] [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: 07/23/2024] [Revised: 12/15/2024] [Indexed: 01/12/2025]
Abstract
Human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC) shows a robust response to the combined therapy based HER2-targeted therapy. The application of these therapies is highly dependent on the evaluation of tumor HER2 status. However, there are many risks and challenges in HER2 assessment in GC. Therefore, an economically viable and readily available instrument is requisite for distinguishing HER2 status among patients diagnosed with GC. The study has innovatively developed a deep learning model, HER2Net, which can predict the HER2 status by quantitatively calculating the proportion of HER2 high-expression regions. The HER2Net is trained on an internal training set derived from 531 hematoxylin & eosin (H&E) whole slide images (WSI) of 520 patients. Subsequently, the performance of HER2Net is validated on an internal test set from 115 H&E WSI of 111 patients and an external multi-center test set from 102 H&E WSI of 101 patients. The HER2Net achieves an accuracy of 0.9043 on the internal test set, and an accuracy of 0.8922 on an external test set from multiple institutes. This discovery indicates that the HER2Net can potentially offer a novel methodology for the identification of HER2-positive GC.
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Affiliation(s)
- Yuhan Liao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xinhua Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Shupeng Hu
- School of Computer Science, University of Manchester, Manchester, M13 9PL, UK
| | - Bing Chen
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xinghua Zhuo
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Hao Xu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xiaojin Wu
- Department of Pathology, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan, Guangdong, 528399, China
| | - Xiaofeng Zeng
- Department of Pathology, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan, Guangdong, 528399, China
| | - Huimin Zeng
- Department of Pathology, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan, Guangdong, 528399, China
| | - Donghui Zhang
- Department of Pathology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China
| | - Yunfei Zhi
- Department of Gastroenterology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan, Guangdong, 528399, China
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Dash S, Anirvan P, Samantaray S, Swain PK, Parida PK, Rout N, Ranjit M. Human epidermal growth factor receptor-2/neu expression in gallbladder cancer is significantly associated with clinicopathological parameters and survival. Indian J Gastroenterol 2025:10.1007/s12664-024-01723-x. [PMID: 39899204 DOI: 10.1007/s12664-024-01723-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 12/06/2024] [Indexed: 02/04/2025]
Abstract
BACKGROUND Anti-human epidermal growth factor receptor-2 (Her-2/neu) target therapy has substantially improved the disease outcome of patients with breast and gastric/gastroesophageal cancers characterized by Her-2/neu overexpression and/or amplification. Consequently, evaluating Her-2/neu expression in other cancers to predict response to Her-2/neu targeting agents emerges as a crucial approach. We aimed at investigating the positivity rate of this receptor in gallbladder cancer (GBC) and assess the relationship between Her-2/neu status, clinicopathological parameters and survival to identify patients who would benefit most from anti-Her-2/neu-targeted therapy. The Her-2/neu expression was correlated with clinicopathological parameters and survival of GBC cases. METHODS Total 235 surgically resected and histopathologically proven primary GBC cases were collected over a five-year period from January 1, 2017, to December 31, 2020. Her-2/neu expression in these cases was analyzed using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). RESULTS Employing testing algorithms (IHC scoring based on gastric cancer criteria, followed by FISH in equivocal cases), Her-2/neu positivity was identified in 43 (18.29%) GBC cases and was significantly associated with grade-I tumors, tumor stage > T2, perineural invasion, surgical margin positivity and advanced Tumor-Node-Metastasis (TNM) stage. The mean survival time for Her-2/neu-positive cases was 14 months (SE, 1.1; 95% CI, 11.7-16.06), while it was 20 months (SE, 0.69; 95%CI, 18.1-20.9) for Her-2-negative cases (p < 0.001). CONCLUSION Her-2/neu is expressed in about one-fifth of GBC patients and is significantly associated with tumor behavior and patient survival. Utilizing novel targeted agents may hold the key to improving the prognosis of these patients.
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Affiliation(s)
- Sashibhusan Dash
- Department of Pathology, Acharya Harihar Postgraduate Institute of Cancer, Cuttack 753 007, India
- Department of Molecular Epidemiology, ICMR-Regional Medical Research Centre, Bhubaneswar 751 023, India
| | - Prajna Anirvan
- Department of Translational Research, Kalinga Gastroenterology Foundation, Cuttack 753 001, India.
| | - Sagarika Samantaray
- Department of Pathology, Acharya Harihar Postgraduate Institute of Cancer, Cuttack 753 007, India
| | - Prafulla Kumar Swain
- Department of Statistics, Utkal University, Vanibihar, Bhubaneswar 751 004, India
| | - Prasant Kumar Parida
- Department of Medical Oncology, Acharya Harihar Postgraduate Institute of Cancer, Cuttack 753 007, India
| | - Niranjan Rout
- Patholab Healthcare Private Limited, Cuttack 753 001, India
| | - Manoranjan Ranjit
- Department of Molecular Epidemiology, ICMR-Regional Medical Research Centre, Bhubaneswar 751 023, India.
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Cai X, Cao M, Yang Q, Yu X, Feng XH, Zhao RY. HER2-targeted ADC DX126-262 combined with chemotherapy demonstrates superior antitumor efficacy in HER2-positive gastric cancer. Am J Cancer Res 2024; 14:5752-5768. [PMID: 39803638 PMCID: PMC11711518 DOI: 10.62347/qcdr9612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 01/16/2025] Open
Abstract
Gastric cancer is a common malignant tumor with high incidence and mortality. The overexpression of Human epidermal growth factor receptor 2 (HER2) is associated with increased metastatic potential and poor clinical outcome in gastric cancer. Despite the proven clinical response rates of approved HER2-targeted therapies, including Trastuzumab combined with chemotherapy, their limited long-term clinical benefits and inevitable disease progression still pose significant challenges to the clinical treatment of gastric cancer. Hence, exploring novel strategies to enhance therapeutic outcomes for HER2-positive patients is extremely crucial and urgent. Here, we reported that DX126-262, a novel HER2-targeted antibody-drug conjugate, generated by conjugating a potent Tubulysin B analogue (Tub-114) to humanized anti-HER2 monoclonal antibody, exhibited a significant synergistic inhibitory effect with both Cisplatin and 5-FU in HER2-positive gastric cancer NCI-N87 cells. Moreover, the triple-drug combination strategy of DX126-262 combined with Cisplatin and 5-FU showed much better in vitro and in vivo therapeutic efficacy than monotherapy or double-drug combination (Cisplatin plus 5-FU) or first-line standard-of-care (SOC, Herceptin plus Cisplatin and 5-FU), and comparable or even superior in vivo efficacy than third-line SOC (DS-8201a) in NCI-N87 cells and xenograft models. Meanwhile, the triple-drug combination therapy did not exhibit superimposed toxicity. Taken together, our findings provide compelling evidence that DX126-262 in combination with Cisplatin and 5-FU exerts synergistic antitumor activity and is a promising strategy to improve the clinical efficacy of HER2-positive advanced or metastatic gastric cancer.
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Affiliation(s)
- Xiaobo Cai
- Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityHangzhou 310058, Zhejiang, China
- Hangzhou DAC Biotechnology Co., Ltd.No. 369 Qiaoxin Road, Qiantang District, Hangzhou 310018, Zhejiang, China
| | - Min Cao
- Hangzhou DAC Biotechnology Co., Ltd.No. 369 Qiaoxin Road, Qiantang District, Hangzhou 310018, Zhejiang, China
| | - Qingliang Yang
- Hangzhou DAC Biotechnology Co., Ltd.No. 369 Qiaoxin Road, Qiantang District, Hangzhou 310018, Zhejiang, China
| | - Xiazhen Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of MedicineHangzhou 310003, Zhejiang, China
| | - Xin-Hua Feng
- Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityHangzhou 310058, Zhejiang, China
| | - Robert Yongxin Zhao
- Hangzhou DAC Biotechnology Co., Ltd.No. 369 Qiaoxin Road, Qiantang District, Hangzhou 310018, Zhejiang, China
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Kong Y, Dong Q, Jin P, Li MY, Ma L, Yi QJ, Miao YE, Liu HY, Liu JG. Inetetamab combined with S-1 and oxaliplatin as first-line treatment for human epidermal growth factor receptor 2-positive gastric cancer. World J Gastroenterol 2024; 30:4367-4375. [PMID: 39494102 PMCID: PMC11525863 DOI: 10.3748/wjg.v30.i40.4367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/07/2024] [Accepted: 09/23/2024] [Indexed: 10/16/2024] Open
Abstract
BACKGROUND Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer have poor outcomes. Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive advanced gastric cancer. Inetetamab is a novel anti-HER2 drug, and its efficacy and safety in gastric cancer have not yet been reported. AIM To evaluate the efficacy and safety of the S-1 plus oxaliplatin (SOX) regimen combined with inetetamab as a first-line treatment for HER2-positive advanced gastric cancer. METHODS Thirty-eight patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma were randomly divided into two groups: One group received inetetamab combined with the SOX regimen, and the other group received trastuzumab combined with the SOX regimen. After 4-6 cycles, patients with stable disease received maintenance therapy. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoints were the objective response rate, disease control rate, and adverse events (AEs). RESULTS Thirty-seven patients completed the trial, with 18 patients in the inetetamab group and 19 patients in the trastuzumab group. In the inetetamab group, the median PFS was 8.5 months, whereas it was 7.3 months in the trastuzumab group (P = 0.046); this difference was significant. The median OS in the inetetamab group vs the trastuzumab group was 15.4 months vs 14.3 months (P = 0. 33), and the objective response rate was 50% vs 42% (P = 0.63), respectively; these differences were not significant. Common AEs included leukopenia, thrombocytopenia, nausea, and vomiting. The incidence rates of grade ≥ 3 AEs were 56% in the inetetamab group and 47% in the trastuzumab group (P = 0.63), with no significant difference. CONCLUSION In the first-line treatment of HER2-positive advanced gastric cancer, inetetamab and trastuzumab showed comparable efficacy. The inetetamab group showed superior PFS, and both groups had good safety.
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Affiliation(s)
- Ying Kong
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Qi Dong
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Peng Jin
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Ming-Yan Li
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Li Ma
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Qi-Jun Yi
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Yu-E Miao
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Hai-Yan Liu
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Jian-Gang Liu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
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Cheng J, Cai M, Wang G, Tao K. HER2 becomes a novel survival biomarker for gastric cancer patients: a pooled analysis. Ther Adv Med Oncol 2024; 16:17588359241271913. [PMID: 39281969 PMCID: PMC11401144 DOI: 10.1177/17588359241271913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 07/02/2024] [Indexed: 09/18/2024] Open
Abstract
Background Although anti-HER2 therapies have been widely used against gastric carcinoma, the prognostic significance of HER2 overexpression remains unclear. Previous studies failed to provide convincible evidence due to inconsistent HER2 evaluation criteria and heterogeneous clinical characteristics. Objectives To figure out the prognostic significance of HER2 expression in gastric cancer, we rigorously designed and conducted this study. Design Meta-analysis. Data sources and methods Record retrieval was performed by searching PubMed, Web of Science, Cochrane Library, Embase, ASCO, and ESMO meeting libraries from inception to November 2022. Cohort studies investigating overall survival comparison between HER2-positive and HER2-negative gastric cancer patients were included. Both resectable and advanced cases were separately collected while HER2 evaluation standards should be consistent across eligible studies. Newcastle-Ottawa Scale was used for quality assessment. Overall survival was the only endpoint and effect size was presented by hazard ratio (HR) with its 95% confidence interval. The pooled calculation was conducted on Review Manager 5.4. Results Thirty studies were eligible, including 9945 patients. Eligible studies were mostly high quality (n = 31). Regarding resectable cases (n = 22), HER2-positive groups had significantly worse prognosis than HER2-negative counterparts (HR 1.56, 95%CI 1.32-1.85, p < 0.00001). For HER2-positive patients with advanced gastric cancer (n = 10), HER2 overexpression was also an unfavorable survival indicator (HR 1.70, 95%CI 1.23-2.35, p = 0.001). Potential heterogeneous studies had been eliminated while outcomes remained stable by sensitivity analysis. Subgroup analysis suggested HER2-positive patients had a poorer prognosis in both East Asian (resectable: HR 1.56; advanced: HR 1.32) and non-East Asian countries (HR 1.58; HR 3.27). Conclusion As a novel survival biomarker in gastric cancer, HER2 overexpression indicates unfavorable prognosis among both resectable and advanced patients, irrespective of East Asian or non-East Asian populations. Trial registration PROSPERO (CRD42020168051).
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Affiliation(s)
- Ji Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
| | - Ming Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guobin Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Mohammed O, Gizaw ST, Degef M. Potential diagnostic, prognostic, and predictive biomarkers of gastric cancer. Health Sci Rep 2024; 7:e2261. [PMID: 39040881 PMCID: PMC11260885 DOI: 10.1002/hsr2.2261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 06/29/2024] [Accepted: 07/04/2024] [Indexed: 07/24/2024] Open
Abstract
Background Gastric cancer (GC), a malignant epithelial tumor, is the fourth leading cause of cancer-related death worldwide. Therapeutic strategies for GC, despite the biggest challenges, can significantly improve survival rates through early detection and effective screening methods. Aim To provide brief information on the necessity of multiple specific diagnostic, prognostic, and predictive markers for GC. Methods This review was conducted using a variety of search engines, including PubMed Central, Scopus, Web of Science, Google Scholar, and others. Results Some potential biomarkers that provide essential information include circulating tumor cells (CTCs), DNA methylation, claudin 18.2, fibroblast growth factor receptor 2 (FGFR2), long noncoding RNAs (lncRNAs), cell-free DNA (cfDNA), microRNAs, and serum pepsinogens. Conclusion Multiple tumor markers are essential for screening, tumor identification, staging, prognostic assessment, and monitoring recurrence after therapy due to the absence of a single tumor indicator for diagnosing, prognosticating, and predicting GC.
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Affiliation(s)
- Ousman Mohammed
- Department of Medical Laboratory SciencesCollege of Medicine and Health Sciences, Wollo UniversityDessieEthiopia
| | - Solomon Tebeje Gizaw
- Department of Medical BiochemistrySchool of Medicine, College of Health Sciences, AAUAddis AbabaEthiopia
| | - Maria Degef
- Department of Medical BiochemistrySchool of Medicine, College of Health Sciences, AAUAddis AbabaEthiopia
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Qi X, Liu M, Xu K, Tan F, Gao P, Yao Z, Zhang N, Yang H, Zhang C, Xing J, Cui M, Su X. Risk factors and clinical significance of lower perigastric lymph node metastases in Siewert type II and III esophagogastric junction adenocarcinoma: a retrospective cohort study. Surg Endosc 2024; 38:3828-3837. [PMID: 38822144 PMCID: PMC11219428 DOI: 10.1007/s00464-024-10875-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 04/20/2024] [Indexed: 06/02/2024]
Abstract
BACKGROUND No consensus has been concluded with regarding to the scope of lymph node (LN) dissection for Siewert type II and III adenocarcinoma of the esophagogastric junction (AEG). This study aimed to explore risk factors for lower perigastric LN (LPLN) metastases (including no. 4d, 5, 6, and 12a LN stations) and analyze the indications for LPLN dissection. METHODS In total, 302 consecutive patients with Siewert type II and III AEG who underwent total gastrectomy (TG) were enrolled. The logistic regression model was used to perform uni- and multivariate analyses of risk factors for LPLN metastases. Kaplan-Meier curves were used for survival analysis, and log-rank tests were used for group comparisons. Basing on the guidelines of Japanese Gastric Cancer Association, the LN metastases (LNM) as well as the efficiency index (EI) of each LN station was further evaluated. RESULTS The independent risk factors for LPLN metastases in patients with Siewert type II and III AEG were distance from the esophagogastric junction (EGJ) to the distal end of the tumor (> 4.0 cm), preoperative carcinoembryonic antigen (CEA) ( +), pT4 stage, and HER-2 ( +). LPLN metastases was an independent risk factor for overall survival following TG. The LNM and EI of LPLN were 8.6% and 2.31%, respectively. The LNM of LPLN > 10% under the stratification of the distance from the EGJ to the distal end of the tumor (> 4.0 cm), pT4, preoperative CEA ( +), and HER-2 ( +) exhibited EI values of 3.55%, 2.09%, 2.51%, and 3.64%, respectively. CONCLUSIONS LPLN metastases was a malignant factor for the prognosis of patients with Siewert type II and III AEG. For patients with preoperative CEA ( +), pT4 stage, HER-2 ( +), and the distance from the EGJ to the distal end of the tumor (> 4.0 cm), TG with LPLN dissection is prioritized for clinical recommendation.
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Affiliation(s)
- Xinyu Qi
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China
| | - Maoxing Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China
| | - Kai Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China
| | - Fei Tan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China
| | - Pin Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China
| | - Zhendan Yao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China
| | - Nan Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China
| | - Hong Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China
| | - Chenghai Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China
| | - Jiadi Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China.
| | - Ming Cui
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China
| | - Xiangqian Su
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing, China.
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Lai MY, Guan WL, Yang J, Sun YT, Lu SX, Yang LQ, Yang DJ, Qiu MZ. The relationship between brain metastasis and HER2 expression status in gastric cancer. Clin Transl Oncol 2024; 26:765-773. [PMID: 37620706 DOI: 10.1007/s12094-023-03306-2] [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: 06/26/2023] [Accepted: 08/08/2023] [Indexed: 08/26/2023]
Abstract
BACKGROUND Brain metastasis (BM) in gastric cancer (GC) is underestimated, and human epidermal growth factor receptor 2 (HER2) overexpression is a durable poor prognostic factor. We explored the relationship between the two and made a survival analysis. METHODS HER2 expression and BM status were collected from GC patients who were diagnosed between December 2009 and May 2021. We collected GC patients diagnosed between 2010 and 2016 from the SEER database. The primary endpoint was survival from the diagnosis of BM. Multivariable logistic regression was used to determine potential risk factors of BM at diagnosis in SEER database. Survival analysis was performed using the Kaplan-Meier method. RESULT There were 513 HER2-positive GC patients, including 16 (3.1%) with BM. Among 38 brain metastasis GC patients we collected, 16 (42.1%) patients were HER2 positive. We collected 34,199 GC patients from the SEER database and there were 260 (0.76%) patients with BM at diagnosis. GC patients that are male, white, of younger age, with primary lesions located in the proximal stomach or with distant lymph nodes, liver, bone, or lung metastasis are more likely to develop BM. The median overall survival time from diagnosis of BM was 12.73 months, and the survival time from brain metastasis of HER2-positive patients was numerically shorter, though the difference was not significant (5.30 months vs.16.13 months, P = 0.28.) CONCLUSION: The incidence of BM in patients with HER2-positive gastric cancer is 4.08 times higher than that in general patients. The median overall survival time from BM is shorter for HER2-positive patients.
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Affiliation(s)
- Ming-Yu Lai
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Wen-Long Guan
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Jing Yang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Yu-Ting Sun
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Shi-Xun Lu
- Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Li-Qiong Yang
- Department of Experiment Research, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Da-Jun Yang
- Department of Experiment Research, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, China.
| | - Miao-Zhen Qiu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, China.
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10
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Chong X, Li Y, Lu J, Feng X, Li Y, Zhang X. Tracking circulating PD-L1-positive cells to monitor the outcome of patients with gastric cancer receiving anti-HER2 plus anti-PD-1 therapy. Hum Cell 2024; 37:258-270. [PMID: 37889437 PMCID: PMC10764514 DOI: 10.1007/s13577-023-00990-8] [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: 05/14/2023] [Accepted: 09/29/2023] [Indexed: 10/28/2023]
Abstract
Dual blockade of HER2 and PD-1/PD-L1 is the most promising regimen for HER2-positive patients with gastric cancer (GC); PD-L1 combined positive score, rather than HER2 status, indicates potential benefit. Circulating tumor cells (CTCs) and circulating endothelial cells (CECs) derived from the tumor microenvironment provide platforms for the dynamic evaluation of PD-L1 expression. Whether PD-L1 positive CTCs/CECs (PD-L1+CTCs/CECs) can serve as biomarkers for evaluating the efficacy of combination therapy remains unknown. Therefore, this study investigated PD-L1 expression and heterogeneous karyotypic features of CTCs/CECs and their involvement in the clinical response to treatment in 72 patients with advanced GC by applying a pre-established surface molecule-independent subtraction enrichment (SE)-iFISH strategy. In the captured PD-L1 positive cells, there were 42.80% and 57.20% of CTCs and CECs, respectively. PD-L1+ CTCs were pre-therapeutically detected in 0% (0/11) of HER2-negative patients and 14.75% (9/61) of HER2-positive patients. The presence of baseline PD-L1+CTCs was relevant to inferior prognosis (mPFS: 14.40 months vs 5.00 months, P = 0.065); post-treatment PD-L1+ CECs were associated with longer irPFS (immunotherapeutic-related PFS) (mPFS: 15.57 months vs 6.73 months, P = 0.053). Further dynamic karyotype-based profiling of PD-L1+ CTCs/CECs indicated that multiploidy and triploidy were the dominant subtypes of baseline PD-L1+ CTCs, and that triploidy was specifically associated with therapeutic resistance. Intratherapeutically detected multiploid PD-L1+ CECs demonstrated a superior clinical response; triploidy and tetraploidy contributed to acquired resistance. The karyotypic features of PD-L1+CTCs/CECs should be dynamically profiled in patients with GC treated with anti-HER2 plus anti-PD-1 therapy. Triploid-PD-L1+ CTCs and multiploid-PD-L1+ CECs are potential indicators of therapeutic response.
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Affiliation(s)
- Xiaoyi Chong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Yanyan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Jialin Lu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Xujiao Feng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Yilin Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China.
| | - Xiaotian Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China.
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11
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Wang F, Zhang X, Tang L, Wu Q, Cai M, Li Y, Qu X, Qiu H, Zhang Y, Ying J, Zhang J, Sun L, Lin R, Wang C, Liu H, Qiu M, Guan W, Rao S, Ji J, Xin Y, Sheng W, Xu H, Zhou Z, Zhou A, Jin J, Yuan X, Bi F, Liu T, Liang H, Zhang Y, Li G, Liang J, Liu B, Shen L, Li J, Xu R. The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023. Cancer Commun (Lond) 2024; 44:127-172. [PMID: 38160327 PMCID: PMC10794017 DOI: 10.1002/cac2.12516] [Citation(s) in RCA: 75] [Impact Index Per Article: 75.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 12/17/2023] [Accepted: 12/18/2023] [Indexed: 01/03/2024] Open
Abstract
The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.
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Affiliation(s)
- Feng‐Hua Wang
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Xiao‐Tian Zhang
- Department of Gastrointestinal OncologyKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer HospitalBeijingP. R. China
| | - Lei Tang
- Department of RadiologyPeking University Cancer HospitalBeijingP. R. China
| | - Qi Wu
- Department of Endoscopy CenterPeking University Cancer HospitalBeijingP. R. China
| | - Mu‐Yan Cai
- Department of PathologySun Yat‐sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer MedicineGuangzhouGuangdongP. R. China
| | - Yuan‐Fang Li
- Department of Gastric SurgerySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Xiu‐Juan Qu
- Department of Medical OncologyThe First Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Hong Qiu
- Department of Medical OncologyTongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Yu‐Jing Zhang
- Department of RadiotherapySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Jie‐Er Ying
- Department of Medical OncologyZhejiang Cancer HospitalHangzhouZhejiangP. R. China
| | - Jun Zhang
- Department of Medical OncologyRuijin HospitalShanghai Jiaotong University School of MedicineShanghaiP. R. China
| | - Ling‐Yu Sun
- Department of Surgical OncologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangP. R. China
| | - Rong‐Bo Lin
- Department of Medical OncologyFujian Cancer HospitalFuzhouFujianP. R. China
| | - Chang Wang
- Tumor CenterThe First Hospital of Jilin UniversityChangchunJilinP. R. China
| | - Hao Liu
- Department of General SurgeryNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Miao‐Zhen Qiu
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Wen‐Long Guan
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Sheng‐Xiang Rao
- Department of RadiologyZhongshan HospitalFudan UniversityShanghaiP. R. China
| | - Jia‐Fu Ji
- Department of Gastrointestinal SurgeryPeking University Cancer HospitalBeijingP. R. China
| | - Yan Xin
- Pathology Laboratory of Gastrointestinal TumorThe First Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Wei‐Qi Sheng
- Department of PathologyZhongshan Hospital Affiliated to Shanghai Fudan UniversityShanghaiP. R. China
| | - Hui‐Mian Xu
- Department of Gastrointestinal Oncology Surgery. The First Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Zhi‐Wei Zhou
- Department of Gastric SurgerySun Yat‐sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer MedicineGuangzhouGuangdongP. R. China
| | - Ai‐Ping Zhou
- Department of OncologyNational Cancer CenterNational Clinical Research Center for CancerCancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Jing Jin
- Department of Radiation OncologyShenzhen hospitalCancer Hospital of Chinese Academy of Medical SciencesBeijingP. R. China
| | - Xiang‐Lin Yuan
- Department of OncologyTongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Feng Bi
- Department of Abdominal OncologyWest China Hospital of Sichuan UniversityChengduSichuanP. R. China
| | - Tian‐Shu Liu
- Department of Medical OncologyZhongshan Hospital Affiliated to Fudan UniversityShanghaiP. R. China
| | - Han Liang
- Department of Gastric SurgeryTianjin Medical University Cancer Institute & HospitalTianjinP. R. China
| | - Yan‐Qiao Zhang
- Department of Medical OncologyCancer Hospital of Harbin Medical UniversityHarbinHeilongjiangP. R. China
| | - Guo‐Xin Li
- Department of General SurgeryNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Jun Liang
- Department of Medical OncologyPeking University International HospitalBeijingP. R. China
| | - Bao‐Rui Liu
- Department of Medical OncologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingP. R. China
| | - Lin Shen
- Department of GI OncologyKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer HospitalBeijingP. R. China
| | - Jin Li
- Department of OncologyEaster Hospital affiliated to Shanghai Tongji UniversityShanghaiP. R. China
| | - Rui‐Hua Xu
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
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12
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Nemtsova MV, Kuznetsova EB, Bure IV. Chromosomal Instability in Gastric Cancer: Role in Tumor Development, Progression, and Therapy. Int J Mol Sci 2023; 24:16961. [PMID: 38069284 PMCID: PMC10707305 DOI: 10.3390/ijms242316961] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/23/2023] [Accepted: 11/29/2023] [Indexed: 12/18/2023] Open
Abstract
According to the Cancer Genome Atlas (TCGA), gastric cancers are classified into four molecular subtypes: Epstein-Barr virus-positive (EBV+), tumors with microsatellite instability (MSI), tumors with chromosomal instability (CIN), and genomically stable (GS) tumors. However, the gastric cancer (GC) with chromosomal instability remains insufficiently described and does not have effective markers for molecular and histological verification and diagnosis. The CIN subtype of GC is characterized by chromosomal instability, which is manifested by an increased frequency of aneuploidies and/or structural chromosomal rearrangements in tumor cells. Structural rearrangements in the CIN subtype of GC are not accidental and are commonly detected in chromosomal loci, being abnormal because of specific structural organization. The causes of CIN are still being discussed; however, according to recent data, aberrations in the TP53 gene may cause CIN development or worsen its phenotype. Clinically, patients with the CIN subtype of GC demonstrate poor survival, but receive the maximum benefit from adjuvant chemotherapy. In the review, we consider the molecular mechanisms and possible causes of chromosomal instability in GC, the common rearrangements of chromosomal loci and their impact on the development and clinical course of the disease, as well as the driver genes, their functions, and perspectives on their targeting in the CIN subtype of GC.
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Affiliation(s)
- Marina V. Nemtsova
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (E.B.K.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
| | - Ekaterina B. Kuznetsova
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (E.B.K.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
| | - Irina V. Bure
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (E.B.K.)
- Russian Medical Academy of Continuous Professional Education, 125993 Moscow, Russia
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Hu CT, Pei SJ, Wang JL, Zu LD, Shen WW, Yuan L, Gao F, Jiang LR, Yau SST, Fu GH. Quantitative proteomics profiling reveals the inhibition of trastuzumab antitumor efficacy by phosphorylated RPS6 in gastric carcinoma. Cancer Chemother Pharmacol 2023; 92:341-355. [PMID: 37507485 DOI: 10.1007/s00280-023-04571-2] [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: 03/24/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023]
Abstract
BACKGROUND The anti-HER2 antibody trastuzumab is a standard treatment for gastric carcinoma with HER2 overexpression, but not all patients benefit from treatment with HER2-targeted therapies due to intrinsic and acquired resistance. Thus, more precise predictors for selecting patients to receive trastuzumab therapy are urgently needed. METHODS We applied mass spectrometry-based proteomic analysis to 38 HER2-positive gastric tumor biopsies from 19 patients pretreated with trastuzumab (responders n = 10; nonresponders, n = 9) to identify factors that may influence innate sensitivity or resistance to trastuzumab therapy and validated the results in tumor cells and patient samples. RESULTS Statistical analyses revealed significantly lower phosphorylated ribosomal S6 (p-RPS6) levels in responders than nonresponders, and this downregulation was associated with a durable response and better overall survival after anti-HER2 therapy. High p-RPS6 levels could trigger AKT/mTOR/RPS6 signaling and inhibit trastuzumab antitumor efficacy in nonresponders. We demonstrated that RPS6 phosphorylation inhibitors in combination with trastuzumab effectively suppressed HER2-positive GC cell survival through the inhibition of the AKT/mTOR/RPS6 axis. CONCLUSIONS Our findings provide for the first time a detailed proteomics profile of current protein alterations in patients before anti-HER2 therapy and present a novel and optimal predictor for the response to trastuzumab treatment. HER2-positive GC patients with low expression of p-RPS6 are more likely to benefit from trastuzumab therapy than those with high expression. However, those with high expression of p-RPS6 may benefit from trastuzumab in combination with RPS6 phosphorylation inhibitors.
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Affiliation(s)
- Chun-Ting Hu
- Department of Pathology, Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shao-Jun Pei
- School of Public Health, Peking University, Beijing, 100191, People's Republic of China
- Department of Mathematical Sciences, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Jing-Long Wang
- Department of Pathology, Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li-Dong Zu
- Department of Pathology, Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei-Wei Shen
- Department of Pathology, Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Yuan
- Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Gao
- Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li-Ren Jiang
- Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Stephen S-T Yau
- Yanqi Lake Beijing Institute of Mathematical Sciences and Applications (BIMSA), Huairou District, Beijing, 101400, People's Republic of China.
- Department of Mathematical Sciences, Tsinghua University, Beijing, 100084, People's Republic of China.
| | - Guo-Hui Fu
- Department of Pathology, Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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14
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Zhang LF, Li JL, Wang YH, Tai XH, Liu L, Zhang XX, An YW, Li HL. The Correlation Between 18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography Semiquantitative Parameters and the Clinical Features and Pathological Biological Indexes of Gastric Cancer. Cancer Biother Radiopharm 2023; 38:364-370. [PMID: 34529925 DOI: 10.1089/cbr.2020.4150] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Objective: This study explored the application value of the maximum standard uptake value (SUVmax) of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) in gastric cancer. Materials and Methods: Data of 164 patients with gastric cancer who had undergone18F-FDG PET/CT before a biopsy were collected, and the correlation of SUVmax with clinical stage, pathological differentiation degree, human epidermal growth factor receptor-2 (HER-2) status, and Ki-67 index of gastric cancer was analyzed. Results: The SUVmax of poorly differentiated adenocarcinoma was significantly higher than that of moderately differentiated adenocarcinoma and signet-ring cell carcinoma (p < 0.01), and SUVmax in the well-differentiated adenocarcinoma group was higher than that in the signet-ring cell carcinoma group (p < 0.01). The SUVmax in the HER-2 negative group was higher than that in the HER-2 positive group (p < 0.01). The SUVmax was higher in the Ki-67 high expression group than in the low expression group (p < 0.01), and there was a significant positive correlation between the two (p < 0.01). Conclusion: 18F-FDG PET/CT SUVmax can, to some extent, predict the degree of differentiation, HER-2 status, and Ki-67 index of gastric cancer patients.
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Affiliation(s)
- Ling-Fang Zhang
- Department of Oncology, Gansu Provincial Hospital, Lanzhou, China
| | - Jun-Liang Li
- Department of General Surgical, Gansu Provincial Hospital, Lanzhou, China
| | - Yan-Hong Wang
- Department of Oncology, Gansu Provincial Hospital, Lanzhou Petrochemical General Hospital of Gansu Province, Lanzhou, China
| | - Xiao-Hui Tai
- Department of Oncology, Gansu Provincial Hospital, Lanzhou, China
| | - Le Liu
- Department of Oncology, Gansu Provincial Hospital, Lanzhou, China
| | - Xu-Xia Zhang
- Department of Oncology, Gansu Provincial Hospital, Lanzhou, China
| | - Yi-Wei An
- Department of Oncology, Gansu Provincial Hospital, Lanzhou, China
| | - Hong-Ling Li
- Department of Oncology, Gansu Provincial Hospital, Lanzhou, China
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15
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Wang X, Hui S, Tan C, Deng Z, Wang X, Weng W, Zhang M, Ni S, Wang L, Huang D, Wang W, Xu M, Sheng W. Comprehensive analysis of immune subtypes reveals the prognostic value of cytotoxicity and FAP + fibroblasts in stomach adenocarcinoma. Cancer Immunol Immunother 2023; 72:1763-1778. [PMID: 36650362 PMCID: PMC10991216 DOI: 10.1007/s00262-023-03368-9] [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: 11/09/2022] [Accepted: 01/04/2023] [Indexed: 01/18/2023]
Abstract
BACKGROUND The heterogeneity limits the effective application of immune checkpoint inhibitors for patients with stomach adenocarcinoma (STAD). Precise immunotyping can help select people who may benefit from immunotherapy and guide postoperative management by describing the characteristics of tumor microenvironment. METHODS Gene expression profiles and clinical information of patients were collected from ACRG and TCGA-STAD datasets. The immune subtypes (ISs) were identified by consensus clustering analysis. The tumor immune microenvironments (TIME) of each IS were characterized using a series of immunogenomics methods and further confirmed by multiplex immunohistochemistry (mIHC) staining in clinical samples. Two online datasets and one in-house dataset were utilized to construct and validate a prognostic immune-related gene (IRG) signature. RESULTS STAD patients were stratified into five reproducible ISs. IS1 (immune deserve subtype) had low immune infiltration and the highest degree of HER2 gene mutation. With abundant CD8+ T cells infiltration and activated cytotoxicity reaction, patients in the IS2 (immune-activated subtype) had the best overall survival (OS). IS3 and IS4 subtypes were both in the reactive stroma state and indicated the worst prognosis. However, IS3 (immune-inhibited subtype) was characterized by enrichment of FAP+ fibroblasts and upregulated TGF-β signaling pathway, while IS4 (activated stroma subtype) was characterized by enrichment of ACTA2+ fibroblasts. In addition, mIHC staining confirmed that TGF-β upregulated FAP+ fibroblasts were independent risk factor of OS. IS5 (chronic inflammation subtype) displayed moderate immune cells infiltration and had a relatively good survival. Lastly, we developed a nine-IRG signature model with a robust performance on overall survival prognostication. CONCLUSIONS The immunotyping is indicative for characterize the TIME heterogeneity and the prediction of tumor prognosis for STADs, which may provide valuable stratification for the design of future immunotherapy.
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Affiliation(s)
- Xin Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Institute of Pathology, Fudan University, Shanghai, 200032, People's Republic of China
| | - Sun Hui
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Institute of Pathology, Fudan University, Shanghai, 200032, People's Republic of China
| | - Cong Tan
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Institute of Pathology, Fudan University, Shanghai, 200032, People's Republic of China
| | - Zhenzhong Deng
- Department of Oncology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, People's Republic of China
| | - Xu Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Institute of Pathology, Fudan University, Shanghai, 200032, People's Republic of China
| | - Weiwei Weng
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Institute of Pathology, Fudan University, Shanghai, 200032, People's Republic of China
| | - Meng Zhang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Institute of Pathology, Fudan University, Shanghai, 200032, People's Republic of China
| | - Shujuan Ni
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Institute of Pathology, Fudan University, Shanghai, 200032, People's Republic of China
| | - Lei Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Institute of Pathology, Fudan University, Shanghai, 200032, People's Republic of China
| | - Dan Huang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Institute of Pathology, Fudan University, Shanghai, 200032, People's Republic of China
| | - Wenfeng Wang
- Shanghai Urological Cancer Institute, Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China.
| | - Midie Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
- Institute of Pathology, Fudan University, Shanghai, 200032, People's Republic of China.
| | - Weiqi Sheng
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
- Institute of Pathology, Fudan University, Shanghai, 200032, People's Republic of China.
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16
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Gao X, Zhao L, Zhang N, Han W, Liu K, Yan J, Chen L, Pan Y, Li R, Li W, Zhang H, Li H, Wang S, Gao X, Niu P, Wang W, Ji G, Zhao Q, Lu Y, Li Z, Shang L, Liang H, Wu K, Deng J, Chen Y, Nie Y. Impact of HER2 on prognosis and benefit from adjuvant chemotherapy in stage II/III gastric cancer patients: a multicenter observational study. Int J Surg 2023; 109:1330-1341. [PMID: 37037586 PMCID: PMC10389606 DOI: 10.1097/js9.0000000000000370] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 03/16/2023] [Indexed: 04/12/2023]
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) is a well-developed therapeutic target in breast and gastric cancer (GC). However, the impact of HER2 on survival and benefit from fluorouracil-based adjuvant chemotherapy remains unclear in patients with GC. MATERIALS AND METHODS This multicenter cohort study involved 5622 consecutive stage II/III GC patients. HER2 expression was assessed prospectively via immunohistochemistry (IHC). The staining intensity was graded on a scale of 0 to 3+. An IHC score of 2+or 3+was defined as high expression, and a score of 3+was defined as overexpression. RESULTS HER2 overexpression was independently associated with a lower 5-year overall survival (OS) in stage II [hazard ratio (HR), 2.10; 95% CI: 1.41-3.11], but not in stage III GC (HR, 1.00; 95% CI, 0.82-1.20). Further analysis revealed that stage II patients with high HER2 expression showed a poorer response to chemotherapy than stage II patients with low HER2 expression ( Pinteraction =0.024). The HRs for 5-year OS were 0.51 (95% CI, 0.38-0.70) for stage II patients with low HER2 expression, 0.58 (95% CI, 0.51-0.66) for stage III patients with low HER2 expression, 1.13 (95% CI, 0.61-2.09) for stage II patients with high HER2 expression, and 0.47 (95% CI, 0.36-0.61) for stage III patients with high HER2 expression. CONCLUSIONS Fluorouracil-based adjuvant chemotherapy is insufficient for stage II GC patients with high HER2 expression, indicating that prospective trials are required to validate alternative HER2-targeted adjuvant therapies in the individuals above.
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Affiliation(s)
- Xianchun Gao
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
- Department of Health Statistics, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health
| | - Lulu Zhao
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Nannan Zhang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer
- Key Laboratory of Cancer Prevention and Therapy
- Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China
| | - Weili Han
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Kun Liu
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Junya Yan
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Ling Chen
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi’an
| | - Yan Pan
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Renlong Li
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Wenjiao Li
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Haohao Zhang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Hongwei Li
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Shibo Wang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Xiaoliang Gao
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Penghui Niu
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Wanqing Wang
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Gang Ji
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Qingchuan Zhao
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Yuanyuan Lu
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Zengshan Li
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi’an
| | - Lei Shang
- Department of Health Statistics, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health
| | - Han Liang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer
- Key Laboratory of Cancer Prevention and Therapy
- Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China
| | - Kaichun Wu
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Jingyu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer
- Key Laboratory of Cancer Prevention and Therapy
- Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China
| | - Yingtai Chen
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
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17
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Yang J, Shi Z, Zhang X, Liu Q, Cui X, Li L, Liu B, Wei J. Real-world clinical outcomes of the combination of anti-PD-1 antibody, trastuzumab, and chemotherapy for HER2-positive gastric/gastroesophageal junction cancer. Cancer Med 2023; 12:9517-9526. [PMID: 36912199 PMCID: PMC10166915 DOI: 10.1002/cam4.5722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 01/18/2023] [Accepted: 02/08/2023] [Indexed: 03/14/2023] Open
Abstract
BACKGROUND Previous clinical trials indicated the addition of anti-PD-1 antibody remarkably improved the efficacy of trastuzumab and chemotherapy in patients with HER2-positive gastric/gastroesophageal junction (GEJ) cancer. However, no real-world experiences have been reported yet. METHODS We retrospectively analyzed 1212 patients with gastric/GEJ cancer treated at Nanjing Drum Tower Hospital between 2019 and 2022. Among 138 patients with HER2-positive gastric/GEJ cancer, 47 patients receiving at least two doses of the combination regimen with anti-PD-1 antibody, trastuzumab, and chemotherapy were recruited in the study population, and 38 out of 47 patients with measurable disease were included in the efficacy population. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity profiles were reported. RESULTS In the study population, 37 (78.7%) received the study therapy as a first-line treatment. In the efficacy population, the ORR and DCR were 76.3% and 94.7%, respectively. The overall median PFS was 9.1 months (95% confidence interval [CI] 6.3-11.9 months). For the first-line treatment, the mPFS was 10 months, and 7 months for the second-line. Among 14 patients who failed the study treatment, three (21.4%) developed brain metastasis as the first failure site. No significant association was found between PFS and the expression of PD-L1. 22.2% of patients developed grade 3 treatment-related adverse events (TRAEs). No treatment-related grade ≥4 adverse events or deaths occurred. CONCLUSION This real-world study validated the combination regimen's high efficacy and good tolerance in patients with HER2-positive gastric/GEJ cancer. An increased incidence of brain metastasis was observed in patients who failed this regimen.
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Affiliation(s)
- Ju Yang
- The Comprehensive Cancer Centre of Drum Tower HospitalMedical School of Nanjing University and Clinical Cancer Institute of Nanjing UniversityNanjingChina
| | - Zhan Shi
- The Comprehensive Cancer Centre of Drum Tower HospitalMedical School of Nanjing University and Clinical Cancer Institute of Nanjing UniversityNanjingChina
| | - Xin Zhang
- The Comprehensive Cancer Centre of Drum Tower HospitalMedical School of Nanjing University and Clinical Cancer Institute of Nanjing UniversityNanjingChina
| | - Qin Liu
- The Comprehensive Cancer Centre of Drum Tower HospitalMedical School of Nanjing University and Clinical Cancer Institute of Nanjing UniversityNanjingChina
| | - Xiaobin Cui
- The Department of Pathology of Drum Tower HospitalMedical School of Nanjing UniversityNanjingChina
| | - Lin Li
- The Department of Pathology of Drum Tower HospitalMedical School of Nanjing UniversityNanjingChina
| | - Baorui Liu
- The Comprehensive Cancer Centre of Drum Tower HospitalMedical School of Nanjing University and Clinical Cancer Institute of Nanjing UniversityNanjingChina
| | - Jia Wei
- The Comprehensive Cancer Centre of Drum Tower HospitalMedical School of Nanjing University and Clinical Cancer Institute of Nanjing UniversityNanjingChina
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18
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Zhao H, Liang P, Yong L, Cheng M, Zhang Y, Huang M, Gao J. Development and external validation of a radiomics model for assessment of HER2 positivity in men and women presenting with gastric cancer. Insights Imaging 2023; 14:20. [PMID: 36720737 PMCID: PMC9889592 DOI: 10.1186/s13244-022-01361-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 12/19/2022] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND To develop and externally validate a conventional CT-based radiomics model for identifying HER2-positive status in gastric cancer (GC). METHODS 950 GC patients who underwent pretreatment CT were retrospectively enrolled and assigned into a training cohort (n = 388, conventional CT), an internal validation cohort (n = 325, conventional CT) and an external validation cohort (n = 237, dual-energy CT, DECT). Radiomics features were extracted from venous phase images to construct the "Radscore". On the basis of univariate and multivariate analyses, a conventional CT-based radiomics model was built in the training cohort, combining significant clinical-laboratory characteristics and Radscore. The model was assessed and validated regarding its diagnostic effectiveness and clinical practicability using AUC and decision curve analysis, respectively. RESULTS Location, clinical TNM staging, CEA, CA199, and Radscore were independent predictors of HER2 status (all p < 0.05). Integrating these five indicators, the proposed model exerted a favorable diagnostic performance with AUCs of 0.732 (95%CI 0.683-0.781), 0.703 (95%CI 0.624-0.783), and 0.711 (95%CI 0.625-0.798) observed for the training, internal validation, and external validation cohorts, respectively. Meanwhile, the model would offer more net benefits than the default simple schemes and its performance was not affected by the age, gender, location, immunohistochemistry results, and type of tissue for confirmation (all p > 0.05). CONCLUSIONS The conventional CT-based radiomics model had a good diagnostic performance of HER2 positivity in GC and the potential to generalize to DECT, which is beneficial to simplify clinical workflow and help clinicians initially identify potential candidates who might benefit from HER2-targeted therapy.
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Affiliation(s)
- Huiping Zhao
- grid.440288.20000 0004 1758 0451Department of CT, Shaanxi Provincial People’s Hospital, No. 256, Youyi West Road, Xi’an, 710068 Shaanxi Province China ,grid.412633.10000 0004 1799 0733Department of Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052 Henan Province China ,Henan Key Laboratory of Image Diagnosis and Treatment for Digestive System Tumor & Henan International Joint Laboratory of Medical Imaging & Henan Engineering Laboratory of Tumor Imaging & Henan Key Laboratory of CT Imaging & Zhengzhou Key Laboratory of Medical Imaging Technology and Diagnosis, No. 1, East Jianshe Road, Zhengzhou, 450052 Henan Province China
| | - Pan Liang
- grid.412633.10000 0004 1799 0733Department of Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052 Henan Province China ,Henan Key Laboratory of Image Diagnosis and Treatment for Digestive System Tumor & Henan International Joint Laboratory of Medical Imaging & Henan Engineering Laboratory of Tumor Imaging & Henan Key Laboratory of CT Imaging & Zhengzhou Key Laboratory of Medical Imaging Technology and Diagnosis, No. 1, East Jianshe Road, Zhengzhou, 450052 Henan Province China
| | - Liuliang Yong
- grid.412633.10000 0004 1799 0733Department of Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052 Henan Province China ,Henan Key Laboratory of Image Diagnosis and Treatment for Digestive System Tumor & Henan International Joint Laboratory of Medical Imaging & Henan Engineering Laboratory of Tumor Imaging & Henan Key Laboratory of CT Imaging & Zhengzhou Key Laboratory of Medical Imaging Technology and Diagnosis, No. 1, East Jianshe Road, Zhengzhou, 450052 Henan Province China
| | - Ming Cheng
- Henan Key Laboratory of Image Diagnosis and Treatment for Digestive System Tumor & Henan International Joint Laboratory of Medical Imaging & Henan Engineering Laboratory of Tumor Imaging & Henan Key Laboratory of CT Imaging & Zhengzhou Key Laboratory of Medical Imaging Technology and Diagnosis, No. 1, East Jianshe Road, Zhengzhou, 450052 Henan Province China ,grid.412633.10000 0004 1799 0733Department of Medical Information, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052 Henan Province China
| | - Yan Zhang
- grid.440288.20000 0004 1758 0451Department of CT, Shaanxi Provincial People’s Hospital, No. 256, Youyi West Road, Xi’an, 710068 Shaanxi Province China
| | - Minggang Huang
- grid.440288.20000 0004 1758 0451Department of CT, Shaanxi Provincial People’s Hospital, No. 256, Youyi West Road, Xi’an, 710068 Shaanxi Province China
| | - Jianbo Gao
- grid.412633.10000 0004 1799 0733Department of Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052 Henan Province China ,Henan Key Laboratory of Image Diagnosis and Treatment for Digestive System Tumor & Henan International Joint Laboratory of Medical Imaging & Henan Engineering Laboratory of Tumor Imaging & Henan Key Laboratory of CT Imaging & Zhengzhou Key Laboratory of Medical Imaging Technology and Diagnosis, No. 1, East Jianshe Road, Zhengzhou, 450052 Henan Province China
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19
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Zhang Y, Qiu MZ, Wang JF, Zhang YQ, Shen A, Yuan XL, Zhang T, Wei XL, Zhao HY, Wang DS, Zhao Q, Xiong GZ, Ji YP, Liang XJ, Xia G, Xu RH. Phase 1 multicenter, dose-expansion study of ARX788 as monotherapy in HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma. Cell Rep Med 2022; 3:100814. [PMID: 36384091 PMCID: PMC9729820 DOI: 10.1016/j.xcrm.2022.100814] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 09/13/2022] [Accepted: 10/17/2022] [Indexed: 11/17/2022]
Abstract
ARX788 is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate with AS269 as cytotoxic payload. In this phase 1 multicenter dose-expansion clinical trial, patients with HER2-positive advanced gastric/gastroesophageal junction adenocarcinoma failing to respond to prior trastuzumab-based standard treatment were enrolled. Between July 15th, 2019, and March 14th, 2022, 30 participants were enrolled. Twenty-eight (93.3%) patients experienced at least one drug-related adverse event (AE) and 13.3% experienced grade 3 ARX788-related AEs. The confirmed objective response rate is 37.9% (95% confidence interval [CI]: 20.7%-57.7%) and the disease control rate is 55.2% (95% CI: 35.7%-73.6%). With a median follow up of 10 months, the median progression-free survival and overall survival are 4.1 (95% CI: 1.4-6.4) and 10.7 months (95% CI: 4.8-not reached), respectively. The median duration of response is 8.4 (95% CI: 2.1-18.9) months. ARX788 is well tolerated and has promising anti-tumor activity in patients with HER2-positive advanced gastric adenocarcinoma (ChinaDrugTrials.org.cn: CTR20190639).
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Affiliation(s)
- Yang Zhang
- Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Miao-Zhen Qiu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China
| | - Ju-Feng Wang
- Department of Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, P.R. China
| | - Yan-Qiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, P.R. China
| | - Ao Shen
- Bioinformatics Platform, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Xiang-Lin Yuan
- Department of Medical Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Tao Zhang
- Department of Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Xiao-Li Wei
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China
| | - Hong-Yun Zhao
- Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - De-Shen Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China
| | - Qi Zhao
- Bioinformatics Platform, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | | | - Yan-Ping Ji
- Novocodex Biopharmaceuticals, Shaoxing, P.R. China
| | | | - Gang Xia
- Novocodex Biopharmaceuticals, Shaoxing, P.R. China
| | - Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China.
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20
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Li W, Zhang X, Du Y, Zhang Y, Lu J, Hu W, Zhao J. HER2-targeted advanced metastatic gastric/gastroesophageal junction adenocarcinoma: treatment landscape and future perspectives. Biomark Res 2022; 10:71. [PMID: 36175985 PMCID: PMC9524015 DOI: 10.1186/s40364-022-00416-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 09/01/2022] [Indexed: 11/10/2022] Open
Abstract
Recently, the global incidence of gastric/gastroesophageal junction (G/GEJ) cancer has remained high. China is also a large country with a high gastric cancer (GC) incidence rate, where the cases of GC account for 40% of all cases worldwide. More than 90% of GEJ cancers are the adenocarcinoma pathological type. Patients with early-stage G/GEJ adenocarcinoma may have a better prognosis after surgery. In contrast, patients with advanced metastatic G/GEJ adenocarcinoma usually choose comprehensive treatment based on systemic pharmacotherapy, but the subsequent long-term survival is not optimistic. The discovery of various biomarkers, especially microsatellite instability (MSI), programmed cell death-ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), tumor mutational burden (TMB) and Epstein-Barr virus (EBV), has led to the identification of an increasing number of targeted populations and has greatly improved the clinical efficacy of treatments for G/GEJ adenocarcinoma. The ToGA trial added trastuzumab to standard chemotherapy, showed improved survival of patients with HER2-positive advanced G/GEJ adenocarcinoma and brought these patients into a new era of HER2-targeted therapy. Moreover, many HER2-targeted agents have been developed and studied in patients with advanced HER2-positive G/GEJ adenocarcinoma who have demonstrated excellent clinical outcomes. However, many patients experience disease progression with HER2-targeted therapy; hence, new anti-HER2 drugs keep being developed, significantly reducing HER2 resistance. This paper reviews HER2-targeted drugs for advanced metastatic G/GEJ adenocarcinoma, potential resistance mechanisms and future directions.
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Affiliation(s)
- Weiling Li
- Department of Oncology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, 046000, Shanxi, China
- Graduate School, Changzhi Medical College, Changzhi, 046000, Shanxi, China
| | - Xiaoling Zhang
- Department of Oncology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, 046000, Shanxi, China
| | - Yunyi Du
- Department of Oncology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, 046000, Shanxi, China
| | - Ying Zhang
- Department of Oncology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, 046000, Shanxi, China
- Graduate School, Changzhi Medical College, Changzhi, 046000, Shanxi, China
| | - Jing Lu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Wenqing Hu
- Department of Gastrointestinal Surgery, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, 046000, Shanxi, China
| | - Jun Zhao
- Department of Oncology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi, 046000, Shanxi, China.
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21
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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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Deng S, Gu J, Jiang Z, Cao Y, Mao F, Xue Y, Wang J, Dai K, Qin L, Liu K, Wu K, He Q, Cai K. Application of nanotechnology in the early diagnosis and comprehensive treatment of gastrointestinal cancer. J Nanobiotechnology 2022; 20:415. [PMID: 36109734 PMCID: PMC9479390 DOI: 10.1186/s12951-022-01613-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/30/2022] [Indexed: 02/08/2023] Open
Abstract
Gastrointestinal cancer (GIC) is a common malignant tumour of the digestive system that seriously threatens human health. Due to the unique organ structure of the gastrointestinal tract, endoscopic and MRI diagnoses of GIC in the clinic share the problem of low sensitivity. The ineffectiveness of drugs and high recurrence rates in surgical and drug therapies are the main factors that impact the curative effect in GIC patients. Therefore, there is an urgent need to improve diagnostic accuracies and treatment efficiencies. Nanotechnology is widely used in the diagnosis and treatment of GIC by virtue of its unique size advantages and extensive modifiability. In the diagnosis and treatment of clinical GIC, surface-enhanced Raman scattering (SERS) nanoparticles, electrochemical nanobiosensors and magnetic nanoparticles, intraoperative imaging nanoparticles, drug delivery systems and other multifunctional nanoparticles have successfully improved the diagnosis and treatment of GIC. It is important to further improve the coordinated development of nanotechnology and GIC diagnosis and treatment. Herein, starting from the clinical diagnosis and treatment of GIC, this review summarizes which nanotechnologies have been applied in clinical diagnosis and treatment of GIC in recent years, and which cannot be applied in clinical practice. We also point out which challenges must be overcome by nanotechnology in the development of the clinical diagnosis and treatment of GIC and discuss how to quickly and safely combine the latest nanotechnology developed in the laboratory with clinical applications. Finally, we hope that this review can provide valuable reference information for researchers who are conducting cross-research on GIC and nanotechnology.
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Affiliation(s)
- Shenghe Deng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Junnan Gu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Zhenxing Jiang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Yinghao Cao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Fuwei Mao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Yifan Xue
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Jun Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Kun Dai
- Department of Neonatal Intensive Care Unit, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Le Qin
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Ke Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Ke Wu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Qianyuan He
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
| | - Kailin Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
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Tumor Characteristics Associated with Lymph Node Metastasis and Prognosis in Patients with ERBB2-Positive Gastric Cancer. JOURNAL OF ONCOLOGY 2022; 2022:7592046. [PMID: 36059809 PMCID: PMC9436560 DOI: 10.1155/2022/7592046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/18/2022] [Accepted: 07/28/2022] [Indexed: 11/17/2022]
Abstract
Gastric cancers (GCs) that express human erb-b2 receptor tyrosine kinase 2 (ERBB2, also known as HER2) account for 7.3%–20.2% of GCs. The pathological and prognostic factors associated with lymph node metastasis of such tumors are still unclear. Therefore, we aimed to identify the risk factors for lymph node metastasis and prognostic factors of patients with ERBB2-positive GC. We conducted a retrospective analysis of pathological specimens after D2 radical surgery for locally advanced GC and D1+ surgery performed for early GC in our hospital from January 2015 to December 2018. Patients with ERBB2-positive GC were selected and the potential risk factors for lymph node metastasis and potential factors affecting prognosis were evaluated. Among 1,124 GC patients, 122 diagnosed with ERBB2-positive GC were included in the study. We found that risk factors for lymph node metastasis included tumor size (hazard ratio (HR)- 6.213, 95% confidence interval (CI)- 2.097–18.407, p = 0.001), neural invasion (HR- 2.876, 95% CI - 1.011–8.184, p = 0.048), and vascular invasion (HR- 16.881, 95% CI - 5.207–54.727, p < 0.001). T stage (HR- 4.615, 95% CI - 2.182–9.759, p < 0.001) and vascular invasion (HR- 3.036, 95% CI - 1.369–6.736, p = 0.006) were significant prognostic variables. These findings shed new light on the pathology and prognosis of patients with ERBB2-positive GC.
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24
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Xu C, Sun M, Jin M, Li Z, Qin R, Ren G, Sun W, Chen L, Luan L, Liu Y, Jiang D, Chen L, Luo R, Hou Y. Dual block HER2 assessment increased HER2 immunohistochemistry positive rate in resected specimens of gastric cancer: a prospective multicenter clinical trial from China. Diagn Pathol 2022; 17:54. [PMID: 35765007 PMCID: PMC9238183 DOI: 10.1186/s13000-022-01230-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 05/18/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Former single center studies indicated that HER2 assessment with two primary tumor blocks (dual block HER2 assessment) could be an efficient and practical approach to overcome the adverse impact of heterogeneity and acquire a HER2 positive rate in gastric cancer (GC). This multicenter prospective clinical trial (NCT 02843412) was launched to verify its value and generality.
Methods
A total of 3806 participants with primary GCs have been enrolled from 8 hospitals in China. Two primary tumor blocks were selected and recorded as block 1 and block 2 after histological evaluation. An HER2 (4B5) rabbit monoclonal antibody was used for the immunohistochemistry (IHC) analysis.
Results
In total patients, HER2 IHC positive (3+) rate with dual block assessment (9.4%) was higher than that with single block assessment (block 1: 7.8%, block 2: 7.8%) (P < 0.001). Compared with single-block assessment, dual-block assessment increased the positive rate by approximate 20%. Similarly, HER2 equivocal (2+) rate was increased in dual block assessment (25.8%), which was higher than that in single block assessment (block 1: 20.3%, block 2: 20.9%) (P < 0.001). Conversely, dual block assessment demonstrated a lower HER2 negative (0/1+) rate (64.8%) than single block assessment (block1: 71.9%, block 2: 71.3%) (P < 0.001). These findings were also confirmed in individual hospitals.
Conclusions
Dual block HER2 assessment effectively increased HER2 IHC positive rate in resected specimens of GC. We recommended dual block HER2 assessment be promoted in routine clinical practice in GC.
Trial registration
ClinicalTrials.gov, NCT 02843412. Registered 1 July 2016 - Retrospectively registered.
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25
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The Influence of Heavy Metals on Gastric Tumorigenesis. JOURNAL OF ONCOLOGY 2022; 2022:6425133. [PMID: 35669240 PMCID: PMC9167133 DOI: 10.1155/2022/6425133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 05/01/2022] [Accepted: 05/12/2022] [Indexed: 12/24/2022]
Abstract
Objectives This study aimed to observe the relationship among heavy metals concentration, microsatellite instability (MSI), and human epidermal growth factor receptor type 2 (HER2) gene amplification in gastric cancer (GC) patients. Methods The concentrations of 18 heavy metals in the plasma of GC patients and healthy controls were measured by inductive coupled plasma emission spectrometry (ICP-MS). MSI detection was conducted by detecting 5 microsatellite repeat markers by PCR analysis. HER2 gene amplification was detected by fluorescence in situ hybridization (FISH). The relationship among heavy metal elements, tumor biomarkers, HER2 amplification, and MSI status was analyzed by Pearson correlation analysis. Results A total of 105 GC patients and 62 healthy controls were recruited in this study. The concentration of arsenic (As), chromium (Cr), cuprum (Cu), mercury (Hg), manganese (Mn), lead (Pb), stibium (Sb), selenium (Se), stannum (Sn), strontium (Sr), thallium (Tl), vanadium (V), and zinc (Zn) were significantly different between GC patients and controls. Among 105 GC patients, including 87 microsatellite-stable (MSS) samples and 18 MSI samples, the concentration of Ga is significantly higher in the MSI group than that in the MSS group. Meanwhile, in 97 GC patients having detected HER2 gene amplification, 69 of 97 had negative HER2 gene amplification and the rest 28 GC patients had positive HER2 gene amplification. The concentration of Hg, Sn, and Tl is noticeably higher in the HER2 positive group than in the HER2 negative group. Only Sb was positively correlated with MSI, but none of these heavy metals was correlated with HER2 gene amplification. Conclusions The results indicated that Sb has significant positive correlation with the MSI status, which suggests that Sb may cause MSI in GC. However, further research studies are required to elucidate the mechanisms in the near feature.
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26
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Ni S, Wang X, Chang J, Sun H, Weng W, Wang X, Tan C, Zhang M, Wang L, Huang Z, Huang D, Xu M, Sheng W. Human Epidermal Growth Factor Receptor 2 Overexpression and Amplification in Patients With Colorectal Cancer: A Large-Scale Retrospective Study in Chinese Population. Front Oncol 2022; 12:842787. [PMID: 35574415 PMCID: PMC9097912 DOI: 10.3389/fonc.2022.842787] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Background Cumulative evidence in colorectal cancer (CRC) suggests that patients with human epidermal growth factor receptor 2 (HER2) overexpression or amplification can benefit from anti-HER2 therapy. The purpose of our study was to evaluate HER2 status and its correlation with clinicopathological characteristics and survival according to currently utilized HER2 diagnostic criteria in a large cohort of Chinese CRC patients. Methods HER2 protein expression was tested by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded (FFPE) samples from 4,836 CRC patients in our institution. Breast cancer (BC) and gastroesophageal adenocarcinoma (GEA) criteria, as well as the HERACLES criteria, were used for the determination of HER2 status. Dual-color silver-enhanced in situ hybridization (DSISH) was performed in all IHC 2+~3+ cases determined by BC/GEA criteria. Results The HER2 expression rate of IHC (1+~3+) was 7.01% (339/4,836) and 6.02% (291/4,836) in CRCs based on the BC/GEA criteria and the HERACLES criteria, respectively, while combined DSISH results in the HER2 amplification/overexpression ratio of 3.39% (164/4,836) in our cohort. HER2 expression detected by IHC was positively correlated with the female gender, whereas the HER2 overexpression/amplification showed no correlation with any clinicopathological parameter. In addition, no significant correlation was found between HER2 statuses and either disease-free survival or overall survival regardless of the evaluation criterion used. However, patients with HER2 1+ CRC showed a tendency of having the shortest overall survival as compared with any other group of patients according to the HERACLES criteria, and this trend has always existed in the rectal location, T3 stage, and TNM stage II, medium differentiation, and perineural invasion stratified group. Furthermore, the HER2 protein expression was significantly negatively correlated with RAS/BRAF mutations according to the HERACLES criteria. Conclusion To our knowledge, this is the largest study of HER2 status in Asian patients with CRC. Our findings suggest that the current most commonly used HERACLES criteria might be too strict for patients with CRC. Future studies are needed to explore the most suitable criteria for screening CRC patients who could benefit from anti-HER2 therapy as much as possible.
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Affiliation(s)
- Shujuan Ni
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Xin Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Jinjia Chang
- Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Hui Sun
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Weiwei Weng
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Xu Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Cong Tan
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Meng Zhang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Lei Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Zhaohui Huang
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Dan Huang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Midie Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Weiqi Sheng
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
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27
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Li H, Zhang X, Xu Z, Li L, Liu W, Dai Z, Zhao Z, Xiao L, Li H, Hu C. Preclinical evaluation of MRG002, a novel HER2-targeting antibody-drug conjugate with potent antitumor activity against HER2-positive solid tumors. Antib Ther 2021; 4:175-184. [PMID: 34532642 DOI: 10.1093/abt/tbab017] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 12/30/2022] Open
Abstract
Background ERBB2 is a proto-oncogene of multiple cancers including breast and gastric cancers with HER2 protein overexpression or gene amplification and has been proven clinically as a valid target for these cancers. HER2-targeting agents such as Herceptin®, Kadcyla® and ENHERTU® have been approved by the FDA for the treatment of breast cancer, but these drugs still face the challenge of acquired resistance and/or severe adverse reactions in clinical use. Therefore, there is significant unmet medical need for developing new agents that are more effective and safer for patients with advanced HER2-positive solid tumors including breast and gastric cancers. Methods We report here the making of MRG002, a novel HER2-targeted antibody drug conjugate (ADC), and preclinical characterization including pharmacology, pharmacodynamics and toxicology and discuss its potential as a novel agent for treating patients with HER2-positive solid tumors. Results MRG002 exhibited similar antigen binding affinity but much reduced antibody-dependent cellular cytotoxicity (ADCC) activity compared to trastuzumab. In addition to potent in vitro cytotoxicity, MRG002 showed tumor regression in both high- and medium-to-low HER2 expressing in vivo xenograft models. Furthermore, MRG002 showed enhanced antitumor activity when used in combination with an anti-PD-1 antibody. Main findings from toxicology studies are related to the payload and are consistent with literature report of other ADCs with monomethyl auristatinE. Conclusion MRG002 has demonstrated a favorable toxicity profile and potent antitumor activities in the breast and gastric PDX models with varying levels of HER2 expression, and/or resistance to trastuzumab or T-DM1. A phase I clinical study of MRG002 in patients with HER2-positive solid tumors is ongoing (CTR20181778).
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Affiliation(s)
- Hu Li
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Xiao Zhang
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Zhenyi Xu
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Lingrui Li
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Wenchao Liu
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Zhenyu Dai
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Zhongrun Zhao
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Lili Xiao
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Hongfeng Li
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
| | - Chaohong Hu
- Research and Development, Shanghai Miracogen, Suite 4E, Bldg. 3, No. 1238 Zhangjiang Road, Pudong District, Shanghai 201203, China
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28
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Wang F, Zhang X, Li Y, Tang L, Qu X, Ying J, Zhang J, Sun L, Lin R, Qiu H, Wang C, Qiu M, Cai M, Wu Q, Liu H, Guan W, Zhou A, Zhang Y, Liu T, Bi F, Yuan X, Rao S, Xin Y, Sheng W, Xu H, Li G, Ji J, Zhou Z, Liang H, Zhang Y, Jin J, Shen L, Li J, Xu R. The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2021. Cancer Commun (Lond) 2021; 41:747-795. [PMID: 34197702 PMCID: PMC8360643 DOI: 10.1002/cac2.12193] [Citation(s) in RCA: 424] [Impact Index Per Article: 106.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 06/21/2021] [Accepted: 06/23/2021] [Indexed: 02/05/2023] Open
Abstract
There exist differences in the epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selections between gastric cancer patients from the Eastern and Western countries. The Chinese Society of Clinical Oncology (CSCO) has organized a panel of senior experts specializing in all sub-specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually. Taking into account regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China. The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis, treatment, follow-up, and screening of gastric cancer. Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines, this updated guideline integrates the results of major clinical studies from China and overseas for the past year, focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations. For the comprehensive treatment of non-metastatic gastric cancer, attentions were paid to neoadjuvant treatment. The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated. For the comprehensive treatment of metastatic gastric cancer, recommendations for immunotherapy were included, and immune checkpoint inhibitors from third-line to the first-line of treatment for different patient groups with detailed notes are provided.
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Huang W, Zhan D, Li Y, Zheng N, Wei X, Bai B, Zhang K, Liu M, Zhao X, Ni X, Xia X, Shi J, Zhang C, Lu Z, Ji J, Wang J, Wang S, Ji G, Li J, Nie Y, Liang W, Wu X, Cui J, Meng Y, Cao F, Shi T, Zhu W, Wang Y, Chen L, Zhao Q, Wang H, Shen L, Qin J. Proteomics provides individualized options of precision medicine for patients with gastric cancer. SCIENCE CHINA-LIFE SCIENCES 2021; 64:1199-1211. [PMID: 34258712 DOI: 10.1007/s11427-021-1966-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 06/17/2021] [Indexed: 12/19/2022]
Abstract
While precision medicine driven by genome sequencing has revolutionized cancer care, such as lung cancer, its impact on gastric cancer (GC) has been minimal. GC patients are routinely treated with chemotherapy, but only a fraction of them receive the clinical benefit. There is an urgent need to develop biomarkers or algorithms to select chemo-sensitive patients or apply targeted therapy. Here, we carried out retrospective analyses of 1,020 formalin-fixed, paraffin-embedded GC surgical resection samples from 5 hospitals and developed a mass spectrometry-based workflow for proteomic subtyping of GC. We identified two proteomic subtypes: the chemo-sensitive group (CSG) and the chemo-insensitive group (CIG) in the discovery set. The 5-year overall survival of CSG was significantly improved in patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (64.2% vs. 49.6%; Cox P-value=0.002), whereas no such improvement was observed in CIG (50.0% vs. 58.6%; Cox P-value=0.495). We validated these results in an independent validation set. Further, differential proteome analysis uncovered 9 FDA-approved drugs that may be applicable for targeted therapy of GC. A prospective study is warranted to test these findings for future GC patient care.
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Affiliation(s)
- Wenwen Huang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Dongdong Zhan
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.,Center for Bioinformatics and Computational Biology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yazhuo Li
- Department of Pathology, The Fourth Medical Center of PLA General Hospital, Beijing, 100048, China
| | - Nairen Zheng
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Xin Wei
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.,Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Bin Bai
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Kecheng Zhang
- Department of General Surgery & Institute of General Surgery, Chinese PLA General Hospital First Medical Center, Beijing, 100853, China
| | - Mingwei Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Xuefei Zhao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Xiaotian Ni
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Xia Xia
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Jinwen Shi
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Cheng Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Zhihao Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Jiafu Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Juan Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Shiqi Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Gang Ji
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Jipeng Li
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Wenquan Liang
- Department of General Surgery & Institute of General Surgery, Chinese PLA General Hospital First Medical Center, Beijing, 100853, China
| | - Xiaosong Wu
- Department of General Surgery & Institute of General Surgery, Chinese PLA General Hospital First Medical Center, Beijing, 100853, China
| | - Jianxin Cui
- Department of General Surgery & Institute of General Surgery, Chinese PLA General Hospital First Medical Center, Beijing, 100853, China
| | - Yongsheng Meng
- Department of tumor biobank, Shanxi Cancer Hospital, Taiyuan, 030013, China
| | - Feilin Cao
- Department of tumor biobank, Shanxi Cancer Hospital, Taiyuan, 030013, China
| | - Tieliu Shi
- Center for Bioinformatics and Computational Biology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Weimin Zhu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Yi Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Lin Chen
- Department of General Surgery & Institute of General Surgery, Chinese PLA General Hospital First Medical Center, Beijing, 100853, China.
| | - Qingchuan Zhao
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China.
| | - Hongwei Wang
- Department of Pathology, The Fourth Medical Center of PLA General Hospital, Beijing, 100048, China.
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, 100142, China.
| | - Jun Qin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China. .,State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Fudan University, Shanghai, 200433, China.
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Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021; 398:27-40. [PMID: 34102137 PMCID: PMC8436782 DOI: 10.1016/s0140-6736(21)00797-2] [Citation(s) in RCA: 1709] [Impact Index Per Article: 427.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/30/2021] [Accepted: 03/31/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone. METHODS In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116. FINDINGS From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified. INTERPRETATION Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients. FUNDING Bristol Myers Squibb, in collaboration with Ono Pharmaceutical.
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Affiliation(s)
- Yelena Y Janjigian
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
| | - Markus Moehler
- Department of Medicine, Johannes-Gutenberg University Clinic, Mainz, Germany
| | - Marcelo Garrido
- Department of Hemato-Oncology, Clinica San Carlos de Apoquindo, Pontificia Universidad Católica, Santiago, Chile
| | - Pamela Salman
- Department of Medical Oncology, Oncovida Cancer Center, Fundación Arturo López Pérez, Providencia, Chile
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing, Peking University Cancer Hospital and Institute, Beijing, China
| | - Lucjan Wyrwicz
- Klinika Onkologii i Radioterapii, Narodowy Instytut Onkologii, Warsaw, Poland
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tomasz Skoczylas
- II Klinika Chirurgii Ogólnej, Gastroenterologicznej i Nowotworów Układu Pokarmowego, Medical University of Lublin, Lublin, Poland
| | | | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Michael Schenker
- Department of Medical Oncology, Sfantul Nectarie Oncology Center, Dolj, Romania
| | - Patricio Yanez
- Department of Internal Medicine, Oncology Unit, Universidad de La Frontera, Temuco, Chile
| | - Mustapha Tehfe
- Hematology-Oncology, Oncology Center-Centre Hospitalier de l'Universite de Montreal, Montreal, QC, Canada
| | - Ruben Kowalyszyn
- Instituto Multidisciplinario de Oncologia, Clinica Viedma SA, Viedma, Argentina
| | - Michalis V Karamouzis
- Department of Biological Chemistry and Laiko General Hospital Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Ricardo Bruges
- Internal Medicine, Clinical Oncology, Instituto Nacional de Cancerología Empresa Social del Estado, Bogotá, Colombia
| | - Thomas Zander
- Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düesseldorf, University Hospital of Cologne, Cologne, Germany
| | - Roberto Pazo-Cid
- Department of Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Erika Hitre
- Department of Chemotherapy, National Institute of Oncology, Budapest, Hungary
| | - Kynan Feeney
- Department of Oncology, Haematology and Palliative Care, St John of God Murdoch Hospital, Murdoch, WA, Australia
| | - James M Cleary
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | | | - Ming Lei
- Bristol Myers Squibb, Princeton, NJ, USA
| | - Hong Xiao
- Bristol Myers Squibb, Princeton, NJ, USA
| | | | | | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Dual-Energy CT-Based Nomogram for Decoding HER2 Status in Patients With Gastric Cancer. AJR Am J Roentgenol 2021; 216:1539-1548. [PMID: 33852330 DOI: 10.2214/ajr.20.23528] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE. The purpose of this study was to develop and evaluate a dual-energy CT (DECT)-based nomogram for noninvasive identification of the status of human epidermal growth factor receptor 2 (HER2; also known as ERBB2) expression in gastric cancer (GC). MATERIALS AND METHODS. A total of 206 patients with histologically proven GC who underwent pretreatment DECT were retrospectively recruited and randomly allocated to a training cohort (n = 144) or a test cohort (n = 62). Information on clinical characteristics, qualitative imaging features, and quantitative DECT parameters was collected. Univariate analysis and multivariate logistic regression were implemented to screen independent predictors of HER2 status. An individualized nomogram was built, and its discrimination, calibration, and clinical usefulness were assessed. RESULTS. Tumor location, the iodine concentration of the tumor in the venous phase, and the normalized iodine concentration of the tumor in the venous phase were significant factors predictive of HER2 status (all p < .05). After these three indicators were integrated, the proposed nomogram showed a favorable diagnostic performance, with AUCs of 0.807 (95% CI, 0.718-0.897) in the training cohort and 0.815 (95% CI, 0.661-0.968) in the test cohort. The nomogram showed a preferable fitting (all p > .05 by the Hosmer-Lemeshow test) and would offer more net benefits than simple default strategies within a wide range of threshold probabilities in both cohorts. CONCLUSION. The DECT-based nomogram has great application potential in terms of detecting HER2 status in GC, and can serve as a novel substitute for invasive testing.
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Zheng S, Fu GB, Shen HC, Liu Q, Wang WB. Inhibitory effects of combinations of trastuzumab and cytotoxic chemotherapy drugs in HER2-positive gastric cancer. ALL LIFE 2021. [DOI: 10.1080/26895293.2021.1906330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Affiliation(s)
- Shu Zheng
- Department of Oncology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China
| | - Guo-Bin Fu
- Department of Oncology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China
| | - Hong-Chang Shen
- Department of Oncology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China
| | - Qi Liu
- Department of Oncology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China
| | - Wei-Bo Wang
- Department of Oncology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China
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Zhang J, Fan J, Zeng X, Nie M, Chen W, Wang Y, Luan J, Zhu Z, Chang X, Ju D, Feng L, Yin K. Targeting the autophagy promoted antitumor effect of T-DM1 on HER2-positive gastric cancer. Cell Death Dis 2021; 12:288. [PMID: 33731670 PMCID: PMC7969610 DOI: 10.1038/s41419-020-03349-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 12/02/2020] [Accepted: 12/14/2020] [Indexed: 01/31/2023]
Abstract
Trastuzumab emtansine (T-DM1), an antibody-drug conjugate consisted of the HER2-targeted monoclonal antibody trastuzumab and the tubulin inhibitor emtansine, has shown potent therapeutic value in HER2-positive breast cancer (BC). However, a clinical trial indicated that T-DM1 exerts a limited effect on HER2-positive gastric cancer (GC), but the underlying mechanism is inconclusive. Our research attempted to reveal the probable mechanism and role of autophagy in T-DM1-treated HER2-positive GC. In this study, our results showed that T-DM1 induced apoptosis and exhibited potent therapeutic efficacy in HER2-positive GC cells. In addition, autophagosomes were observed by transmission electron microscopy. Autophagy was markedly activated and exhibited the three characterized gradations of autophagic flux, consisting of the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and the deterioration of autophagosomes in autolysosomes. More importantly, autophagic inhibition by the suppressors 3-methyladenine (3-MA) and LY294002 significantly potentiated cytotoxicity and apoptosis in HER2-positive GC cells in vitro, while the combined use of LY294002 and T-DM1 elicited potent anti-GC efficacy in vivo. In mechanistic experiments, immunoblot analysis indicated the downregulated levels of Akt, mTOR, and P70S6K and confocal microscopy analysis clearly showed that autophagic inhibition promoted the fusion of T-DM1 molecules with lysosomes in GC cells. In conclusion, our research demonstrated that T-DM1 induced apoptosis as well as cytoprotective autophagy, and autophagic inhibition could potentiate the antitumor effect of T-DM1 on HER2-positive GC. Furthermore, autophagic inhibition might increase the fusion of T-DM1 with lysosomes, which might accelerate the release of the cytotoxic molecule emtansine from the T-DM1 conjugate. These findings highlight a promising therapeutic strategy that combines T-DM1 with an autophagy inhibitor to treat HER-positive GC more efficiently.
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Affiliation(s)
- Jinghui Zhang
- Department of Gastrointestinal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, P. R. China
| | - Jiajun Fan
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, P. R. China
| | - Xian Zeng
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, P. R. China
| | - Mingming Nie
- Department of Gastrointestinal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, P. R. China
| | - Wei Chen
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, P. R. China
| | - Yichen Wang
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, P. R. China
| | - Jingyun Luan
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, P. R. China
| | - Zeguo Zhu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, P. R. China
| | - Xusheng Chang
- Department of Gastrointestinal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, P. R. China
| | - Dianwen Ju
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, P. R. China.
- Department of Endoscopy Center, Minhang Hospital, Fudan University, 170 Xinsong Road, Shanghai, 201199, P. R. China.
| | - Li Feng
- Department of Endoscopy Center, Minhang Hospital, Fudan University, 170 Xinsong Road, Shanghai, 201199, P. R. China.
| | - Kai Yin
- Department of Gastrointestinal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, P. R. China.
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Lv H, Zhang J, Sun K, Nie C, Chen B, Wang J, Xu W, Wang S, Liu Y, Chen X. Expression of Human Epidermal Growth Factor Receptor-2 Status and Programmed Cell Death Protein-1 Ligand Is Associated With Prognosis in Gastric Cancer. Front Oncol 2021; 10:580045. [PMID: 33598422 PMCID: PMC7882725 DOI: 10.3389/fonc.2020.580045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 12/14/2020] [Indexed: 11/23/2022] Open
Abstract
Background PD-L1 and HER-2 are routine biomarkers for gastric cancer (GC). However, little research has been done to investigate the correlation among PD-L1, HER-2, immune microenvironment, and clinical features in GC. Methods Between January 2013 and May 2020, a total of 120 GC patients treated with chemotherapy were admitted to Henan Tumor Hospital. We retrospectively identified PD-L1, HER-2 level before chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between PD-L1/HER-2 levels and progression-free survival (PFS). The mRNA and tumor microenvironment of 343 patients with GC from The Cancer Genome Atlas (TCGA) were used to explore the underlying mechanism. Results We retrospectively analyzed 120 patients with gastric cancer, including 17 patients with HER-2 positive and 103 patients with HER-2 negative GC. The results showed that the expression of PD-L1 was closely correlated with HER-2 (P = 0.015). Patients with PD-L1/HER-2 positive obtained lower PFS compared to PD-L1/HER-2 negative (mPFS: 6.4 vs. 11.1 months, P = 0.014, mPFS: 5.3 vs. 11.1 months, P = 0.002, respectively), and the PD-L1 negative and HER-2 negative had the best PFS than other groups (P = 0.0008). In a multivariate model, PD-L1 status, HER-2 status, tumor location, and tumor differentiation remained independent prognostic indicators for PFS (P < 0.05). The results of database further analysis showed that the proportion of PD-L1+/CD8A+ in HER-2 negative patients was higher than that in HER-2 positive patients (37.6 vs 20.3%), while PD-L1−/CD8A− was significantly higher in HER-2 positive patients than HER-2 negative patients (57.8 vs. 28.8%). In addition, it showed that not only CD4+T cells, macrophages, and CD8+T cells, but also the associated inflammatory pathways such as IFN-γ/STAT1 were associated with HER-2. Conclusion HER-2 status could predict the efficacy of immune checkpoint inhibitors, and HER-2 status combined with PD-L1 level could predict the prognosis of GC patients.
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Affiliation(s)
- Huifang Lv
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Junling Zhang
- Medical Department, 3D Medicines Inc., Shanghai, China
| | - Keran Sun
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Caiyun Nie
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Beibei Chen
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Jianzheng Wang
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Weifeng Xu
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Saiqi Wang
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
| | - Yingjun Liu
- Department of Surgery, Henan Cancer Hospital, Zhengzhou, China
| | - Xiaobing Chen
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, China
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Chao G, Chen X, Zhang S. Study on the correlation between Helicobacter Pylori and biological characteristics of early Gastric Cancer. J Cancer 2021; 12:1838-1845. [PMID: 33613772 PMCID: PMC7890311 DOI: 10.7150/jca.46392] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 12/29/2020] [Indexed: 01/08/2023] Open
Abstract
Objective: Retrospective analysis was used to determine the population diagnosed with EGC, and HP infection was used as the cut-off point to further evaluate the correlation between helicobacter pylori (HP) infection and tumor biological characteristics of early gastric cancer (EGC). Methods: All cases were collected from patients diagnosed with EGC through endoscopic surgery or surgical procedures from January 2009 to October 2018. General information, tumor site, tumor pathology, HER2 immunohistochemical results, and degree of HP infection were collected for retrospective analysis. Results: A total of 111 cases were collected in this study. Among the HP negative group, there were statistically significant differences in tumor sites between the uninfected group and the previously infected group (P<0.05).There were significant differences in monocyte infiltration and neutrophil infiltration between the positive and negative groups (P<0.05).The differentiated adenocarcinoma in the positive group was significantly lower than that in the negative group. The incidence rate of Mixed type cancer was significantly higher than that in the positive group (P<0.01). In the positive group of HP, there was a statistically significant difference in HER2 between the unsterilized group and the previously sterilized group (P<0.05).There was a statistically significant difference in HER2 between the HP positive group and the HP negative group (P<0.01). HP infection was significantly correlated with HER2 index and presented a positive correlation (P=0.014). Conclusion: HP infection is related to the tumor site and mucosal inflammatory infiltration of EGC. The malignant degree of EGC complicated with HP infection is higher, and most of them are mixed type. The degree of HP infection was positively correlated with the degree of invasion and malignancy of ECG. Furthermore, the tumor indicator HER2 is closely related to HP infection, and the detection of HP combined with HER2 is of great significance in the discovery of EGC and the evaluation of its malignancy.
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Affiliation(s)
- Guanqun Chao
- Department of Family Medicine, Sir Run Run Shaw Hospital, Zhejiang University, China
| | - Xinli Chen
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, China
| | - Shuo Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, China
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Li F, Meng G, Tan B, Chen Z, Ji Q, Wang X, Liu C, Niu S, Li Y, Liu Y. Relationship between HER2 expression and tumor interstitial angiogenesis in primary gastric cancer and its effect on prognosis. Pathol Res Pract 2020; 217:153280. [PMID: 33253925 DOI: 10.1016/j.prp.2020.153280] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/31/2020] [Accepted: 11/01/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Her2-positive gastric cancer is a unique subtype of disease, requiring different diagnosis and treatment strategies and methods. Neoplasms are significantly correlated with the occurrence, invasion and metastasis of tumors. The purpose of this study was to explore the correlation between HER2 amplification and tumor interstitial angiogenesis in patients with gastric cancer. METHODS The data of 1121 patients with gastric cancer were retrospectively analyzed, and the amplification of HER2 was detected by immunohistochemistry (IHC) and FISH. CD34 IHC was used to label MVD. We analyzed the factors affecting HER2 amplification, the difference in MVD under different HER2 states, the factors related to 5-year survival rate of patients, and predicted the independent factors affecting 5-year survival rate of gastric cancer patients. RESULTS We found 115 cases with HER2 positive rate of 10.26 %. HER2 amplification was more likely in gastric cancer patients with more than 5.2 cm tumor diameter, Lauren intestinal type, tubular adenocarcinoma, and the depth of infiltration at stage T2, (P < 0.05). Gender, age, tumor location, number of lymph node metastasis, distant metastasis, clinical stage, nerve invasion and vascular tumor thrombi were not the factors affecting HER2 amplification of gastric cancer (P > 0.05). MVD count of HER2-positive gastric cancer was significantly higher than that of HER2-negative gastric cancer, (P < 0.05). The 5-year overall survival rate of 1121 patients with gastric cancer was 51.92 %. HER2 amplification, high MVD count, large tumor size, tubular adenocarcinoma, Lauren intestinal type, deep tumor infiltration, numerous lymph node metastases and late clinical stage are all associated with low 5-year survival rate, indicating poor prognosis in gastric cancer patients, (P < 0.05). The 5-year survival rate of gastric cancer patients was not correlated with gender, age, tumor location, distant metastasis, nerve invasion and vascular cancer plug, (P > 0.05). Multivariate analysis showed that Lauren classification, Infiltrating depth, Nodal status, Clinical stage, HER2 expression, MVD count were independent factors affecting the prognosis of gastric cancer patients, (P < 0.05). CONCLUSION HER2 overexpression was not only closely related to gastric cancer neovascularization, but also an independent predictor of prognosis of gastric cancer. In clinical treatment, anti-HER2 targeted therapy and anti-angiogenesis drugs can be adopted to achieve effective treatment.
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Affiliation(s)
- Fang Li
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Guiqing Meng
- Department of Pathology Gastroscopy, Pingxiang General Hospital, Pingxiang, Xingtai, China
| | - Bibo Tan
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zihao Chen
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qiang Ji
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaoxiao Wang
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chang Liu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shuyao Niu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yong Li
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
| | - Yueping Liu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
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Zhou Q, Lan X, Li N, Yuan D, Zhang J. Analysis of Prognostic Factors and Design of Prognosis Model for Patients with Stage IV Gastric Cancer Following First-Line Palliative Chemotherapy. Cancer Manag Res 2020; 12:10461-10468. [PMID: 33122945 PMCID: PMC7588669 DOI: 10.2147/cmar.s263320] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 09/14/2020] [Indexed: 01/13/2023] Open
Abstract
Background This study was to investigate the prognostic factors of patients with advanced gastric cancer and described a sample model to better differentiate the patients who could better benefit from palliative chemotherapy. Patients and Methods In this retrospective study, 112 gastric cancer patients at stage IV following first-line chemotherapy were enrolled from July 2013 to September 2019. The clinical factors including age, sex, ECOG, pathologic types, metastatic sites, blood indexes, response of first-line chemotherapy, and survival were collected. The treatment responses were evaluated using the response evaluation criteria in solid tumors (RECIST). The survival curves were drawn by the Kaplan–Meier method, and the independent prognostic factors of overall survival (OS) were analyzed by Cox proportional hazards regression model. Results In this study, the median overall survival (mOS) of gastric cancer patients was 10.5 months, the disease remission rate (PR) was 21.4%, and the disease control rate (DCR) was 86.6%. Multivariate analysis identified 5 independent prognostic factors: peritoneal metastasis [P = 0.002; hazard risk (HR), 2.394; 95% CI 1.394–4.113], hemoglobin <90g/L [P = 0.001; hazard risk (HR), 2.674; 95% CI 1.536–4.655], LDH ≥225 U/L [P = 0.033; hazard risk (HR), 1.818; 95% CI 1.409–3.150], and 3 times higher level of CEA [P = 0.006; hazard risk (HR), 2.123; 95% CI 1.238–3.640] along with CA199 [P = 0.005; hazard risk (HR), 2.544; 95% CI 1.332–4.856] than upper limit of normal. Based on the obtained data, a prognostic index was constructed, dividing the patients into three risk groups: low (n = 67), intermediate (n = 35), and high-risk group (n = 10). The mOS for low, intermediate, and high-risk groups was 13.9 months (95% CI 10.7–17.1), 8.1 months (95% CI 5.7–10.4), and 3.9 months (95% CI 2.6–5.3), respectively, whereas the 1-year survival rate was 56.4%, 20.0%, and 0.0%, respectively (P < 0.001). Conclusion This model should facilitate the prediction of treatment outcomes and then individualized treatment of advanced gastric cancer patients.
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Affiliation(s)
- Qiyin Zhou
- Department of Oncology, Chengdu Seventh People Hospital (Chengdu Tumorous Disease Quality Control Center), Chengdu 610000, People's Republic of China
| | - Xi Lan
- Department of Oncology, Chengdu Seventh People Hospital (Chengdu Tumorous Disease Quality Control Center), Chengdu 610000, People's Republic of China
| | - Ni Li
- Department of Oncology, Chengdu Seventh People Hospital (Chengdu Tumorous Disease Quality Control Center), Chengdu 610000, People's Republic of China
| | - Daozu Yuan
- Department of Oncology, Chengdu Seventh People Hospital (Chengdu Tumorous Disease Quality Control Center), Chengdu 610000, People's Republic of China
| | - Jiliang Zhang
- Department of Oncology, Chengdu Seventh People Hospital (Chengdu Tumorous Disease Quality Control Center), Chengdu 610000, People's Republic of China
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Hu Z, Hu Y, Jiang H. Overexpression of COX-2 and clinicopathological features of gastric cancer: a meta-analysis. Transl Cancer Res 2020; 9:2200-2209. [PMID: 35117580 PMCID: PMC8798741 DOI: 10.21037/tcr.2020.03.52] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 02/14/2020] [Indexed: 01/11/2023]
Abstract
Background To evaluate the correlation between COX-2 overexpression and clinicopathological features of gastric cancer, thus providing theoretical basis for anti-COX-2 targeted therapy. Methods The literature about COX-2 expression and gastric cancer was searched in PubMed, Wangfang, VIP, CNKI from the inception to September 2019, with “gastric cancer”, “COX-2”, “cyclooxygenase” as keywords. Stata 15.0 was used to analyze. Age, gender, differentiation, infiltration depth, lymph node metastasis, tumor size, TNM staging were analyzed by OR (95% CI). Results Nine studies involving 1,289 patients with gastric cancer were identified, among which 878 cases existed COX-2 overexpression. COX-2 overexpression was related to the infiltration depth (OR=1.76; 95% CI: 1.01–1.306; P<0.01) and lymph node metastasis (OR=3.08; 95% CI: 1.64–5.79; P<0.01). While, it was not related to age, gender, differentiation and tumor size. Conclusions COX-2 overexpression is valuable in predicting infiltration depth and lymph node metastasis, and could be a predictor of poor prognosis in gastric cancer. COX-2-targeted therapy can be considered as one of the comprehensive treatments for gastric cancer.
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Affiliation(s)
- Zhili Hu
- Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China.,Department of General Surgery, The Affiliated Hospital of Xiangnan University, Chenzhou 423000, China
| | - Yangzhi Hu
- Department of General Surgery, The Affiliated Hospital of Xiangnan University, Chenzhou 423000, China
| | - Haiping Jiang
- Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China
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Xi Y, Xu C, Liu Y, Yan X, Huang C, Liu Y, Mei J, Wang Z, Liu B, Li X, Li W, Lan J, Gao P, Wu J, Zheng J, Hou Y. The age variation of HER2 immunohistochemistry positive rate in biopsy specimens of gastric cancer. Pathol Res Pract 2020; 216:152882. [PMID: 32113795 DOI: 10.1016/j.prp.2020.152882] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 01/23/2020] [Accepted: 02/12/2020] [Indexed: 02/07/2023]
Abstract
AIMS The aim of this study was to explore HER2 status and characteristics in biopsy specimens of gastric cancer (GC) in Chinese population. METHODS AND RESULTS A total of 27,787 biopsy specimens of GC from 103 hospitals were obtained. Immunohistochemistry (IHC) staining of HER2 was performed. Overall HER2 IHC positive rate was 11.2 %. HER2 positive rate elevated with the increase of age in total patients and both genders. The rates were 7.1 %, 8.1 %, 9.0 %, 10.9 %, 11.8 %, 12.6 %, and 12.1 % when patient age was ≤30, 31-40, 41-50, 51-60, 61-70, 71-80, and >80, respectively (P < 0.001). In male, the rates were 6.5 %, 8.4 %, 9.6 %, 11.5 %, 12.4 %, 13.3 %, and 12.1 % (P < 0.001). In female, the rates were 7.4 %, 7.9 %, 8.0 %, 9.0 %, 9.6 %, 10.6 %, and 11.9 % (P = 0.128). The changes in male were more dramatic than in female (P < 0.001). Furthermore, the proportion of the intestinal type GCs increased with age in total patients and both genders (P < 0.001), and in male the changes were more dramatic (P < 0.001). While the proportion of the diffuse type showed the opposite tendency to that of the intestinal type (P < 0.001). HER2 IHC positive rate showed a positive correlation with the proportion of the intestinal type (r=0.986, P < 0.001), and a negative correlation with the proportion of the diffuse type (r=0.984, P < 0.001). CONCLUSIONS The HER2 IHC positive rate showed age variation in biopsy specimens of GC. In male the variation was more dramatic than in female. The variation of HER2 positive rate can be attributed to the age variation of the Lauren subtypes.
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Affiliation(s)
- Yanfeng Xi
- Department of Pathology, Shanxi Cancer Hospital, Taiyuan, China
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital; Department of Pathology, School of Basic Sciences & Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yiqiang Liu
- Department of Pathology, Beijing Cancer Hospital, Beijing, China
| | - Xiaochu Yan
- Department of Pathology, The First Hospital Affiliated to AMU (Southwest Hospital), Chongqing, China
| | - Chuansheng Huang
- Department of Pathology, Jiangxi Cancer Hospital, Nanchang, China
| | - Yueping Liu
- Department of Pathology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jinhong Mei
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhe Wang
- Department of Pathology, Xijing Hospital, Air Force Medical University (The Fourth Military Medical University), Xi'an, China
| | - Bin Liu
- Department of Pathology, Lanzhou General Hospital of People's Liberation Army, Lanzhou, China
| | - Xiaoming Li
- Department of Pathology, Lanzhou University Second Hospital, Lanzhou, China
| | - Wencai Li
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianyun Lan
- Department of Pathology, Yancheng City No.1 People's Hospital, Yancheng, China
| | - Peng Gao
- Department of Pathology, Qilu Hospital of Shandong University, Jinan, China
| | - Jifeng Wu
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jianming Zheng
- Department of Pathology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital; Department of Pathology, School of Basic Sciences & Zhongshan Hospital, Fudan University, Shanghai, China.
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40
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Bonelli P, Borrelli A, Tuccillo FM, Silvestro L, Palaia R, Buonaguro FM. Precision medicine in gastric cancer. World J Gastrointest Oncol 2019; 11:804-829. [PMID: 31662821 PMCID: PMC6815928 DOI: 10.4251/wjgo.v11.i10.804] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 07/11/2019] [Accepted: 09/05/2019] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is a complex disease linked to a series of environmental factors and unhealthy lifestyle habits, and especially to genetic alterations. GC represents the second leading cause of cancer-related deaths worldwide. Its onset is subtle, and the majority of patients are diagnosed once the cancer is already advanced. In recent years, there have been innovations in the management of advanced GC including the introduction of new classifications based on its molecular characteristics. Thanks to new technologies such as next-generation sequencing and microarray, the Cancer Genome Atlas and Asian Cancer Research Group classifications have also paved the way for precision medicine in GC, making it possible to integrate diagnostic and therapeutic methods. Among the objectives of the subdivision of GC into subtypes is to select patients in whom molecular targeted drugs can achieve the best results; many lines of research have been initiated to this end. After phase III clinical trials, trastuzumab, anti-Erb-B2 receptor tyrosine kinase 2 (commonly known as ERBB2) and ramucirumab, anti-vascular endothelial growth factor receptor 2 (commonly known as VEGFR2) monoclonal antibodies, were approved and introduced into first- and second-line therapies for patients with advanced/metastatic GC. However, the heterogeneity of this neoplasia makes the practical application of such approaches difficult. Unfortunately, scientific progress has not been matched by progress in clinical practice in terms of significant improvements in prognosis. Survival continues to be low in contrast to the reduction in deaths from many common cancers such as colorectal, lung, breast, and prostate cancers. Although several target molecules have been identified on which targeted drugs can act and novel products have been introduced into experimental therapeutic protocols, the overall approach to treating advanced stage GC has not substantially changed. Currently, surgical resection with adjuvant or neoadjuvant radiotherapy and chemotherapy are the most effective treatments for this disease. Future research should not underestimate the heterogeneity of GC when developing diagnostic and therapeutic strategies aimed toward improving patient survival.
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Affiliation(s)
- Patrizia Bonelli
- Molecular Biology and Viral Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G Pascale, Napoli 80131, Italy
| | - Antonella Borrelli
- Molecular Biology and Viral Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G Pascale, Napoli 80131, Italy
| | - Franca Maria Tuccillo
- Molecular Biology and Viral Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G Pascale, Napoli 80131, Italy
| | - Lucrezia Silvestro
- Abdominal Medical Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G Pascale, Napoli 80131, Italy
| | - Raffaele Palaia
- Gastro-pancreatic Surgery Division, Istituto Nazionale Tumori - IRCCS - Fondazione G Pascale, Napoli 80131, Italy
| | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G Pascale, Napoli 80131, Italy
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41
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Wang Y, Zhang B, Gao G, Zhang Y, Xia Q. GEFT protein expression in digestive tract malignant tumors and its clinical significance. Oncol Lett 2019; 18:5577-5590. [PMID: 31620201 DOI: 10.3892/ol.2019.10915] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 08/13/2019] [Indexed: 01/23/2023] Open
Abstract
Guanine nucleotide exchange factor T (GEFT), a member of the Rho guanine nucleotide exchange factor family, is expressed in a variety of tumors. In the present study, the expression and clinical significance of GEFT in malignant digestive tract tumors was assessed. Tumor and adjacent control samples from 180 patients were tested. Positive GEFT expression rates were 80, 83.33 and 86.67% in esophageal squamous carcinoma (ESCC), gastric carcinoma (GC) and colorectal cancer (CRC), respectively. GEFT expression was associated with diffuse type carcinoma according to the Lauren classification (χ2=12.525, P=0.002) and tumor-node-metastasis (TNM) stages III/IV (χ2=4.033, P=0.045) in GC, and with vessel carcinoma embolus (χ2=7.890, P=0.005) and lymph node metastasis (χ2=5.455, P=0.020) in CRC, but was not associated with other clinicopathological parameters. Patients with high levels of GEFT protein expression had a less favorable outcome compared with patients with low levels of GEFT expression in patients with CRC (χ2=3.876, P=0.049). However, a significant association was not found between GEFT expression and overall survival in patients with ESCC (χ2=0.040, P=0.842) or GC (χ2=0.501, P=0.479). The rate of human epidermal growth factor receptor 2 upregulation in patients with GC was 13.33% and it was associated with nerve invasion (χ2=4.005, P=0.045) and TNM stages III/IV (χ2=5.600, P=0.018). Mismatch repair protein (MMRP) defect was observed in six cases, and the KRAS mutation rate was 26.67% in patients with CRC. GEFT expression was significantly correlated with MMRP (r=-0.285, P=0.027) and KRAS mutation in patients with CRC (r=0.697, P<0.001). These findings revealed frequent GEFT upregulation in malignant digestive tract tumors, which may have promoted tumor development. GEFT expression in CRC may be associated with microsatellite instability and KRAS mutation status, suggesting that GEFT may be a potential therapeutic target for patients with CRC.
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Affiliation(s)
- Yuanyuan Wang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| | - Bing Zhang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| | - Ge Gao
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| | - Yinping Zhang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| | - Qingxin Xia
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
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Zubarayev M, Min EK, Son T. Clinical and molecular prognostic markers of survival after surgery for gastric cancer: tumor-node-metastasis staging system and beyond. Transl Gastroenterol Hepatol 2019; 4:59. [PMID: 31559340 DOI: 10.21037/tgh.2019.08.05] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 07/30/2019] [Indexed: 12/12/2022] Open
Abstract
For accurately predicting prognosis and for effectively describing cancer states at a certain point during treatment to other care providers and patients, various staging systems have been utilized in gastric cancer. Among these, the UICC/AJCC tumor-node-metastasis (TNM) staging system is most widely used. However, even within the same substage, gastric cancers can vary substantially in regards to prognosis after treatment. For more accurate and individualized prognostication, staging systems have been found to benefit from including molecular markers and genomic subtypes, in addition to clinicopathological parameters, such as age, sex, tumor size, tumor location, Lauren classification, number of lymph nodes resected, extent of surgical resection, lymphovascular invasion, and adjuvant chemotherapy. In this review article, we review and summarize relevant biomarkers for gastric cancer that can be incorporated into the current anatomy-based TNM staging system, as well as results from validation studies thereof.
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Affiliation(s)
- Mykola Zubarayev
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.,GI laparoscopic & Robotic Surgery, National Cancer Institute, Kiev, Ukraine
| | - Eun-Ki Min
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Taeil Son
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.,Gastric Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea
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43
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Kannangara DKS, Lokuhetty MDS, Subasinghe D, Gunawardene YINS, Dassanayake RS. Could quantitative real-time polymerase chain reaction assay serve as an alternative test method to evaluate human epidermal growth factor receptor 2 status of gastric carcinoma in the South Asian setting? Indian J Gastroenterol 2019; 38:317-324. [PMID: 31401730 DOI: 10.1007/s12664-019-00955-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 04/14/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) protein overexpression and/or HER2 gene amplification are/is linked to a dismal outcome of gastric carcinoma (GCa). Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are key methods to identify patients for HER2 targeted therapy. Drawbacks of both the methods warrant novel tests. Hence, we evaluated the value of quantitative real-time polymerase chain reaction (qPCR) as an alternative test method, relative to IHC to detect HER2 status of GCa and to find relationship between these results with demographic/clinicopathological data. METHOD Twenty GCa patients with known IHC HER2 scores were evaluated. qPCR was performed for the HER2 gene and amyloid precursor protein (reference gene) in formalin-fixed paraffin-embedded GCa tissue. Cycle threshold values (Ct) were analyzed using the Pfaffl method to detect HER2 gene amplification. RESULTS HER2 positivity rates by IHC and qPCR were 20% and 35%, respectively. The sensitivity and specificity of qPCR were 67% and 76%, respectively, relative to IHC. qPCR results were reproducible. The diagnostic consistency between IHC and qPCR (κ = 0.146) was slightly agreeable (0.01 < k < 0.20), with a 65% concordance. Based on McNemar's test, there was no significant difference between the results of the two tests. IHC HER2 protein expression had relationship with the tumor (TNM) stage and Lauren histological type (p < 0.05). Positive HER2 gene expression by qPCR showed relationship with depth of invasion, lymph node involvement, and degree of differentiation (p < 0.05). CONCLUSION Cost-effective qPCR could serve as an alternative test method for detection of HER2 status of GCa. Both HER2 overexpression by IHC and gene amplification by qPCR are associated with adverse clinicopathological features.
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Affiliation(s)
- D K S Kannangara
- Post Graduate Institute of Medicine, University of Colombo, Colombo, Sri Lanka
| | - M D S Lokuhetty
- Department of Pathology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - D Subasinghe
- Department of Surgery, Faculty of Medicine, The National Hospital of Sri Lanka, University of Colombo/University Surgical Unit, Colombo, Sri Lanka
| | - Y I N S Gunawardene
- Molecular Medicine Unit, Faculty of Medicine, University of Kelaniya, Colombo, Sri Lanka
| | - R S Dassanayake
- Department of Chemistry, Faculty of Science, University of Colombo, Colombo, Sri Lanka.
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44
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Wang DS, Liu ZX, Lu YX, Bao H, Wu X, Zeng ZL, Liu Z, Zhao Q, He CY, Lu JH, Wang ZQ, Qiu MZ, Wang F, Wang FH, Li YH, Wang XN, Xie D, Jia WH, Shao YW, Xu RH. Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer. Gut 2019; 68:1152-1161. [PMID: 30269082 DOI: 10.1136/gutjnl-2018-316522] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 08/28/2018] [Accepted: 09/01/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To monitor trastuzumab resistance and determine the underlying mechanisms for the limited response rate and rapid emergence of resistance of HER2+ metastatic gastric cancer (mGC). DESIGN Targeted sequencing of 416 clinically relevant genes was performed in 78 paired plasma and tissue biopsy samples to determine plasma-tissue concordance. Then, we performed longitudinal analyses of 97 serial plasma samples collected from 24 patients who were HER2+ to track the resistance during trastuzumab treatment and validated the identified candidate resistance genes. RESULTS The results from targeted sequencing-based detection of somatic copy number alterations (SCNA) of HER2 gene were highly consistent with fluorescence in situ hybridisation data, and the detected HER2 SCNA was better than plasma carcinoembryonic antigen levels at predicting tumour shrinkage and progression. Furthermore, most patients with innate trastuzumab resistance presented high HER2 SCNA during progression compared with baseline, while HER2 SCNA decreased in patients with acquired resistance. PIK3CA mutations were significantly enriched in patients with innate resistance, and ERBB2/4 genes were the most mutated genes, accounting for trastuzumab resistance in six (35.3%) and five (29.4%) patients in baseline and progression plasma, respectively. Patients with PIK3CA/R1/C3 or ERBB2/4 mutations in the baseline plasma had significantly worse progression-free survival. Additionally, mutations in NF1 contributed to trastuzumab resistance, which was further confirmed through in vitro and in vivo studies, while combined HER2 and MEK/ERK blockade overcame trastuzumab resistance. CONCLUSION Longitudinal circulating tumour DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2+mGC.
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Affiliation(s)
- De-Shen Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ze-Xian Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yun-Xin Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hua Bao
- Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Canada
| | - Xue Wu
- Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Canada
| | - Zhao-Lei Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zekun Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qi Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Cai-Yun He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jia-Huan Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhi-Qiang Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Miao-Zhen Qiu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Feng Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Feng-Hua Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yu-Hong Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | | | - Dan Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wei-Hua Jia
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yang W Shao
- Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Canada.,School of Public Health, Nanjing Medical University, Nanjing, China
| | - Rui-Hua Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
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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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Wang FH, Shen L, Li J, Zhou ZW, Liang H, Zhang XT, Tang L, Xin Y, Jin J, Zhang YJ, Yuan XL, Liu TS, Li GX, Wu Q, Xu HM, Ji JF, Li YF, Wang X, Yu S, Liu H, Guan WL, Xu RH. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer. Cancer Commun (Lond) 2019; 39:10. [PMID: 30885279 PMCID: PMC6423835 DOI: 10.1186/s40880-019-0349-9] [Citation(s) in RCA: 306] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 02/01/2019] [Indexed: 02/08/2023] Open
Abstract
China is one of the countries with the highest incidence of gastric cancer. There are differences in epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selection between gastric cancer patients from the Eastern and Western countries. Non-Chinese guidelines cannot specifically reflect the diagnosis and treatment characteristics for the Chinese gastric cancer patients. The Chinese Society of Clinical Oncology (CSCO) arranged for a panel of senior experts specializing in all sub-specialties of gastric cancer to compile, discuss, and revise the guidelines on the diagnosis and treatment of gastric cancer based on the findings of evidence-based medicine in China and abroad. By referring to the opinions of industry experts, taking into account of regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted experts' consensus judgement on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes. This guideline uses tables and is complemented by explanatory and descriptive notes covering the diagnosis, comprehensive treatment, and follow-up visits for gastric cancer.
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Affiliation(s)
- Feng-Hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Jin Li
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120 P. R. China
| | - Zhi-Wei Zhou
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Han Liang
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Tianjin’s Clinical Research Cancer for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060 P. R. China
| | - Xiao-Tian Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Lei Tang
- Medical Imaging Department, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Yan Xin
- Pathology Laboratory of Gastrointestinal Tumor, The First Hospital of China Medical University, Shenyang, 110001 Liaoning P. R. China
| | - Jing Jin
- Department of Radiation Oncology, National Cancer Center, China and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 P. R. China
| | - Yu-Jing Zhang
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Xiang-Lin Yuan
- Department of Medical Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030 Hubei P. R. China
| | - Tian-Shu Liu
- Department of Medical Oncology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, 200032 P. R. China
| | - Guo-Xin Li
- Department of General Surgery, Nanfang Hospital Affiliated to Southern Medical University, Guangzhou, 510515 Guangdong P. R. China
| | - Qi Wu
- Department of Endoscopy Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Hui-Mian Xu
- Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang, 110001 Liaoning P. R. China
| | - Jia-Fu Ji
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Yuan-Fang Li
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Xin Wang
- Department of Radiation Oncology, National Cancer Center, China and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 P. R. China
| | - Shan Yu
- Department of Medical Oncology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, 200032 P. R. China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital Affiliated to Southern Medical University, Guangzhou, 510515 Guangdong P. R. China
| | - Wen-Long Guan
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
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47
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Matsuoka T, Yashiro M. Biomarkers of gastric cancer: Current topics and future perspective. World J Gastroenterol 2018; 24:2818-2832. [PMID: 30018477 PMCID: PMC6048430 DOI: 10.3748/wjg.v24.i26.2818] [Citation(s) in RCA: 300] [Impact Index Per Article: 42.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 05/19/2018] [Accepted: 06/01/2018] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most prevalent malignant types in the world and an aggressive disease with a poor 5-year survival. This cancer is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Although the incidence is declining, the outcome of patients with GC remains dismal. Thus, the detection at an early stage utilizing useful screening approaches, selection of an appropriate treatment plan, and effective monitoring is pivotal to reduce GC mortalities. Identification of biomarkers in a basis of clinical information and comprehensive genome analysis could improve diagnosis, prognosis, prediction of recurrence and treatment response. This review summarized the current status and approaches in GC biomarker, which could be potentially used for early diagnosis, accurate prediction of therapeutic approaches and discussed the future perspective based on the molecular classification and profiling.
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Affiliation(s)
- Tasuku Matsuoka
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Masakazu Yashiro
- Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
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48
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Nadaf AS, Rani H, Dinesh US. Immuno-Histochemical Assessment of HER2NEU Expression in Gastric Adenocarcinoma in North Karnataka, India. Asian Pac J Cancer Prev 2018; 19:1381-1385. [PMID: 29802704 PMCID: PMC6031826 DOI: 10.22034/apjcp.2018.19.5.1381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background and Objectives: Gastric cancer is the fourth most common cancer worldwide and ranks fifth in India.
Surgical resection is curative in early stage gastric cancers. Most of the gastric cancers are diagnosed at an advanced
stage necessitating multimodality treatment strategies. Based on the ToGA trial, the international regulatory agencies
have recently approved trastuzumab in locally advanced and metastatic gastric and gastroesophageal adenocarcinomas
expressing HER2. Since there are limited studies from India and no published data available from this part of North
Karnataka, we undertook this study to evaluate the frequency of expression of HER2 in gastric and gastroesophageal
adenocarcinomas and to correlate it with various clinicopathological variables. Methodology: The study was conducted
in the Department of Pathology, SDM College of Medical Sciences and Hospital, Dharwad, Karnataka from May 2012
to January 2016. The samples included both endoscopic biopsies and gastrectomies. Histopathological slides from 70
cases were reviewed. Immunohistochemical staining for HER2 was performed in all the cases and Hoffman’s gastric
cancer scoring system was employed. The results of HER2 expression was correlated with various clinicopathological
parameters. Results: HER2 positivity was seen in 16/70 cases (23%). 6 cases (8.5%) were equivocal and 48/70 cases
(68.5%) were HER2 negative. HER2 positivity was more common in GEJ cancers and intestinal type of adenocarcinoma.
However, it did not correlate with age, gender, grade and stage. Conclusion: HER2 positivity was noted in 23% of the
cases. 23.4% of intestinal type and 21.7% of diffuse type were HER2 positive. HER2 positivity did not significantly
depend on age, gender, tumour type, grade and stage. Hence, HER2 remains as an independent biomarker and should be
tested in all patients of gastric cancer regardless of the clinicopathological findings for offering a personalized treatment.
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Affiliation(s)
- Asmanaz Saleem Nadaf
- Department of Pathology, SDM Medical College and Hospital, Dharwad, Karnataka, India.
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49
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Dai F, Xuan Y, Jin JJ, Yu S, Long ZW, Cai H, Liu XW, Zhou Y, Wang YN, Chen Z, Huang H. CtBP2 overexpression promotes tumor cell proliferation and invasion in gastric cancer and is associated with poor prognosis. Oncotarget 2018; 8:28736-28749. [PMID: 28404932 PMCID: PMC5438687 DOI: 10.18632/oncotarget.15661] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 01/23/2017] [Indexed: 12/20/2022] Open
Abstract
C-terminal binding protein-2 (CtBP2), a transcriptional corepressor, has been reported to correlate with tumorigenesis and progression and predict a poor prognosis in several human cancers. However, few studies on CtBP2 in gastric cancer (GC) have been performed. In this research, we evaluated the correlations between CtBP2 expression and the clinicopathological characteristics, as well as prognosis of GC patients. The effects of silencing CtBP2 expression on GC cells biology activity were also assessed. The results showed that CtBP2 was overexpressed in GC tissues and closely correlated with poor differentiation, advanced tumor stage and poor prognosis in GC patients. CtBP2 induced epithelial-to-mesenchymal transition (EMT) and repressed PTEN to increase proliferation rate, migration, and invasion in GC cells. Silencing CtBP2 inhibited GC growth in nude mice model. In conclusion, CtBP2 is overexpressed in GC and may accelerate GC tumorigenesis and metastasis, which could represent an independent prognostic marker and promising therapeutic target for GC.
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Affiliation(s)
- Faxiang Dai
- Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Jiangsu Province, Nantong 226001, China
| | - Yi Xuan
- Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jie-Jie Jin
- Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Shengjia Yu
- Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zi-Wen Long
- Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Hong Cai
- Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiao-Wen Liu
- Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ye Zhou
- Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ya-Nong Wang
- Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhong Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Jiangsu Province, Nantong 226001, China
| | - Hua Huang
- Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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50
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Xu C, Liu Y, Jiang D, Li Q, Ge X, Zhang Y, Huang J, Su J, Ji Y, Hou J, Lu S, Hou Y, Liu T. Poor efficacy response to trastuzumab therapy in advanced gastric cancer with homogeneous HER2 positive and non-intestinal type. Oncotarget 2018; 8:33185-33196. [PMID: 28388541 PMCID: PMC5464860 DOI: 10.18632/oncotarget.16567] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 03/16/2017] [Indexed: 12/20/2022] Open
Abstract
Introduction Factors affecting trastuzumab efficacy in advanced gastric cancer (GC) are largely unknown. Heterogeneity is a notable feature of HER2 in GC. Whether the heterogeneity influences trastuzumab efficacy is still unknown. Results The HER2homogeneous group and HER2heterogeneous group showed no statistical difference in RR (46.4% vs 55.0%, P = 0.558), PFS (5.80 vs 6.30 months, P = 0.804) and OS (16.00 vs 16.00 months, P = 0.787). The Laurenintestinal group and Laurennon-intestinal group demonstrated no discrepancy in PFS (6.00 vs 6.00 months, P = 0.912) and OS (16.50 vs 14.00 months, P = 0.227). However, by combining HER2 heterogeneity and Lauren classification, PFS and OS of HER2homogeneous/Laurennon-intestinal subgroup was the shortest among the 4 subgroups (P = 0.012 and P = 0.037), which was much shorter than the other patients (PFS:3.00 vs 6.30 months, P = 0.003; OS: 4.50 vs 16.50 months, P = 0.004). Univariate and multivariate analysis showed that HER2 heterogeneity combined with Lauren classification was an independent prognostic factor in both PFS (P = 0.031 and P = 0.002) and OS (P = 0.039 and P = 0.013). Materials and Methods 48 patients with HER2 positive advanced GCs accepting trastuzumab treatment were retrospectively analyzed. Based on HER2 heterogeneity, the patients were divided into a HER2homogeneous group and a HER2heterogeneous group. Response rate (RR), progression free survival (PFS), and overall survival (OS) were compared. Main clinicopathological factors including Lauren classification were subjected to subgroup analysis. Conclusions HER2 heterogeneity alone may not correlate with trastuzumab efficacy in HER2 positive advanced GCs. HER2 heterogeneity combined with Lauren classification may help to identify a subgroup with poor response to trastuzumab which is homogeneous HER2 positive and non-intestinal type.
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Affiliation(s)
- Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yalan Liu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dongxian Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qian Li
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaowen Ge
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying Zhang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Huang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jieakesu Su
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jun Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shaohua Lu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Pathology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tianshu Liu
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
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