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Shen K, Hu C, Zhang Y, Cheng X, Xu Z, Pan S. Advances and applications of multiomics technologies in precision diagnosis and treatment for gastric cancer. Biochim Biophys Acta Rev Cancer 2025; 1880:189336. [PMID: 40311712 DOI: 10.1016/j.bbcan.2025.189336] [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: 01/25/2025] [Revised: 04/24/2025] [Accepted: 04/25/2025] [Indexed: 05/03/2025]
Abstract
Gastric cancer (GC), one of the most prevalent malignancies worldwide, is distinguished by extensive genetic and phenotypic heterogeneity, posing persistent challenges to conventional diagnostic and therapeutic strategies. The significant global burden of GC highlights an urgent need to unravel its complex underlying mechanisms, discover novel diagnostic and prognostic biomarkers, and develop more effective therapeutic interventions. In this context, this review comprehensively examines the transformative roles of cutting-edge technologies, including radiomics, pathomics, genomics, transcriptomics, epigenomics, proteomics, and metabolomics, in advancing precision diagnosis and treatment for GC. Multiomics data analysis not only deepens our understanding of GC pathogenesis and molecular subtypes but also identifies promising biomarkers, facilitating the creation of tailored therapeutic approaches. Additionally, integrating multiomics approaches holds immense potential for elucidating drug resistance mechanisms, predicting patient outcomes, and uncovering novel therapeutic targets, thereby laying a robust foundation for precision medicine in the comprehensive management of GC.
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Affiliation(s)
- Ke Shen
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, China
| | - Can Hu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
| | - Yanqiang Zhang
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
| | - Xiangdong Cheng
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
| | - Zhiyuan Xu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China.
| | - Siwei Pan
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China.
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Kim YS. Gastric Carcinoma. Curr Top Microbiol Immunol 2025. [PMID: 40423781 DOI: 10.1007/82_2025_303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2025]
Abstract
Epstein-Barr virus (EBV)-associated gastric cancers (EBVaGCs) account for about 10% of gastric cancers globally, with higher prevalence in East Asia and Latin America. These cancers develop through a "gastritis-infection-cancer sequence" and are characterized by unique molecular signatures, including CpG island methylator phenotype and mutations in ARID1A and PIK3CA genes. EBVaGCs typically present in the proximal stomach with diffuse-type histology and dense lymphocytic infiltration. Key viral proteins EBNA1 and LMP2A drive oncogenesis by altering cellular processes and immune responses. The IFN-γ signature and extensive epigenetic modifications contribute to their distinct profile. Despite often presenting at advanced stages, EBVaGCs generally have a more favorable prognosis. EBV employs sophisticated strategies to evade immune detection, utilizing latent proteins and noncoding RNAs. Paradoxically, despite an immune-hot environment, EBVaGCs demonstrate effective immune evasion, partly due to the expression of immune checkpoint molecules like PD-L1 and LAG3. Treatment approaches vary based on disease stage, from endoscopic resection for early-stage cancers to systemic therapies for advanced cases. Immunotherapy, particularly PD-1/PD-L1 inhibitors, shows promising results. Emerging research suggests combining these with LAG3 inhibitors may enhance efficacy. Ongoing research and advanced genomic techniques continue to reveal new insights, paving the way for personalized therapies and novel diagnostic approaches.
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Affiliation(s)
- Young-Sik Kim
- Department of Pathology, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
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Wang X, Gu Y, Yi L, Wu T, Wang L, Tian J, Lu Y, Jin P, Yang X, Yang Y. Pathologic complete response after Sintilimab combined with FOLFOX therapy in MSI-H type patients with locally advanced GC: a case report. Front Oncol 2025; 15:1560450. [PMID: 40406249 PMCID: PMC12094948 DOI: 10.3389/fonc.2025.1560450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 03/27/2025] [Indexed: 05/26/2025] Open
Abstract
As one of the most common gastrointestinal tumors, Gastric Cancer (GC) poses a serious threat to human health due to its high morbidity and mortality. The current treatment strategy is a comprehensive treatment program mainly based on surgery, especially for advanced GC patients. The emergence of immune checkpoint inhibitors has completely changed this status quo, and the synergistic effect of neoadjuvant immunotherapy combined with chemotherapy has significantly improved the resection and radical rate and overall survival of patients with advanced local GC. We present a case of locally advanced GC (cT4N0Mx) with microsatellite instability high (MSI-H) and PD-L1 Combined Positive Score (CPS)=2. The patient received neoadjuvant therapy with Sintilimab combined with FOLFOX (folinic acid (leucovorin), 5-fluorouracil (5-FU), and oxaliplatin), and significantly reduced tumor volume after 3 cycles of treatment. Then she underwent subtotal gastrectomy with gastrojejunostomy and D2 lymph node dissection. The postoperative pathological results showed that no cancerous tissue remained in the tumor tissue, and pathologic complete response (pCR) was achieved. The first cycle of adjuvant therapy with the same protocol was received after surgery. During adjuvant therapy, patients mainly experienced side effects such as dyspepsia, nausea and mild myelosuppression. Therefore, immunotherapy with Sintilimab combined with FOLFOX chemotherapy has the potential to be an effective treatment option for patients with resectable locally advanced MSI-H GC.
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Affiliation(s)
- Xiaoke Wang
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu, China
- First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Yuanhui Gu
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Lin Yi
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Tao Wu
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu, China
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Ling Wang
- Pathology Department, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Jiao Tian
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Yuyuan Lu
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Penghui Jin
- First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Xin Yang
- First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Yan Yang
- Pharmacy Department, Gansu Provincial Hospital, Lanzhou, Gansu, China
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4
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He MY, Liu M, Yuan J, Lv J, Li W, Yan Q, Tang Y, Wang L, Guo L, Liu F. Spatial transcriptomics reveals tumor microenvironment heterogeneity in EBV positive diffuse large B cell lymphoma. Sci Rep 2025; 15:15878. [PMID: 40335578 PMCID: PMC12058988 DOI: 10.1038/s41598-025-00410-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 04/28/2025] [Indexed: 05/09/2025] Open
Abstract
Accumulating research suggests that Epstein-Barr Virus-positive Diffuse Large B-cell Lymphoma (EBV+DLBCL) is associated with immune dysfunction and tumor microenvironment (TME) heterogeneity. While the prognostic role of the TME in EBV-DLBCL is established, its impact on EBV+DLBCL survival remains unclear. Here, we integrated 10X Visium spatial transcriptomics (ST) with single-cell RNA sequencing (scRNA-seq) to map TME heterogeneity in EBV+DLBCL. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses identified PD-1/PD-L1 signaling as a hallmark of EBV+DLBCL's immunosuppressive TME. Functional validation using the PD-1/PD-L1 inhibitor BMS202 revealed dose-dependent suppression of proliferation and enhanced apoptosis in EBV+Farage cells, with TLR4 emerging as a downstream effector showing EBV-status-dependent regulation. These findings not only link TME-driven PD-1/PD-L1 activation to EBV+DLBCL's poor prognosis but also provide preclinical evidence for PD-1/PD-L1 blockade as a therapeutic strategy.
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Affiliation(s)
- Mei-Yao He
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Meng Liu
- School of Life and Health Technology, Dongguan University of Technology, Dongguan, 523808, People's Republic of China
| | - Jiayin Yuan
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Jin Lv
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Wei Li
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Qianwen Yan
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Yujiao Tang
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Luyi Wang
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Li Guo
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Fang Liu
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China.
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Dai H, Ren J, Wang C, Huang J, Wang X. Prognostic molecular subtype reveals the heterogeneity of tumor immune microenvironment in gastric cancer. Sci Rep 2025; 15:14453. [PMID: 40281016 PMCID: PMC12032113 DOI: 10.1038/s41598-025-96686-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 03/31/2025] [Indexed: 04/29/2025] Open
Abstract
Gastric cancer (GC) remains a leading cause of cancer-related deaths and exhibits considerable heterogeneity among patients. Thus, accurate classifications are essential for predicting prognosis and developing personalized therapeutic strategies. To address this, we retrospectively analyzed multi-omics data from 359 GC samples, incorporating transcriptomic RNA (mRNA), DNA methylation, mutation data, and clinical parameters. Using ten clustering algorithms, we integrated these datasets to classify GC into molecular subtypes. The robustness of our clustering approach was externally validated using an independent cohort generated from different sequencing technologies, and we characterized the heterogeneity of each subtype. Our analysis identified three distinct molecular subtypes of GC, designated CS1, CS2, and CS3. These subtypes exhibited significant differences in survival outcomes, activation of cancer-related pathways, immune microenvironment composition, genomic alterations, and responses to immunotherapy and chemotherapy. Notably, Cathepsin V (CTSV) was significantly downregulated in the immunologically active and highly responsive CS3 subtype, while it was upregulated in the immunologically exhausted CS2 subtype. These findings suggest that CTSV could serve as both a prognostic marker and a molecular classifier. Furthermore, this study provides the first evidence of CTSV's high expression in GC and its potential role in tumor progression. The novel clustering approach, based on ten clustering algorithms and comprehensive analysis of multi-omics data in gastric cancer, can guide prognosis, characterize different clinical and biological features, and elucidate the tumor immune microenvironment, providing insights into the intratumor heterogeneity of GC and potential novel therapeutic strategies. Additionally, CTSV emerges as a prognostic marker linked to tumor immunity and disease progression, which lays the foundation for improved stratification strategies and the development of targeted therapeutic approaches in GC.
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Affiliation(s)
- Hui Dai
- Medical School, Nantong University, Nantong, 226001, Jiangsu, China
| | - Jing Ren
- Medical School, Nantong University, Nantong, 226001, Jiangsu, China
| | - Chun Wang
- Medical School, Nantong University, Nantong, 226001, Jiangsu, China
| | - Jianfei Huang
- Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Xudong Wang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, No. 20, Xisi Road, Nantong, 226001, Jiangsu, China.
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de la Fouchardière C, Cammarota A, Svrcek M, Alsina M, Fleitas-Kanonnikoff T, Lordick Obermannová R, Wagner AD, Yap Wei Ting D, Enea D, Petrillo A, Smyth EC. How do I treat dMMR/MSI gastro-oesophageal adenocarcinoma in 2025? A position paper from the EORTC-GITCG gastro-esophageal task force. Cancer Treat Rev 2025; 134:102890. [PMID: 39933210 DOI: 10.1016/j.ctrv.2025.102890] [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: 12/16/2024] [Revised: 01/23/2025] [Accepted: 01/24/2025] [Indexed: 02/13/2025]
Abstract
In less than a decade, immune checkpoint inhibitors (ICIs) have transformed the management of mismatch repair-deficient (dMMR) and microsatellite instability-high (MSI) cancers. However, beyond colorectal cancer (CRC), much of the evidence is mostly derived from non-randomized phase II studies or post-hoc analyses of broader clinical trials. dMMR/MSI tumours represent a specific subgroup of gastro-esophageal adenocarcinomas (GEA), accounting for approximately 9 % of cases, with a higher prevalence in early-stage compared to advanced-stage disease and older female patients. These tumours are predominantly sporadic, often linked to MLH1 promoter methylation, and rarely exhibit HER2 overexpression/ERBB2 amplification or other oncogenic drivers. The treatment landscape for early stage dMMR/MSI GEA is likely to change substantially soon, as ICIs have shown high pathological complete response (pCR) rates in small phase II trials, raising questions on optimisation of neoadjuvant therapy, and paving the way for organ preservation. The standard of treatment for untreated patients with advanced dMMR/MSI GEA is chemotherapy + ICI irrespectively of PDL-1 status. However, the role of chemotherapy-free regimen consisting of CTLA-4 plus PD-1 inhibitors remains undetermined. This review addresses these and other emerging questions, offering expert opinions and insights into the future therapeutic landscape for dMMR/MSI GEA.
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Affiliation(s)
- Christelle de la Fouchardière
- Institut PAOLI-CALMETTES, 232 Boulevard Sainte-Marguerite 13009, Marseille, France; Unicancer GI (UCGI) Group, Paris, France; EORTC-GITC Group, Brussels, Belgium.
| | - Antonella Cammarota
- EORTC-GITC Group, Brussels, Belgium; Hepatobiliary Immunopathology Lab, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Magali Svrcek
- Sorbonne Université, AP-HP, Saint-Antoine Hospital, Department of Pathology, France; LIMICS, UMRS 1142, Campus des Cordeliers 75006, Paris, France
| | - Maria Alsina
- EORTC-GITC Group, Brussels, Belgium; Hospital Universitario de Navarra, Navarrabiomed - IdiSNA, c. de Irunlarrea 3 31008, Pamplona, Spain
| | - Tania Fleitas-Kanonnikoff
- EORTC-GITC Group, Brussels, Belgium; Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain
| | - Radka Lordick Obermannová
- EORTC-GITC Group, Brussels, Belgium; Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute and Faculty of Medicine, Masaryk University, Czech Republic
| | - Anna Dorothea Wagner
- EORTC-GITC Group, Brussels, Belgium; Anna Dorothea Wagner, Department of Oncology, Division of Medical Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), 1011, Lausanne, Switzerland
| | | | - Diana Enea
- Sorbonne Université, AP-HP, Saint-Antoine Hospital, Department of Pathology, France
| | - Angelica Petrillo
- EORTC-GITC Group, Brussels, Belgium; Medical Oncology Unit, Ospedale del Mare, Naples, Italy
| | - Elizabeth C Smyth
- EORTC-GITC Group, Brussels, Belgium; Oxford NIHRBiomedical Research Centre, Churchill Hospital, Oxford OX3 7LE, UK
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Tomaszewski M, Styczeń A, Krysa M, Michalski A, Morawska-Michalska I, Hymos A, Wawer J, Rolińska A, Rahnama M, Urbanowicz T, Grywalska E. Lymphocyte Involvement in the Pathology of Pulmonary Arterial Hypertension. Int J Mol Sci 2024; 25:13455. [PMID: 39769220 PMCID: PMC11676877 DOI: 10.3390/ijms252413455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 12/07/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary vascular resistance and right heart failure, with emerging evidence suggesting a key role for immune dysregulation in its pathogenesis. This study aimed to assess the involvement of lymphocytes, particularly regulatory T cells (Tregs), and the expression of immune checkpoint molecules PD-1 and PD-L1 on peripheral blood subpopulations in patients diagnosed with PAH. The study involved 25 patients; peripheral blood mononuclear cells were isolated and subsequently analyzed using flow cytometry to quantify the Treg cell percentage and evaluate PD-1 and PD-L1 expression across the T and B cells. We observed a significantly higher percentage of Tregs in idiopathic PAH (iPAH) patients compared to healthy controls and those with congenital heart disease-associated PAH (CHD-PAH), connective tissue disease-associated PAH (CTD-PAH), and chronic thromboembolic pulmonary hypertension (CTEPH). An overexpression of PD-1 and PD-L1 was found on CD4+ and CD8+ lymphocytes in all PAH groups, particularly in iPAH and CHD-PAH patients. These findings align with previous research highlighting Treg dysfunction and PD-1/PD-L1 overexpression as contributors to PAH pathogenesis. Our results suggest that targeting immune checkpoints and modulating Treg function could represent novel therapeutic strategies for PAH. Future research should focus on validating these biomarkers in larger, independent cohorts and exploring their clinical utility in diagnosing and managing PAH.
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Affiliation(s)
- Michał Tomaszewski
- Department of Cardiology, Medical University of Lublin, Jaczewskiego 8 Street, 20-954 Lublin, Poland; (M.T.)
| | - Agnieszka Styczeń
- Department of Cardiology, Medical University of Lublin, Jaczewskiego 8 Street, 20-954 Lublin, Poland; (M.T.)
| | - Martyna Krysa
- Department of Cardiology, Medical University of Lublin, Jaczewskiego 8 Street, 20-954 Lublin, Poland; (M.T.)
| | - Adam Michalski
- Department of Clinical Immunology, Medical University of Lublin, Chodźki 4a Street, 20-093 Lublin, Poland
| | - Izabela Morawska-Michalska
- Department of Clinical Immunology, Medical University of Lublin, Chodźki 4a Street, 20-093 Lublin, Poland
| | - Anna Hymos
- Department of Experimental Immunology, Medical University of Lublin, Chodźki 4a Street, 20-093 Lublin, Poland
| | - Joanna Wawer
- Department of Experimental Immunology, Medical University of Lublin, Chodźki 4a Street, 20-093 Lublin, Poland
| | - Agnieszka Rolińska
- Department of Applied Psychology, Medical University of Lublin, Chodźki 7 Street, 20-093 Lublin, Poland
| | - Mansur Rahnama
- Department of Dental Surgery, Medical University of Lublin, Chodźki 6 Street, 20-093 Lublin, Poland
| | - Tomasz Urbanowicz
- Cardiac Surgery and Transplantology Department, Poznań University of Medical Sciences, Fredry 10 Street, 61-107 Poznań, Poland
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, Chodźki 4a Street, 20-093 Lublin, Poland
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Costa M, Lopes Fernandes C, Magalhães H. Perioperative Treatment in Gastric Cancer: A Fast-Changing Field. Cancers (Basel) 2024; 16:4036. [PMID: 39682222 DOI: 10.3390/cancers16234036] [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: 10/28/2024] [Revised: 11/21/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Gastric cancer is the fifth most common cancer worldwide and its incidence is rising. Surgery is the only curative strategy and its association with perioperative chemotherapy is now standard treatment for most resectable tumors. Despite treatment advances, disease relapse is high, even in early stages, and continued improvement in curative treatment is imperative. With deeper knowledge of gastric cancer heterogeneity, molecular subtypes, and the tumor immune microenvironment, new standard treatment strategies may emerge in the near future. This paper provides a comprehensive review of the current treatment landscape in resectable gastric cancer and future perspectives for the next decade regarding new agents such as targeted therapies, immunotherapy, antibody-drug conjugates, and the combination of multiple treatment modalities.
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Affiliation(s)
- Mafalda Costa
- Medical Oncology Department, Pedro Hispano Hospital, 4464-513 Matosinhos, Portugal
| | | | - Helena Magalhães
- Medical Oncology Department, Pedro Hispano Hospital, 4464-513 Matosinhos, Portugal
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McMiller TL, Besharati S, Yarchoan M, Zhu Q, Ünsal-Kaçmaz K, Xu K, Lee J, Bhaijee F, Engle LL, Taube JM, Berger AE, Anders RA, Topalian SL. Immune microenvironment of Epstein-Barr virus (EBV)-negative compared to EBV-associated gastric cancers: implications for immunotherapy. J Immunother Cancer 2024; 12:e010201. [PMID: 39572160 PMCID: PMC11580252 DOI: 10.1136/jitc-2024-010201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 10/29/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Gastric carcinomas (GC) are aggressive malignancies, and only ~15% of patients respond to anti-programmed cell death (ligand) 1 (PD-(L)1) monotherapy. However, Epstein-Barr virus (EBV)-associated GCs (~5-10% of GCs) often harbor PD-L1 and PD-L2 chromosomal amplifications and robust CD8+ T cell infiltrates, and respond at a high rate to anti-PD-1. The current study compares the tumor immune microenvironments (TiMEs) of EBV+ versus EBV(-) GCs. METHODS Over 1000 cases of primary invasive GCs were screened to identify 25 treatment-naïve specimens for study (11 EBV+, 14 EBV(-)). Quantitative immunohistochemistry (IHC) was conducted for markers of immune cell subsets and co-regulatory molecules. Gene expression profiling (GEP) was performed on RNAs isolated from macrodissected areas of CD3+ T cell infiltrates abutting PD-L1+ stromal/tumor cells, using multiplex quantitative reverse transcriptase PCR for a panel of 122 candidate immune-related genes. RESULTS IHC revealed that 17/25 GCs contained PD-L1+ stromal cells, with no significant difference between EBV+/- specimens; however, only 3/25 specimens (all EBV+) contained PD-L1+ tumor cells. CD8+ T cell densities were higher in EBV+ versus EBV(-) tumors (p=0.044). With GEP normalized to the pan-leukocyte marker PTPRC/CD45, EBV+ GCs overexpressed ITGAE (CD103, marking intraepithelial T cells and a dendritic cell subset) and the interferon-inducible genes CXCL9 and IDO1. In contrast, EBV(-) tumors overexpressed several functionally-related gene groups associated with myeloid cells (CD163, IL1A, NOS2, RIGI), immunosuppressive cytokines/chemokines (CXCL2, CXCR4, IL10, IL32), coinhibitory molecules (HAVCR2/TIM-3 and VSIR/VISTA), and adenosine pathway components (ENTPD1/ CD39 and NT5E/CD73). Notably, compared with EBV+ GCs, EBV(-) GCs also overexpressed components of the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway associated with cancer-promoting inflammation, including PTGS2/COX-2 (most highly upregulated gene, 32-fold, p=0.005); prostaglandin receptors PTGER1 (EP1; up 21-fold, p=0.015) and PTGER4 (EP4; up twofold, p=0.022); and the major COX-2-inducing cytokine IL1B (up 11-fold, p=0.019). Consistent with these findings, COX-2 protein expression trended higher in EBV(-) versus EBV+ GCs (p=0.068). CONCLUSIONS While certain markers of immunosuppression are found in the GC TiME regardless of EBV status, EBV(-) GCs, which are much more common than EBV+ GCs, overexpress components of the COX-2/PGE2 pathway. These findings provide novel insights into the immune microenvironments of EBV+ and EBV(-) GC, and offer potential targets to overcome resistance to anti-PD-(L)1 therapies.
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Affiliation(s)
- Tracee L McMiller
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sepideh Besharati
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mark Yarchoan
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Qingfeng Zhu
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Ke Xu
- Bristol Myers Squibb Co, Princeton, New Jersey, USA
| | - Junghwa Lee
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Feriyl Bhaijee
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Logan L Engle
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Janis M Taube
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Alan E Berger
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Robert A Anders
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Suzanne L Topalian
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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10
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Wang P, Chen P, Yang W, Yang W, Liu W, Yue S, Luo Q. Prognostic and predictive factors in advanced upper gastrointestinal cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis of the current evidence. BMC Cancer 2024; 24:1249. [PMID: 39385078 PMCID: PMC11465923 DOI: 10.1186/s12885-024-12998-w] [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: 01/28/2023] [Accepted: 09/26/2024] [Indexed: 10/11/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have shown encouraging treatment efficacy for upper gastrointestinal cancers (UGICs). However, durable clinical responses only existed in a minority of patients. We evaluated evidence predicting survival benefits to identify the optimal population followed by ICI-based therapy. METHODS A comprehensive search was performed using PubMed, Embase, Cochrane Library, and Web of Science to identify clinical trials for UGICs with ICI-based therapy. The outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation System (GRADE). RESULTS Thirty-six studies comprising 12,440 patients were included for quantitative synthesis. Patients with PD-L1-positive (OR = 2.08, p < 0.00001), EBV+ (OR = 8.47, p = 0.003) tumors were more likely to respond to ICI treatment. Moreover, OS was significantly improved with the statistical subgroup difference concerning sex (p = 0.02) and region (p = 0.02). An exploratory subgroup analysis showed significantly improved OS with ICI plus chemotherapy in patients with CPS ≥ 10 (HR = 0.66, p = 0.001) and CPS ≥ 1 (HR = 0.75, p < 0.00001). CONCLUSION UGIC patients with PD-L1-positive, EBV + status are associated with a better therapeutic response to ICI-based therapy. The male patients and Asian patients could derive more survival benefits following ICI treatment than female and non-Asian ones. A combination of prognostic and predictive factors was suggested to help guide immunotherapy decision-making in UGIC patients.
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Affiliation(s)
- Puxiu Wang
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, Liaoning, PR China
- School of Pharmacy, China Medical University, Shenyang, Liaoning, PR China
| | - Ping Chen
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, Liaoning, PR China
- School of Pharmacy, China Medical University, Shenyang, Liaoning, PR China
| | - Weiting Yang
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, Liaoning, PR China
- School of Pharmacy, China Medical University, Shenyang, Liaoning, PR China
| | - Wenhan Yang
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, Liaoning, PR China
- School of Pharmacy, China Medical University, Shenyang, Liaoning, PR China
| | - Wenqi Liu
- School of Life Sciences, Shenyang Pharmaceutical University, Shenyang, Liaoning, PR China
| | - Song Yue
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, Liaoning, PR China.
- School of Pharmacy, China Medical University, Shenyang, Liaoning, PR China.
| | - Qiuhua Luo
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, Liaoning, PR China.
- School of Pharmacy, China Medical University, Shenyang, Liaoning, PR China.
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11
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Lordick F, Rha SY, Muro K, Yong WP, Lordick Obermannová R. Systemic Therapy of Gastric Cancer-State of the Art and Future Perspectives. Cancers (Basel) 2024; 16:3337. [PMID: 39409957 PMCID: PMC11475804 DOI: 10.3390/cancers16193337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 09/27/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Background: The prognosis of patients diagnosed with locally advanced and metastatic gastric and esophago-gastric junction cancer is critical. The optimal choice of systemic therapy is essential to optimize survival outcomes. Methods: A comprehensive literature review via PubMed and analysis of major oncology congresses (European Society for Medical Oncology and American Society of Clinical Oncology websites) were conducted to ascertain the current status and latest developments in the systemic treatment of patients with localized or advanced gastric and esophago-gastric junction adenocarcinoma. Results: While neoadjuvant and perioperative chemotherapy for localized tumor stages is the preferred approach in the Western Hemisphere, adjuvant chemotherapy remains the preferred course of action in East Asia. The administration of chemotherapy, typically in the form of combinations comprising platinum and fluoropyrimidine compounds in combination with docetaxel, represents a standard of care. Investigations are underway into the potential of immunotherapy and other biologically targeted agents in the perioperative setting. To select the most appropriate therapy for advanced gastric cancer, including adenocarcinoma of the esophago-gastric junction, it is essential to determine biomarkers such as HER2 expression, PD-L1 combined positive score (CPS) (combined positive score), Claudin 18.2, and microsatellite instability (MSI). In the present clinical context, the standard first-line therapy is a combination of fluoropyrimidine and a platinum derivative. The selection of chemotherapy in combination with antibodies is contingent upon the specific biomarker under consideration. Conclusions: This article reviews the current state of the art based on recent clinical trial results and provides an outlook on the future of systemic therapy.
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Affiliation(s)
- Florian Lordick
- Department of Medicine (Oncology, Gastroenterology, Hepatology, Pulmonology), University of Leipzig Medical Center, Cancer Center Central Germany, 04103 Leipzig, Germany
| | - Sun Young Rha
- Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Wei Peng Yong
- Department of Haematology-Oncology, National University Cancer Institute, Singapore 119074, Singapore
| | - Radka Lordick Obermannová
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, 656 53 Brno, Czech Republic
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12
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Garattini SK, Basile D, De Re V, Brisotto G, Miolo G, Canzonieri V, Aprile G, Corvaja C, Buriolla S, Garattini E, Puglisi F. The potential of retinoic acid receptors as prognostic biomarkers and therapeutic targets in gastric cancer. Front Oncol 2024; 14:1453934. [PMID: 39323992 PMCID: PMC11422079 DOI: 10.3389/fonc.2024.1453934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 08/06/2024] [Indexed: 09/27/2024] Open
Abstract
Background Gastric cancer is a heterogeneous collection of tumors characterized by low survival rates. All-trans retinoic acid (retinoic-acid) is a clinically useful therapeutic agent belonging to the chemical family of retinoids, which consists of both natural and synthetic derivatives of vitamin-A. Retinoids are essential components of the normal diet and they regulate different physiological processes. From a therapeutic point of view, retinoic-acid is the first example of clinically useful differentiating agent. Indeed, the differentiating properties of this compound have promoted the use of retinoic-acid as a standard of care in Acute-Promyelocytic-Leukemia, a rare form of acute myeloid leukemia. In this study, we determine the RNA expression of the six isoforms of Retinoic-Acid-Receptors (RARα/RARβ/RARγ/RXRα/RXRβ/RXRγ) in view of their potential use as gastric cancer progression markers and/or therapeutic targets. In addition, we evaluate associations between the expression of these receptors and a simplified molecular classification of stomach tumors as well as the clinical characteristics of the cohort of patients analyzed. Finally, we define the prognostic value of the various Retinoic-Acid-Receptors in gastric cancer. Methods In this single institution and retrospective RAR-GASTRIC study, we consider 55 consecutive gastric cancer patients. We extract total RNA from the pathological specimens and we perform a NanoString Assay using a customized panel of genes. This allows us to determine the expression levels of the RAR and RXR mRNAs as well as other transcripts of interest. Results Our data demonstrate ubiquitous expression of the RAR and RXR mRNAs in gastric cancers. High levels of RARα, RARβ, RXRα and RXRβ show a significant association with stage IV tumors, "de novo" metastatic disease, microsatellite-stable-status, epithelial-to-mesenchymal-transition, as well as PIK3CA and TP53 expression. Finally, we observe a worse overall-survival in gastric cancer patients characterized by high RARα/RARβ/RARγ/RXRβ mRNA levels. Conclusions In gastric cancer, high expression levels of RARα/RARβ/RARγ/RXRβ transcripts are associated with poor clinical and molecular characteristics as well as with reduced overall-survival. Our data are consistent with the idea that RARα, RARβ, RARγ and RXRβ represent potential prognostic markers and therapeutic targets of gastric cancer.
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Affiliation(s)
| | - Debora Basile
- Department of Medical Oncology, San Giovanni di Dio Hospital, Crotone, Italy
| | - Valli' De Re
- Immunopathology and Cancer Biomarkers/Bio-Proteomics Facility, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy
| | - Giulia Brisotto
- Immunopathology and Cancer Biomarkers/Bio-Proteomics Facility, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy
| | - Gianmaria Miolo
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Vincenzo Canzonieri
- Pathology Unit, IRCCS CRO National Cancer Institute, Aviano, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Giuseppe Aprile
- Department of Oncology, University and General Hospital, Udine, Italy
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | - Carla Corvaja
- Division of Thoracic Oncology, European Institute of Oncology (IEO) IRCCS, Milano, Italy
| | - Silvia Buriolla
- Department of Oncology, ASUFC University Hospital, Udine, Italy
| | - Enrico Garattini
- Department of Biochemistry and Molecular Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy
| | - Fabio Puglisi
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
- Departiment of Medicine, University of Udine, Udine, Italy
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13
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Ooki A, Osumi H, Yoshino K, Yamaguchi K. Potent therapeutic strategy in gastric cancer with microsatellite instability-high and/or deficient mismatch repair. Gastric Cancer 2024; 27:907-931. [PMID: 38922524 PMCID: PMC11335850 DOI: 10.1007/s10120-024-01523-4] [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: 04/17/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024]
Abstract
Gastric cancer (GC) is a common malignancy that presents challenges in patient care worldwide. The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that protects genome integrity during replication. Deficient MMR (dMMR) results in an increased accumulation of genetic errors in microsatellite sequences, leading to the development of a microsatellite instability-high (MSI-H) phenotype. Most MSI-H/dMMR GCs arise sporadically, mainly due to MutL homolog 1 (MLH1) epigenetic silencing. Unlike microsatellite-stable (MSS)/proficient MMR (pMMR) GCs, MSI-H/dMMR GCs are relatively rare and represent a distinct subtype with genomic instability, a high somatic mutational burden, favorable immunogenicity, different responses to treatment, and prognosis. dMMR/MSI-H status is a robust predictive biomarker for treatment with immune checkpoint inhibitors (ICIs) due to high neoantigen load, prominent tumor-infiltrating lymphocytes, and programmed cell death ligand 1 (PD-L1) overexpression. However, a subset of MSI-H/dMMR GC patients does not benefit from immunotherapy, highlighting the need for further research into predictive biomarkers and resistance mechanisms. This review provides a comprehensive overview of the clinical, molecular, immunogenic, and therapeutic aspects of MSI-H/dMMR GC, with a focus on the impact of ICIs in immunotherapy and their potential as neoadjuvant therapies. Understanding the complexity and diversity of the molecular and immunological profiles of MSI-H/dMMR GC will drive the development of more effective therapeutic strategies and molecular targets for future precision medicine.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan.
| | - Hiroki Osumi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Koichiro Yoshino
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
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14
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Kono K, Nakajima S, Mimura K. Biomarker-oriented chemo-immunotherapy for advanced gastric cancer. Int J Clin Oncol 2024; 29:865-872. [PMID: 38647874 DOI: 10.1007/s10147-024-02525-z] [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: 03/18/2024] [Accepted: 04/01/2024] [Indexed: 04/25/2024]
Abstract
The biomarker-oriented chemo-immunotherapy is useful and promising in the development of new anticancer agents, since the responders can be enriched by selecting patients with biomarkers. Compared to colorectal and lung cancers, the development of biomarker-driven molecular-targeted therapeutics for gastric cancers has been straggled. However, several new biomarkers in gastric cancers have been discovered and clinical trials in enrichment design with certain biomarkers have been conducted. Therefore, there are currently several treatment options to treat gastric cancer patients based on individual biomarker-oriented strategies. In the present review, we describe the useful biomarkers in gastric cancer, with focusing on HER2, PD-L1, and Claudin18.2, in relation to their clinical significance and associated targeted agents.
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Affiliation(s)
- Koji Kono
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, 960-1295, Japan.
| | - Shotaro Nakajima
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, 960-1295, Japan
- Department of Multidisciplinary Treatment of Cancer and Regional Medical Support, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan
| | - Kosaku Mimura
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, 960-1295, Japan
- Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, 960-1295, Japan
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15
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Fick CN, Dunne EG, Sihag S, Molena D, Cytryn SL, Janjigian YY, Wu AJ, Worrell SG, Hofstetter WL, Jones DR, Gray KD. Immunotherapy for Resectable Locally Advanced Esophageal Carcinoma. Ann Thorac Surg 2024; 118:130-140. [PMID: 38408631 PMCID: PMC11194153 DOI: 10.1016/j.athoracsur.2024.02.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/16/2024] [Accepted: 02/05/2024] [Indexed: 02/28/2024]
Abstract
BACKGROUND The current standard of care for locally advanced esophageal and gastroesophageal junction (GEJ) cancers includes neoadjuvant chemoradiotherapy or perioperative chemotherapy with surgical resection; however, disease-free survival in these patients remains poor. Immune checkpoint inhibitors (ICIs) are approved for adjuvant treatment of locally advanced esophageal and GEJ cancers, but their benefit in the perioperative and neoadjuvant settings remains under investigation. METHODS We used the PubMed online database to conduct a literature search to identify studies that investigated immunotherapy for locally advanced esophageal and GEJ carcinoma. A review of ClinicalTrials.gov yielded a list of ongoing trials. RESULTS Adjuvant nivolumab for residual disease after neoadjuvant chemoradiotherapy and surgery is the only approved immunotherapy regimen for locally advanced esophageal cancer. Early-phase trials investigating the addition of neoadjuvant or perioperative ICIs to standard-of-care multimodality approaches have observed pathologic complete response rates as high as 60%. Response rates are highest for ICIs plus chemoradiotherapy for esophageal squamous cell carcinoma and dual checkpoint inhibition in mismatch repair-deficient adenocarcinomas. Safety profiles are acceptable, with a pooled adverse event rate of 27%. Surgical morbidity and mortality with immunotherapy are similar to historical controls with no immunotherapy, and R0 resection rates are high. When reported, disease-free survival among patients treated with perioperative immunotherapy is promising. CONCLUSIONS Outside of clinical trials, immunotherapy for resectable esophageal carcinoma is limited to the adjuvant setting. Phase III trials investigating neoadjuvant and perioperative immunotherapy are now underway and will provide much-needed data on survival that may ultimately lead to practice-changing recommendations.
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Affiliation(s)
- Cameron N Fick
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Elizabeth G Dunne
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Smita Sihag
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Daniela Molena
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Samuel L Cytryn
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yelena Y Janjigian
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Abraham J Wu
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Stephanie G Worrell
- Section of Thoracic Surgery, Department of Surgery, University of Arizona, Tucson, Arizona
| | - Wayne L Hofstetter
- Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David R Jones
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
| | - Katherine D Gray
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
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16
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Duan Y, Li J, Zhou S, Bi F. Effectiveness of PD-1 inhibitor-based first-line therapy in Chinese patients with metastatic gastric cancer: a retrospective real-world study. Front Immunol 2024; 15:1370860. [PMID: 38933261 PMCID: PMC11199409 DOI: 10.3389/fimmu.2024.1370860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 05/21/2024] [Indexed: 06/28/2024] Open
Abstract
Objective Programmed cell death protein-1 (PD-1) inhibitor-based therapy has demonstrated promising results in metastatic gastric cancer (MGC). However, the previous researches are mostly clinical trials and have reached various conclusions. Our objective is to investigate the efficacy of PD-1 inhibitor-based treatment as first-line therapy for MGC, utilizing real-world data from China, and further analyze predictive biomarkers for efficacy. Methods This retrospective study comprised 105 patients diagnosed with MGC who underwent various PD-1 inhibitor-based treatments as first-line therapy at West China Hospital of Sichuan University from January 2018 to December 2022. Patient characteristics, treatment regimens, and tumor responses were extracted. We also conducted univariate and multivariate analyses to assess the relationship between clinical features and treatment outcomes. Additionally, we evaluated the predictive efficacy of several commonly used biomarkers for PD-1 inhibitor treatments. Results Overall, after 28.0 months of follow-up among the 105 patients included in our study, the objective response rate (ORR) was 30.5%, and the disease control rate (DCR) was 89.5% post-treatment, with two individuals (1.9%) achieving complete response (CR). The median progression-free survival (mPFS) was 9.0 months, and the median overall survival (mOS) was 22.0 months. According to both univariate and multivariate analyses, favorable OS was associated with patients having Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. Additionally, normal baseline levels of carcinoembryonic antigen (CEA), as well as the combination of PD-1 inhibitors with chemotherapy and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive MGC, independently predicted longer PFS and OS. However, microsatellite instability/mismatch repair (MSI/MMR) status and Epstein-Barr virus (EBV) infection status were not significantly correlated with PFS or OS extension. Conclusion As the first-line treatment, PD-1 inhibitors, either as monotherapy or in combination therapy, are promising to prolong survival for patients with metastatic gastric cancer. Additionally, baseline level of CEA is a potential predictive biomarker for identifying patients mostly responsive to PD-1 inhibitors.
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Affiliation(s)
| | | | | | - Feng Bi
- Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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17
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Bos J, Groen-van Schooten TS, Brugman CP, Jamaludin FS, van Laarhoven HWM, Derks S. The tumor immune composition of mismatch repair deficient and Epstein-Barr virus-positive gastric cancer: A systematic review. Cancer Treat Rev 2024; 127:102737. [PMID: 38669788 DOI: 10.1016/j.ctrv.2024.102737] [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: 02/13/2024] [Revised: 04/16/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024]
Abstract
BACKGROUND Gastric cancer (GC), known for its unfavorable prognosis, has been classified in four distinct molecular subtypes. These subtypes not only exhibit differences in their genome and transcriptome but also in the composition of their tumor immune microenvironment. The microsatellite instable (MSI) and Epstein-Barr virus (EBV) positive GC subtypes show clear clinical benefits from immune checkpoint blockade, likely due to a neoantigen-driven and virus-driven antitumor immune response and high expression of immune checkpoint molecule PD-L1. However, even within these subtypes response to checkpoint inhibition is variable, which is potentially related to heterogeneity in the tumor immune microenvironment (TIME) and expression of co-inhibitory molecules. We conducted a systematic review to outline the current knowledge about the immunological features on the TIME of MSI and EBV + GCs. METHODS A systematic search was performed in PubMed, EMBASE and Cochrane Library. All articles from the year 1990 and onwards addressing immune features of gastric adenocarcinoma were reviewed and included based on predefined in- and exclusion criteria. RESULTS In total 5962 records were screened, of which 139 were included that reported immunological data on molecular GC subtypes. MSI and EBV + GCs were reported to have a more inflamed TIME compared to non-MSI and EBV- GC subtypes. Compared to microsatellite stable (MSS) tumors, MSI tumors were characterized by higher numbers of CD8 + and FoxP3 + T cells, and tumor infiltrating pro- and anti-inflammatory macrophages. HLA-deficiency was most common in MSI tumors compared to other molecular GC subtypes and associated with lower T and B cell infiltrates compared to HLA-proficient tumors. EBV + was associated with a high number of CD8 + T cells, Tregs, NK cells and macrophages. Expression of PD-L1, CTLA-4, Granzyme A and B, Perforin and interferon-gamma was enriched in EBV + tumors. Overall, MSI tumors harbored a more heterogeneous TIME in terms of immune cell composition and immune checkpoints compared to the EBV + tumors. DISCUSSION AND CONCLUSION MSI and EBV + GCs are highly Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration.; 2019pro-inflammatory immune cell populations. Although studies on the direct comparison of EBV + and MSI tumors are limited, EBV + tumors show less intra-subgroup heterogeneity compared to MSI tumors. More studies are needed to identify how Intra-subgroup heterogeneity impacts response to immunotherapy efficacy.
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Affiliation(s)
- J Bos
- Amsterdam UMC Location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - T S Groen-van Schooten
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands
| | - C P Brugman
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands
| | - F S Jamaludin
- Amsterdam UMC Location University of Amsterdam, Medical Library AMC, Meibergdreef 9, Amsterdam, the Netherlands
| | - H W M van Laarhoven
- Amsterdam UMC Location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands
| | - S Derks
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands.
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18
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Abolhasani M, Mohseni AO, Shakeri R, Khavanin A, Khajehei M, Omidi A, Geramizadeh B, Shafigh E, Naghshvar F, Fathizadeh P, Taghizadehgan L, Gharib A, Gulley ML, Dawsey SM, Malekzadeh R, Rabkin CS, Vasei M. EBV-Associated Gastric Cancer; An In Situ Hybridization Assay on Tissue Microarray: A Multi-Region Study from Four Major Provinces of Iran. ARCHIVES OF IRANIAN MEDICINE 2024; 27:191-199. [PMID: 38685845 PMCID: PMC11097306 DOI: 10.34172/aim.2024.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 02/19/2024] [Indexed: 05/02/2024]
Abstract
BACKGROUND Gastric cancer is the fourth leading cause of cancer-related deaths in the world. The identification of gastric cancer subtypes related to recognizable microbial agents may play a pivotal role in the targeted prevention and treatment of this cancer. The current study is conducted to define the frequency of Epstein-Barr virus (EBV) infection in gastric cancers of four major provinces, with different incidence rates of gastric cancers, in Iran. METHODS Paraffin blocks of 682 cases of various types of gastric cancer from Tehran, South and North areas of Iran were collected. Twelve tissue microarray (TMA) blocks were constructed from these blocks. Localization of EBV in tumors was assessed by in situ hybridization (ISH) for EBV-encoded RNA (EBER). Chi-squared test was used to evaluate the statistical significance between EBV-associated gastric cancer (EBVaGC) and clinicopathologic tumor characteristics. RESULTS Fourteen out of 682 cases (2.1%) of gastric adenocarcinoma were EBER-positive. EBER was positive in 8 out of 22 (36.4%) of medullary carcinomas and 6 out of 660 (0.9%) of non-medullary type, which was a statistically significant difference (P<0.001). The EBVaGCs were more frequent in younger age (P=0.009) and also showed a trend toward the lower stage of the tumor (P=0.075). CONCLUSION EBV-associated gastric adenocarcinoma has a low prevalence in Iran. This finding can be due to epidemiologic differences in risk factors and exposures, and the low number of gastric medullary carcinomas in the population. It may also be related to gastric tumor heterogeneity not detected with the TMA technique.
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Affiliation(s)
- Maryam Abolhasani
- Oncopathology Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Ramin Shakeri
- Digestive Oncology Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Khavanin
- Emergency Medicine Department, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mehrdad Khajehei
- Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abbasali Omidi
- Department of Pathology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bita Geramizadeh
- Department of Pathology, Transplantation Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ensieh Shafigh
- Department of Pathology, Babol University of Medical Sciences, Babol, Iran
| | - Farshad Naghshvar
- Department of Pathology, Mazandaran University of Medical Sciences, Sari, Iran
| | - Payam Fathizadeh
- Department of Pathology and Laboratory Medicine, Apadana Hospital, Ahvaz, Iran
| | | | - Atoosa Gharib
- Department of Pathology, Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Margaret L. Gulley
- Department of Pathology, University of North Carolina, Chapel Hill, NC, USA
| | - Sanford M. Dawsey
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Reza Malekzadeh
- Digestive Oncology Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Charles S. Rabkin
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Mohammad Vasei
- Gene Therapy Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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19
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Colarusso G, Mechahougui H, Koessler T, Friedlaender A. Metastatic gastric cancer: synergizing and sequencing targeted therapy with first-line immunotherapy. Immunotherapy 2024; 16:427-430. [PMID: 38469713 DOI: 10.2217/imt-2024-0040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 02/26/2024] [Indexed: 03/13/2024] Open
Affiliation(s)
- Gina Colarusso
- Oncology Department, Geneva University Hospital, 1205 Geneva, Switzerland
| | - Hiba Mechahougui
- Oncology Department, Geneva University Hospital, 1205 Geneva, Switzerland
| | - Thibaud Koessler
- Oncology Department, Geneva University Hospital, 1205 Geneva, Switzerland
| | - Alex Friedlaender
- Oncology Department, Geneva University Hospital, 1205 Geneva, Switzerland
- Clinique Générale Beaulieu, 1206 Geneva, Switzerland
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20
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Yee EJ, Gilbert D, Kaplan J, van Dyk L, Kim SS, Berg L, Clambey E, Wani S, McCarter MD, Stewart CL. Immune Landscape of Epstein-Barr Virus-Associated Gastric Cancer: Analysis From a Western Academic Institution. J Surg Res 2024; 296:742-750. [PMID: 38368775 PMCID: PMC10947842 DOI: 10.1016/j.jss.2024.01.043] [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: 10/17/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 02/20/2024]
Abstract
INTRODUCTION Epstein-Barr virus-associated gastric cancer (EBVaGC) may be a meaningful biomarker for potential benefit from immunotherapy. Further investigation is needed to characterize the immune landscape of EBVaGC. We assessed our institutional frequency of surgically treated EBVaGC and analyzed the immunologic biomarker profile and tumor-infiltrating lymphocyte (TIL) phenotypes of a series of EBVaGC compared to non-EBVaGC cases. METHODS Available tissue samples from all patients with biopsy-confirmed gastric adenocarcinoma who underwent resection with curative intent from 2012 to 2020 at our institution were collected. In situ hybridization was used to assess EBV status; multiplex immunohistochemistry was performed to assess mismatch repair status, Programmed Death-Ligand 1 (PD-L1) expression, and phenotypic characterization of TILs. RESULTS Sixty-eight samples were included in this study. EBVaGC was present in 3/68 (4%) patients. Among all patients, 27/68 (40%) had positive PD-L1 expression; two of three (67%) EBVaGC patients exhibited positive PD-L1 expression. Compared to non-EBVaGC, EBV-positive tumors showed 5-fold to 10-fold higher density of TILs in both tumor and stroma and substantially elevated CD8+ T cell to Tregulatory cell ratio. The memory subtypes of CD8+ and CD4+ T cells were upregulated in EBVaGC tumors and stromal tissue compared to non-EBVaGC. CONCLUSIONS The incidence of surgically resected EBVaGC at our center was 4%. EBVaGC tumors harbor elevated levels of TILs, including memory subtypes, within both tumor and tumor-related stroma. Robust TIL presence and upregulated PD-L1 positivity in EBVaGC may portend promising responses to immunotherapy agents. Further investigation into routine EBV testing and TIL phenotype of patients with gastric cancer to predict response to immunotherapy may be warranted.
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Affiliation(s)
- Elliott J Yee
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Aurora, Colorado.
| | | | - Jeffrey Kaplan
- Department of Pathology, University of Colorado, Aurora, Colorado
| | - Linda van Dyk
- Department of Immunology & Microbiology, University of Colorado, Aurora, Colorado
| | - Sunnie S Kim
- Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO
| | - Leslie Berg
- Department of Immunology & Microbiology, University of Colorado, Aurora, Colorado
| | - Eric Clambey
- Department of Anesthesiology, University of Colorado, Aurora, Colorado
| | - Sachin Wani
- Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO
| | - Martin D McCarter
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Aurora, Colorado
| | - Camille L Stewart
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Aurora, Colorado
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21
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Zhao P, Jin R, Zhao B, Han L, Chen W, Hao N, Cui Y, Madan A, Awosika J, Lloyd S, Zhang Y. The efficacy-associated biomarkers for immune checkpoint inhibitors in gastrointestinal cancer: a literature review. J Gastrointest Oncol 2024; 15:514-528. [PMID: 38482240 PMCID: PMC10932650 DOI: 10.21037/jgo-23-843] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/01/2024] [Indexed: 01/03/2025] Open
Abstract
BACKGROUND AND OBJECTIVE Immune checkpoint inhibitors (ICIs) have been widely applied and studied in the treatment of gastrointestinal (GI) cancers, and have achieved good results. However, in clinical practice, it has been observed that only some patients respond well to ICIs, and some patients may experience various degrees of adverse reactions during the treatment. Timely evaluation of the potential therapeutic effects and adverse reactions of ICIs for patients has important clinical significance. This review aimed to summarize recent progress regarding efficacy-associated biomarkers for ICIs in GI cancer. METHODS The literature on ICI treatment in GI cancers was searched in the PubMed, Embase, and Cochrane Library databases for publications up to April 2023. KEY CONTENT AND FINDINGS Clinical practice and research has gradually revealed some biomarkers related to the treatment of GI cancers with ICIs, which can be roughly divided into three types: biomarkers that predict the effectiveness of ICIs treatment, biomarkers associated with resistance to ICIs, and biomarkers associated with immune related adverse events (irAEs). This review article provides a literature review on biomarkers related to the efficacy of ICIs in the treatment of GI cancers. CONCLUSIONS According to existing clinical research results, there are multiple biomarkers that can be used for predicting and monitoring the efficacy and risk of adverse events of ICIs in the treatment of digestive system malignant tumors.
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Affiliation(s)
- Peixi Zhao
- Department of Pharmacy, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Rui Jin
- Department of Clinical Pharmacy, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Bin Zhao
- Department of Research and Teaching, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Le Han
- Department of Chest Surgery, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Wenjuan Chen
- Department of Oncology, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Nina Hao
- Department of Research and Teaching, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yi Cui
- Department of Pharmacy, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Ankit Madan
- Medstar Southern Maryland Hospital Center, Clinton, MD, USA
| | - Joy Awosika
- National Institutes of Health, National Cancer Institute, Bethesda, MD, USA
| | - Shane Lloyd
- Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, Salt Lake City, UT, USA
| | - Yili Zhang
- Department of Oncology, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
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22
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Shin J, Park YS. Unusual or Uncommon Histology of Gastric Cancer. J Gastric Cancer 2024; 24:69-88. [PMID: 38225767 PMCID: PMC10774758 DOI: 10.5230/jgc.2024.24.e7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 01/17/2024] Open
Abstract
This review comprehensively examines the diverse spectrum of gastric cancers, focusing on unusual or uncommon histology that presents significant diagnostic and therapeutic challenges. While the predominant form, tubular adenocarcinoma, is well-characterized, this review focuses on lesser-known variants, including papillary adenocarcinoma, micropapillary carcinoma, adenosquamous carcinoma, squamous cell carcinoma (SCC), hepatoid adenocarcinoma, gastric choriocarcinoma, gastric carcinoma with lymphoid stroma, carcinosarcoma, gastroblastoma, parietal cell carcinoma, oncocytic adenocarcinoma, Paneth cell carcinoma, gastric adenocarcinoma of the fundic gland type, undifferentiated carcinoma, and extremely well-differentiated adenocarcinoma. Although these diseases have different nomenclatures characterized by distinct histopathological features, these phenotypes often overlap, making it difficult to draw clear boundaries. Furthermore, the number of cases was limited, and the unique histopathological nature and potential pathogenic mechanisms were not well defined. This review highlights the importance of understanding these rare variants for accurate diagnosis, effective treatment planning, and improving patient outcomes. This review emphasizes the need for ongoing research and case studies to enhance our knowledge of these uncommon forms of gastric cancer, which will ultimately contribute to more effective treatments and better prognostic assessments. This review aimed to broaden the pathological narrative by acknowledging and addressing the intricacies of all cancer types, regardless of their rarity, to advance patient care and improve prognosis.
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Affiliation(s)
- Jinho Shin
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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23
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Kim IH. Emerging Targets for Systemic Treatment of Gastric Cancer: HER2 and Beyond. J Gastric Cancer 2024; 24:29-56. [PMID: 38225765 PMCID: PMC10774754 DOI: 10.5230/jgc.2024.24.e6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/11/2023] [Accepted: 12/11/2023] [Indexed: 01/17/2024] Open
Abstract
In recent years, remarkable progress has been made in the molecular profiling of gastric cancer. This progress has led to the development of various molecular classifications to uncover subtype-specific dependencies that can be targeted for therapeutic interventions. Human epidermal growth factor receptor 2 (HER2) is a crucial biomarker for advanced gastric cancer. The recent promising results of novel approaches, including combination therapies or newer potent agents such as antibody-drug conjugates, have once again brought attention to anti-HER2 targeted treatments. In HER2-negative diseases, the combination of cytotoxic chemotherapy and programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors has become the established standard of care in first-line settings. In the context of gastric cancer, potential biomarkers such as PD-L1 expression, Epstein-Barr virus, microsatellite instability, and tumor mutational burden are being considered for immunotherapy. Recently, promising results have been reported in studies on anti-Claudin18.2 and fibroblast growth factor receptor 2 treatments. Currently, many ongoing trials are aimed at identifying potential targets using novel approaches. Further investigations will be conducted to enhance the progress of these therapies, addressing challenges such as primary and acquired resistance, tumor heterogeneity, and clonal evolution. We believe that these efforts will improve patient prognoses. Herein, we discuss the current evidence of potential targets for systemic treatment, clinical considerations, and future perspectives.
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Affiliation(s)
- In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Gastric Cancer Centre, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea,.
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24
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Taieb J, Bennouna J, Penault-Llorca F, Basile D, Samalin E, Zaanan A. Treatment of gastric adenocarcinoma: A rapidly evolving landscape. Eur J Cancer 2023; 195:113370. [PMID: 37948843 DOI: 10.1016/j.ejca.2023.113370] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/11/2023] [Accepted: 09/26/2023] [Indexed: 11/12/2023]
Abstract
Gastric adenocarcinoma (GC) and gastroesophageal junction adenocarcinoma represent frequent and severe diseases whose management has radically changed over the last 10 years. With the advent of second- and third-line standard therapies for metastatic GC patients in the 2010s, the molecular dismemberment of the disease and positive trials with immunotherapy and targeted agents will mark the 2020s. New treatment options have emerged in the neoadjuvant, adjuvant, and metastatic setting. In addition to improved multimodal treatment in operable patients, new subgroups have emerged depending on molecular alterations (HER2, Microsatellite instability) or expression of specific proteins in the tumour (PDL1, Claudin 18.2) making immunohistochemistry central in profiling the tumour for an optimal individualised management. The aim of this review is to describe the current standards of management of early and late stage GC and the molecular markers needed today to optimally manage our patients together with future perspectives on this disease.
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Affiliation(s)
- Julien Taieb
- Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Institut du Cancer Paris CARPEM, Université Paris Cité, Paris, Hôpital Européen Georges Pompidou, Department of Tumor and Cancer Genomic Medicine, Paris, France.
| | - Jaafar Bennouna
- Department of Medical Oncology, Hopital Foch, Suresnes, France
| | | | - Debora Basile
- Department of Medical Oncology, San Giovanni di Dio Hospital, Crotone, Italy
| | - Emmanuelle Samalin
- Department of Medical Oncology, Institut du Cancer de Montpellier, Univ. Montpellier (ICM), Montpellier, France
| | - Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Institut du Cancer Paris CARPEM, Université Paris Cité, Paris, Hôpital Européen Georges Pompidou, Department of Tumor and Cancer Genomic Medicine, Paris, France
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25
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Hou W, Zhao Y, Zhu H. Predictive Biomarkers for Immunotherapy in Gastric Cancer: Current Status and Emerging Prospects. Int J Mol Sci 2023; 24:15321. [PMID: 37895000 PMCID: PMC10607383 DOI: 10.3390/ijms242015321] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/12/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
Gastric cancer presents substantial management challenges, and the advent of immunotherapy has ignited renewed hope among patients. Nevertheless, a significant proportion of patients do not respond to immunotherapy, and adverse events associated with immunotherapy also occur on occasion, underscoring the imperative to identify suitable candidates for treatment. Several biomarkers, including programmed death ligand-1 expression, tumor mutation burden, mismatch repair status, Epstein-Barr Virus infection, circulating tumor DNA, and tumor-infiltrating lymphocytes, have demonstrated potential in predicting the effectiveness of immunotherapy in gastric cancer. However, the quest for the optimal predictive biomarker for gastric cancer immunotherapy remains challenging, as each biomarker carries its own limitations. Recently, multi-omics technologies have emerged as promising platforms for discovering novel biomarkers that may help in selecting gastric cancer patients likely to respond to immunotherapy. The identification of reliable predictive biomarkers for immunotherapy in gastric cancer holds the promise of enhancing patient selection and improving treatment outcomes. In this review, we aim to provide an overview of clinically established biomarkers of immunotherapy in gastric cancer. Additionally, we introduce newly reported biomarkers based on multi-omics studies in the context of gastric cancer immunotherapy, thereby contributing to the ongoing efforts to refine patient stratification and treatment strategies.
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Affiliation(s)
- Wanting Hou
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu 610065, China; (W.H.); (Y.Z.)
- Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610065, China
| | - Yaqin Zhao
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu 610065, China; (W.H.); (Y.Z.)
- Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610065, China
| | - Hong Zhu
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu 610065, China; (W.H.); (Y.Z.)
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26
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Low YH, Loh CJL, Peh DYY, Chu AJM, Han S, Toh HC. Pathogenesis and therapeutic implications of EBV-associated epithelial cancers. Front Oncol 2023; 13:1202117. [PMID: 37901329 PMCID: PMC10600384 DOI: 10.3389/fonc.2023.1202117] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 09/07/2023] [Indexed: 10/31/2023] Open
Abstract
Epstein-Barr virus (EBV), one of the most common human viruses, has been associated with both lymphoid and epithelial cancers. Undifferentiated nasopharyngeal carcinoma (NPC), EBV associated gastric cancer (EBVaGC) and lymphoepithelioma-like carcinoma (LELC) are amongst the few common epithelial cancers that EBV has been associated with. The pathogenesis of EBV-associated NPC has been well described, however, the same cannot be said for primary pulmonary LELC (PPLELC) owing to the rarity of the cancer. In this review, we outline the pathogenesis of EBV-associated NPC and EBVaGCs and their recent advances. By drawing on similarities between NPC and PPLELC, we then also postulated the pathogenesis of PPLELC. A deeper understanding about the pathogenesis of EBV enables us to postulate the pathogenesis of other EBV associated cancers such as PPLELC.
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Affiliation(s)
- Yi Hua Low
- Duke-NUS Medical School, Singapore, Singapore
| | | | - Daniel Yang Yao Peh
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Axel Jun Ming Chu
- Singapore Health Services Internal Medicine Residency Programme, Singapore, Singapore
| | - Shuting Han
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
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27
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Nevo Y, Ferri L. Current management of gastric adenocarcinoma: a narrative review. J Gastrointest Oncol 2023; 14:1933-1948. [PMID: 37720442 PMCID: PMC10502549 DOI: 10.21037/jgo-22-818] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 05/20/2023] [Indexed: 09/19/2023] Open
Abstract
Gastric adenocarcinoma is a leading cause of cancer death worldwide. The management of this aggressive malignancy largely depends on tumor characteristics especially stage. Superficial early-stage gastric cancer can be safely managed by endoscopic resection, though clear negative deep and lateral margins must be obtained. Optimal surgical resection is an essential part of the treatment for locally advanced gastric adenocarcinoma, with perioperative and adjuvant therapies having significant impact on long-term outcomes. Chemoradiation is reserved for patients with suboptimal surgical resection. Recent therapeutic advances have prolonged survival in patients with metastatic gastric adenocarcinoma, include checkpoint inhibitors and biomarker-directed therapy. Targeted therapies in gastric adenocarcinoma include monoclonal antibodies directed against vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), and human epidermal growth factor receptor 2 (HER2). While anti-VEGF therapies were not found beneficial in the perioperative setting, the effectiveness of HER2 targeted agents in resectable HER2-positive gastric adenocarcinoma is being studied. Microsatellite instability (MSI) varies greatly in patients with gastric adenocarcinoma between 5-20% based on ethnic origin, tumour heterogeneity and staging. The role chemotherapy in the perioperative setting for patients with MSI-high tumors remains controversial while immunotherapy demonstrates promising results in preliminary studies. Immune checkpoint inhibitors in combination with chemotherapy has been shown to improve outcomes in patients with metastatic gastric adenocarcinoma who express programmed cell death 1 ligand 1 (PD-L1) and is now being investigated in the perioperative setting.
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Affiliation(s)
- Yehonatan Nevo
- Division of Thoracic and Upper Gastrointestinal Surgery, Montreal General Hospital, McGill University, Montreal, Quebec, Canada
| | - Lorenzo Ferri
- Division of Thoracic and Upper Gastrointestinal Surgery, Montreal General Hospital, McGill University, Montreal, Quebec, Canada
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28
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Guan WL, He Y, Xu RH. Gastric cancer treatment: recent progress and future perspectives. J Hematol Oncol 2023; 16:57. [PMID: 37245017 DOI: 10.1186/s13045-023-01451-3] [Citation(s) in RCA: 349] [Impact Index Per Article: 174.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 05/10/2023] [Indexed: 05/29/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies worldwide. Most patients are diagnosed at advanced stages due to the subtle symptoms of earlier disease and the low rate of regular screening. Systemic therapies for GC, including chemotherapy, targeted therapy and immunotherapy, have evolved significantly in the past few years. For resectable GC, perioperative chemotherapy has become the standard treatment. Ongoing investigations are exploring the potential benefits of targeted therapy or immunotherapy in the perioperative or adjuvant setting. For metastatic disease, there have been notable advancements in immunotherapy and biomarker-directed therapies recently. Classification based on molecular biomarkers, such as programmed cell death ligand 1 (PD-L1), microsatellite instability (MSI), and human epidermal growth factor receptor 2 (HER2), provides an opportunity to differentiate patients who may benefit from immunotherapy or targeted therapy. Molecular diagnostic techniques have facilitated the characterization of GC genetic profiles and the identification of new potential molecular targets. This review systematically summarizes the main research progress in systemic treatment for GC, discusses current individualized strategies and presents future perspectives.
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Affiliation(s)
- Wen-Long Guan
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People's Republic of China
| | - Ye He
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People's Republic of China
| | - Rui-Hua Xu
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People's Republic of China.
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29
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Liu W, Huo G, Chen P. Efficacy of PD-1/PD-L1 inhibitors in advanced gastroesophageal cancer based on characteristics: a meta-analysis. Immunotherapy 2023. [PMID: 37190983 DOI: 10.2217/imt-2022-0305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/17/2023] Open
Abstract
Objective: Evaluate the potency of anti-PD-1/PD-L1 antibodies in advanced gastroesophageal cancer patients with different clinical features. Methods: Randomized, controlled trials comparing anti-PD-1/PD-L1 antibodies with chemotherapy in individuals with gastroesophageal cancer were retrieved. Results: 15 trials involving 9194 individuals were included. PD-1/PD-L1 inhibitors significantly improved overall survival (OS) but not progression-free survival. Significantly improved OS was observed in PD-L1 combined positive score ≥1, primary esophageal cancer, primary gastric cancer and Asian patients. Subgroup analysis revealed significant OS benefit achieved for esophageal squamous cell carcinoma, but not for esophageal adenocarcinoma. Conclusion: PD-1/PD-L1 inhibitors improved OS in advanced gastroesophageal carcinoma, especially in patients with esophageal cancer. Race, primary tumor sites and PD-L1 combined positive score can be used to predict the potency of immune checkpoint inhibitors.
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Affiliation(s)
- Wenjie Liu
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute & Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention & Therapy of Tianjin; Tianjin's Clinical Research Center for Cancer; Tianjin, 300060, China
| | - Gengwei Huo
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute & Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention & Therapy of Tianjin; Tianjin's Clinical Research Center for Cancer; Tianjin, 300060, China
| | - Peng Chen
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute & Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention & Therapy of Tianjin; Tianjin's Clinical Research Center for Cancer; Tianjin, 300060, China
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30
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Chitapanarux T, Gumrai P, Kongkarnka S, Wannasai K, Lertprasertsuke N. Programmed death-ligand 1 expression and overall survival in Thai patients with gastric cancer. Sci Rep 2023; 13:7241. [PMID: 37142693 PMCID: PMC10160126 DOI: 10.1038/s41598-023-34434-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 04/29/2023] [Indexed: 05/06/2023] Open
Abstract
Programmed death-ligand 1 (PD-L1) expression has now been implicated in gastric cancer (GC). This study was conducted to determine the impact of clinicopathological characteristics on PD-L1 expression and its association with survival in GC patients receiving standard-of-care. In total, 268 GC patients receiving upfront surgery were enrolled at Chiang Mai University Hospital. PD-L1 expression was assayed by immunohistochemistry staining using the Dako 22C3 pharmDx. The rates of PD-L1 positivity by combined positive score (CPS) at a cutoff value of 1 and 5 were 22% and 7%. PD-L1 positivity was significantly higher in patients younger than 55 than those older than 55 (32.6% vs. 16.5%, p = 0.003; 11.6% vs. 4.4%, p = 0.027). PD-L1 positivity was observed more frequently in GC with metastases than without (25.2% vs. 17.1%, p = 0.112; 7.2% vs. 6.7%, p = 0.673). Patients with PD-L1 positive had a significantly shorter median overall survival than those with PD-L1 negative (32.7 vs. 41.6 months, p = 0.042, 27.6 vs. 40.8 months, p = 0.038). In conclusion, PD-L1 expression has been associated with young age, short survival, and metastases, although unrelated to the tumor stage. For GC patients, PD-L1 testing is recommended, especially among young patients with metastases.
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Affiliation(s)
- Taned Chitapanarux
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Northern Thai Research Group of Radiation Oncology (NTRG-RO), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
| | - Pawut Gumrai
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Sarawut Kongkarnka
- Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Komson Wannasai
- Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nirush Lertprasertsuke
- Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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31
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An G, He XC, Bai J, Wang J. Immune checkpoint inhibitors are effective in the treatment of Epstein-Barr virus-associated gastric cancer: A case report. Medicine (Baltimore) 2023; 102:e33377. [PMID: 37000076 PMCID: PMC10063274 DOI: 10.1097/md.0000000000033377] [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: 02/04/2023] [Accepted: 03/08/2023] [Indexed: 04/01/2023] Open
Abstract
RATIONALE Gastric cancer (GC) is one of the most common malignancies globally, and its occurrence and development are associated with genetic, dietary, biological, and immune factors. Epstein-Barr virus-associated gastric cancer (EBVaGC), as a special subtype of GC, has become a research hotspot in recent years. In patients with advanced GC, Epstein-Barr virus infection is closely related to lymph node metastasis, depth of tumor invasion, and poor prognosis. There is great clinical need for a new treatment modality for EBVaGC. Advances in molecular biology and cancer genetics have led to the development of immune checkpoint inhibitors (ICIs); patients treated with ICIs experience clinical benefit and few adverse effects. PATIENT CONCERNS AND DIAGNOSES We report a 31-year-old male with advanced EBVaGC and multiple sites of lymph node metastasis who was intolerant to multiple lines of chemotherapy. INTERVENTIONS AND OUTCOME After immune checkpoint inhibitor treatment, both primary and metastatic tumors shrank significantly without noticeable adverse reactions. After 21 months of progression-free status, the patient underwent R0 resection. LESSONS This case report provides evidence for the use of ICIs in treating EBVaGC. It also shows that detection of Epstein-Barr virus-encoded small nuclear RNA may be a prognostic factor in gastric cancer.
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Affiliation(s)
- Gaili An
- Department of Internal Medicine Oncology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
| | - Xin Cheng He
- Department of Internal Medicine Oncology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
| | - Jun Bai
- Department of Internal Medicine Oncology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
| | - Jianhua Wang
- Department of General Surgery, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
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Epistola R, Sperandio R, Wainberg Z, Iqbal S, Chao J. Role of PD-1 Inhibitors in the Treatment of Esophagogastric Adenocarcinoma: Patient Selection and Reported Outcomes. Cancer Manag Res 2023; 15:265-275. [PMID: 36969544 PMCID: PMC10032141 DOI: 10.2147/cmar.s341468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 02/09/2023] [Indexed: 03/19/2023] Open
Abstract
Esophagogastric cancers are aggressive malignancies, with poor prognosis despite current standard-of-care therapies. PD-1 inhibitors are a newer class of antitumor agents with the potential to improve outcomes among appropriately selected patients. This review provides an overview of the key trials that have guided the use of PD-1 and PD-L1 inhibitors in the refractory and first-line settings. We highlight recent studies investigating the role of genomic classification in predicting therapeutic activity of PD-1 inhibitors. In addition, there is a discussion of the use of different scoring systems and criteria to determine PD-L1 positivity, the impact on the therapeutic use of immune checkpoint inhibition with anti-PD-1 agents, and the controversies in current methods of PD-L1 testing and their implications in patient selection for anti-PD-1 therapy.
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Affiliation(s)
- Raisa Epistola
- Department of Internal Medicine, Division of Hematology and Medical Oncology, Harbor UCLA Medical Center, Torrance, CA, USA
- Correspondence: Raisa Epistola; Joseph Chao, Tel +1-310-501-9393; +1-626-218-2123, Fax +1 424-306-6646; +1 626-301-8233, Email ;
| | - Rubens Sperandio
- Centro de Oncologia e Hematologia Einstein Família Dayan-Daycoval, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Zev Wainberg
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
| | - Syma Iqbal
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Joseph Chao
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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Li G, Zhou Z, Wang Z, Wang Z. Assessing Epstein-Barr virus in gastric cancer: clinicopathological features and prognostic implications. Infect Agent Cancer 2023; 18:11. [PMID: 36803802 PMCID: PMC9938970 DOI: 10.1186/s13027-023-00489-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 02/14/2023] [Indexed: 02/21/2023] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) was a unique molecular subtype of gastric cancer (GC). However, the clinicopathological characteristics and prognostic role of EBV infection remains unclear. We aimed to evaluate the clinicopathological features of EBVaGC and its role on prognosis. METHODS EBV-encoded RNA (EBER) in situ hybridization method was used to evaluate the EBV status in GC. The serum tumor markers AFP, CEA, CA19-9 and CA125 of patients were detected before treatment. HER2 expression and microsatellite instability (MSI) status was evaluated according to established criteria. The relationship between EBV infection and clinicopathological factors as well as its role on prognosis were investigated. RESULTS 420 patients were enrolled in the study and of 53 patients (12.62%) were identified as EBVaGC. EBVaGC was more common in males (p = 0.001) and related to early T stage (p = 0.045), early TNM stage (p = 0.001) and lower level of serum CEA (p = 0.039). No association could be found between EBV infection and HER2 expression, MSI status and other factors (p all > 0.05). Kaplan-Meier analysis revealed that both the overall survival and disease-free survival of EBVaGC patients were similar to that of EBV-negative GC (EBVnGC) patients (p = 0.309 and p = 0.264, respectively). CONCLUSION EBVaGC was more common in males and in patients with the early T stage and TNM stage as well as patients with lower serum CEA level. Difference in overall survival and disease-free survival between EBVaGC and EBVnGC patients cannot be detected.
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Affiliation(s)
- Guanghua Li
- grid.412615.50000 0004 1803 6239Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan 2nd Street, No. 58, Guangzhou, 510080 Guangdong China
| | - Zhihao Zhou
- grid.412615.50000 0004 1803 6239Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan 2nd Street, No. 58, Guangzhou, 510080 Guangdong China
| | - Zhixiong Wang
- grid.412615.50000 0004 1803 6239Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan 2nd Street, No. 58, Guangzhou, 510080 Guangdong China
| | - Zhao Wang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan 2nd Street, No. 58, Guangzhou, 510080, Guangdong, China.
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Gomez K, Schiavoni G, Nam Y, Reynier JB, Khamnei C, Aitken M, Palmieri G, Cossu A, Levine A, van Noesel C, Falini B, Pasqualucci L, Tiacci E, Rabadan R. Genomic landscape of virus-associated cancers. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.02.14.23285775. [PMID: 36824731 PMCID: PMC9949223 DOI: 10.1101/2023.02.14.23285775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
It has been estimated that 15%-20% of human cancers are attributable to infections, mostly by carcinogenic viruses. The incidence varies worldwide, with a majority affecting developing countries. Here, we present a comparative analysis of virus-positive and virus-negative tumors in nine cancers linked to five viruses. We find that virus-positive tumors occur more frequently in males and show geographical disparities in incidence. Genomic analysis of 1,658 tumors reveals virus-positive tumors exhibit distinct mutation signatures and driver gene mutations and possess a lower somatic mutation burden compared to virus-negative tumors of the same cancer type. For example, compared to the respective virus-negative counterparts, virus-positive cases across different cancer histologies had less often mutations of TP53 and deletions of 9p21.3/ CDKN2 A- CDKN1A ; Epstein-Barr virus-positive (EBV+) gastric cancer had more frequent mutations of EIF4A1 and ARID1A and less marked mismatch repair deficiency signatures; and EBV-positive cHL had fewer somatic genetic lesions of JAK-STAT, NF-κB, PI3K-AKT and HLA-I genes and a less pronounced activity of the aberrant somatic hypermutation signature. In cHL, we also identify germline homozygosity in HLA class I as a potential risk factor for the development of EBV-positive Hodgkin lymphoma. Finally, an analysis of clinical trials of PD-(L)1 inhibitors in four virus-associated cancers suggested an association of viral infection with higher response rate in patients receiving such treatments, which was particularly evident in gastric cancer and head and neck squamous cell carcinoma. These results illustrate the epidemiological, genetic, prognostic, and therapeutic trends across virus-associated malignancies.
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Huo G, Liu W, Chen P. Efficacy of PD-1/PD-L1 inhibitors in gastric or gastro-oesophageal junction cancer based on clinical characteristics: a meta-analysis. BMC Cancer 2023; 23:143. [PMID: 36765356 PMCID: PMC9921519 DOI: 10.1186/s12885-023-10605-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 02/03/2023] [Indexed: 02/12/2023] Open
Abstract
PURPOSE Programmed death-1 (PD-1) and its ligand (PD-L1) inhibitors have been reported in several clinical trials for gastric cancer and gastroesophageal junction cancer (GC/GEJC). We presently carried out a meta analysis to evaluate the potency of PD-1/PD-L1 inhibitors in advanced GC/GEJC individuals with different clinical features and to determine patients more probably benefiting from the treatment. METHODS Randomized clinical trials (RCTs) in databases that compared PD-1/PD-L1 inhibitors to chemotherapy in patients with GC/GEJC published before May 2022 were retrieved. Basic characteristics were extracted from the included studies as well as hazard ratios (HR) and 95 percent confidence intervals (CI) for all individuals and subgroups. The inverse variance weighting method was used to evaluate pooled treatment data. FINDINGS Four RCTs involving 2,253 individuals were included. The results suggested that PD-1/PD-L1 inhibitors substantially enhanced overall survival (OS) (HR, 0.91; CI 95%, 0.83-1.00; p = 0.04) but not progression free survival (PFS) (HR, 1.17; CI 95%, 0.83-1.64; p = 0.38) in GC/GEJC individuals compared with chemotherapy. Significantly improved OS was observed in individuals aged < 65 years (HR, 0.84; p = 0.003), and men (HR, 0.88; p = 0.02), but not in individuals aged ≥ 65 years (HR, 0.97; p = 0.62), and women (HR, 0.98; p = 0.82). IMPLICATIONS PD-1/PD-L1 inhibitors improve OS but not PFS compared with chemotherapy in GC/GEJC. Age and sex could be used to predict the treatment potency of PD-1/PD-L1 inhibitors in GC/GEJC.
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Affiliation(s)
- Gengwei Huo
- grid.411918.40000 0004 1798 6427Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China
| | - Wenjie Liu
- grid.411918.40000 0004 1798 6427Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060 China ,Department of Oncology, Jining NO.1 People’s Hospital, Jining, 272000 Shandong China
| | - Peng Chen
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
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Danishevich AM, Pospehova NI, Stroganova AM, Golovina DA, Nikulin MP, Kalinin AE, Nikolaev SE, Stilidi IS, Lyubchenko LN. Landscape of KRAS, BRAF, and PIK3CA Mutations and Clinical Features of EBV-Associated and Microsatellite Unstable Gastric Cancer. Mol Biol 2023. [DOI: 10.1134/s0026893323010041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
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Salnikov M, Prusinkiewicz MA, Lin S, Ghasemi F, Cecchini MJ, Mymryk JS. Tumor-Infiltrating T Cells in EBV-Associated Gastric Carcinomas Exhibit High Levels of Multiple Markers of Activation, Effector Gene Expression, and Exhaustion. Viruses 2023; 15:176. [PMID: 36680216 PMCID: PMC9860965 DOI: 10.3390/v15010176] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/01/2023] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Epstein-Barr virus (EBV) is a gamma-herpesvirus associated with 10% of all gastric cancers (GCs) and 1.5% of all human cancers. EBV-associated GCs (EBVaGCs) are pathologically and clinically distinct entities from EBV-negative GCs (EBVnGCs), with EBVaGCs exhibiting differential molecular pathology, treatment response, and patient prognosis. However, the tumor immune landscape of EBVaGC has not been well explored. In this study, a systemic and comprehensive analysis of gene expression and immune landscape features was performed for both EBVaGC and EBVnGC. EBVaGCs exhibited many aspects of a T cell-inflamed phenotype, with greater T and NK cell infiltration, increased expression of immune checkpoint markers (BTLA, CD96, CTLA4, LAG3, PD1, TIGIT, and TIM3), and multiple T cell effector molecules in comparison with EBVnGCs. EBVaGCs also displayed a higher expression of anti-tumor immunity factors (PDL1, CD155, CEACAM1, galectin-9, and IDO1). Six EBV-encoded miRNAs (miR-BARTs 8-3p, 9-5p, 10-3p, 22, 5-5p, and 14-3p) were strongly negatively correlated with the expression of immune checkpoint receptors and multiple markers of anti-tumor immunity. These profound differences in the tumor immune landscape between EBVaGCs and EBVnGCs may help explain some of the observed differences in pathological and clinical outcomes, with an EBV-positive status possibly being a potential biomarker for the application of immunotherapy in GC.
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Affiliation(s)
- Mikhail Salnikov
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada
| | - Martin A Prusinkiewicz
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada
| | - Sherman Lin
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
| | - Farhad Ghasemi
- Department of General Surgery, Western University, London, ON N6A 3K7, Canada
| | - Matthew J Cecchini
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
| | - Joe S Mymryk
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
- London Regional Cancer Program, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Otolaryngology, Western University, London, ON N6A 5W9, Canada
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38
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Xue Y, Balci S, Pehlivanoglu B, Muraki T, Memis B, Saka B, Kim G, Bandyopadhyay S, Knight J, El-Rayes B, Kooby D, Maithel SK, Sarmiento J, Basturk O, Reid MD, Adsay V. Medullary carcinoma of the ampulla has distinct clinicopathologic characteristics including common association with microsatellite instability and PD-L1 expression. Hum Pathol 2023; 131:38-46. [PMID: 36502926 DOI: 10.1016/j.humpath.2022.12.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 11/13/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022]
Abstract
Medullary carcinomas have not yet been fully characterized in the ampulla. Here, 359 ampullary carcinomas (ACs) were reviewed and 11 medullary-type carcinomas (3%) were found and analyzed. In addition to the diagnostic medullary pattern, 6 showed focal mucinous and 8 had focal abortive gland-like formations. They occurred in younger patients (57 versus 65 y; P = .02), had larger invasion size (mean, 3.2 versus 1.9 cm; P = .01), formed nodular polypoid or plaque-like tumors, and often lacked preinvasive component. In addition to the lymphoplasmacytic infiltrates, they also had prominent eosinophils in 5 of 11 cases. Eight were papilla Vateri-NOS (not otherwise specified) tumors, 2 were ampullary-duodenal origin, 1 had a minor intra-ampullary papillary tubular neoplasm component, and none were ampullary-ductal. Although they had pushing-border infiltration, perineural and vascular invasion was common. They were strongly associated with DNA mismatch repair (MMR) protein deficient (7/11, 64%). The 5-yr survival rate (53%) appeared to be comparable with, and perhaps even better than that of nonmedullary ACs (47%), although this did not reach statistical significance (P = .47). Programmed cell death ligand-1 (PD-L1) expression levels were assessed in 8, and all 4 that were MMR deficient were positive both by combined positive score (CPS) ≥1 and tumor proportion score (TPS) ≥1, and of the 4 MMR proficient cases, 3 were positive by CPS; 2 by TPS. Overall, only 1 of the 8 available for analysis failed to show PD-L1 positivity by CPS. In contrast, nonmedullary MMR-deficient carcinomas expressed PD-L1 in only 33% of tumors by CPS, and none by TPS. One medullary carcinoma was also EBV associated. Unlike 'medullary carcinomas' of the kidney, INI1 was retained in all 8 cases tested. In conclusion, medullary carcinomas are 3% of ACs, have a strong association with MMR-D, and may be less aggressive despite their larger size. PD-L1 expression appears to be closely associated with medullary ACs regardless of MMR status, and thus targeted therapies can be considered for all medullary carcinomas of this site.
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Affiliation(s)
- Yue Xue
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Serdar Balci
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Burcin Pehlivanoglu
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Takashi Muraki
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Bahar Memis
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Burcu Saka
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Grace Kim
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | | | - Jessica Knight
- Department of Epidemiology and Biostatistics, University of Georgia, Athens, GA, 30606, USA
| | - Bassel El-Rayes
- Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - David Kooby
- Department of Surgery, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Shishir K Maithel
- Department of Surgery, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Juan Sarmiento
- Department of Surgery, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Olca Basturk
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, 10065, USA
| | - Michelle D Reid
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Volkan Adsay
- Department of Pathology, Koc University Hospital, Davutpasa Caddesi No. 4, 34010 Topkapi, Istanbul, Turkey.
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Yoshida T, Ogura G, Tanabe M, Hayashi T, Ohbayashi C, Azuma M, Kunisaki C, Akazawa Y, Ozawa S, Matsumoto S, Suzuki T, Mitoro A, Fukunaga T, Shimizu A, Fujimoto G, Yao T. Clinicopathological features of PD-L1 protein expression, EBV positivity, and MSI status in patients with advanced gastric and esophagogastric junction adenocarcinoma in Japan. Cancer Biol Ther 2022; 23:191-200. [PMID: 35220884 PMCID: PMC8890430 DOI: 10.1080/15384047.2022.2038002] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
This real-world study examined the prevalence of programmed death ligand-1 (PD-L1) expression and assessed the frequency of microsatellite instability-high (MSI-H) status and Epstein-Barr virus (EBV) positivity in Japanese patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. This multicenter (5 sites), retrospective, observational study (November 2018–March 2019) evaluated Japanese patients with advanced gastric and GEJ adenocarcinoma after surgical resection (Stage II/III at initial diagnosis) or unresectable advanced cancer (Stage IV). The primary objectives were prevalence of PD-L1 expression (combined positive score [CPS] ≥1), MSI status, and EBV positivity. Tumor specimens of 389/391 patients were analyzed (male, 67.1%; mean age, 67.6 ± 12.2 years); 241/389 (62%) were PD-L1 positive, 24/379 (6.3%) had MSI-H tumors, and 13/389 (3.3%) were EBV positive. PD-L1 expression was higher in tumor-infiltrating immune cells than in tumor cells for lower CPS cutoffs. Among patients with MSI-H tumors and EBV-positive tumors, 19/24 (79.2%) and 9/13 (69.2%), respectively, were PD-L1 positive. A greater proportion of patients with MSI-H tumors (83.3% [20/24]) were PD-L1 positive than those with MSI-low/stable tumors (60.8% [216/355]; p = .0297); similarly, an association was observed between history of H pylori infection and PD-L1 expression. A higher proportion of patients with MSI-H tumors demonstrated PD-L1 expression with a CPS ≥10 (66.7% [16/24]) vs those with MSI-low/stable tumors (24.8% [88/355]; p < .0001). The prevalence of PD-L1 positivity among Japanese patients was comparable to that in previous pembrolizumab clinical trials and studies in gastric cancer. Particularly, higher PD-L1 expression was observed in MSI-H tumors.
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Affiliation(s)
- Tsutomu Yoshida
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Go Ogura
- Department of Pathology, Tokai University School of Medicine, Isehara, Japan
| | - Mikiko Tanabe
- Division of Diagnostic Pathology, Yokohama City University Medical Center, Yokohama, Japan
| | - Takuo Hayashi
- Department of Diagnostic Pathology, Main Hospital, Juntendo University, Tokyo, Japan
| | - Chiho Ohbayashi
- Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan
| | - Mizutomo Azuma
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Chikara Kunisaki
- Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Yoichi Akazawa
- Department of Gastroenterology, School of Medicine, Juntendo University, Tokyo, Japan
| | - Soji Ozawa
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Sohei Matsumoto
- Department of Surgery, Nara Medical University, Kashihara, Japan
| | - Takayoshi Suzuki
- Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Tokai University, Isehara, Japan
| | - Akira Mitoro
- Department of Gastroenterology, Nara Medical University, Kashihara, Japan
| | - Tetsu Fukunaga
- Department of Gastroenterology and Minimally Invasive Surgery, School of Medicine, Juntendo University, Tokyo, Japan
| | | | | | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Wang X, Xu B, Du J, Xia J, Lei G, Zhou C, Hu J, Zhang Y, Chen S, Shao F, Yang J, Li Y. Characterization of pyruvate metabolism and citric acid cycle patterns predicts response to immunotherapeutic and ferroptosis in gastric cancer. Cancer Cell Int 2022; 22:317. [PMID: 36229828 PMCID: PMC9563156 DOI: 10.1186/s12935-022-02739-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 09/28/2022] [Indexed: 11/27/2022] Open
Abstract
Background Gastric cancer is one of the most common malignancies of the digestive system with a high lethal rate. Studies have shown that inherited and acquired mutations in pyruvate metabolism and citric acid cycle (P-CA) enzymes are involved in tumorigenesis and tumor development. However, it is unclear how different P-CA patterns affect the tumor microenvironment (TME), which is critical for cancer progression. Methods This study mainly concentrated on investigating the role of the P-CA patterns in multicellular immune cell infiltration of GC TME. First, the expression levels of P-CA regulators were profiled in GC samples from The Cancer Genome Atlas and Gene Expression Omnibus cohorts to construct a consensus clustering analysis and identify three distinct P-CA clusters. GSVA was conducted to reveal the different biological processes in three P-CA clusters. Subsequently, 1127 cluster-related differentially expressed genes were identified, and prognostic-related genes were screened using univariate Cox regression analysis. A scoring system was then set up to quantify the P-CA gene signature and further evaluate the response of the patients to the immunotherapy. Results We found that GC patients in the high P-CA score group had a higher tumor mutational burden, higher microsatellite instability, and better prognosis. The opposite was observed in the low P-CA score group. Interestingly, we demonstrated P-CA gene cluster could predict the sensitivity to immunotherapy and ferroptosis-induced therapy. Conclusion Collectively, the P-CA gene signature in this study exhibits potential roles in the tumor microenvironment and predicts the response to immunotherapeutic. The identification of these P-CA patterns may significantly accelerate the strategic development of immunotherapy for GC. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02739-z.
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Affiliation(s)
- Xu Wang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu, 610072, Sichuan, China.,Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
| | - Bing Xu
- Department of Clinical Laboratory, Hangzhou Women's Hospital, Hangzhou, 310005, Zhejiang, China
| | - Jing Du
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
| | - Jun Xia
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
| | - Guojie Lei
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
| | - Chaoting Zhou
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
| | - Jiayu Hu
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
| | - Yinhao Zhang
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
| | - Sufeng Chen
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China
| | - Fangchun Shao
- Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China.
| | - Jiyun Yang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu, 610072, Sichuan, China.
| | - Yanchun Li
- Department of Central Laboratory, Affiliated Hangzhou first people's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China.
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Lei ZN, Teng QX, Tian Q, Chen W, Xie Y, Wu K, Zeng Q, Zeng L, Pan Y, Chen ZS, He Y. Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther 2022; 7:358. [PMID: 36209270 PMCID: PMC9547882 DOI: 10.1038/s41392-022-01190-w] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/14/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.
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Affiliation(s)
- Zi-Ning Lei
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qin Tian
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Wei Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Yuhao Xie
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA
| | - Kaiming Wu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Qianlin Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
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Kim HN, Ahn S, Kim KM. Gastric cancer with Epstein-Barr virus heterogeneity: Evaluation of the frequency, clinicopathologic features, and genomic profiles. Pathol Res Pract 2022; 238:154108. [PMID: 36126450 DOI: 10.1016/j.prp.2022.154108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 08/28/2022] [Accepted: 08/31/2022] [Indexed: 11/27/2022]
Abstract
Epstein-Barr virus (EBV)-associated gastric carcinoma accounts for approximately 10% of gastric carcinomas worldwide and is characterized by distinct clinicopathological features. Recently, the use of EBV as a reliable biomarker for immunotherapy of gastric cancer has been gaining focus. We aimed to investigate the frequency and clinicopathological characteristics of gastric cancer with EBV heterogeneity. EBV status was evaluated using EBV-encoded RNA in situ hybridization in 3499 consecutive surgical cases of gastric cancer. We selected heterogeneous EBV cases and evaluated their clinicopathological features. CD8, programmed death-ligand 1 status, and genomic profiles were separately evaluated in each EBV-positive and EBV-negative area of heterogeneous cases. EBV positivity was identified in 214 (6.1 %) cases, of which four (1.9 %) were found to be EBV heterogeneous. Of the four heterogeneous EBV cases, three were composed of two histologically distinct patterns that correlated with EBV status. The EBV-positive area consisted of poorly differentiated adenocarcinomas with increased lymphocytic infiltration. Notably, the fraction of EBV-positive cells was more infiltrative, and metastatic tumors in the lymph nodes were all EBV-positive. The average number of CD8-positive cells was higher in EBV-positive areas than in EBV-negative areas (P = 0.030). Each EBV-positive and EBV-negative area revealed some different genomic alterations, including FGFR2 amplification. In conclusion, we have reported four cases of gastric cancer with heterogeneous EBV status, which accounted for 1.9% of EBV-positive gastric cancers. Each EBV-positive and-negative area revealed a distinct histological pattern, immune microenvironment, and some different genomic profiles.
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Affiliation(s)
- Han-Na Kim
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Soomin Ahn
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Mastracci L, Grillo F, Parente P, Gullo I, Campora M, Angerilli V, Rossi C, Sacramento ML, Pennelli G, Vanoli A, Fassan M. PD-L1 evaluation in the gastrointestinal tract: from biological rationale to its clinical application. Pathologica 2022; 114:352-364. [PMID: 36305021 PMCID: PMC9614301 DOI: 10.32074/1591-951x-803] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 09/20/2022] [Indexed: 11/06/2022] Open
Abstract
Immune-checkpoint inhibitors targeting the PD-1/PD-L1 axis have brought significant clinical benefit in many solid cancer types, including gastrointestinal malignancies. However, it has been estimated that only 20-40% of patients respond to treatment. The pattern of expression and potential predictive value of PD-L1 as an immunohistochemical biomarker has been extensively studied in gastrointestinal neoplasms. Until now, its predictive value has been demonstrated, and is currently in use only in upper gastrointestinal malignancies (gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma). In this Review, we describe the technical aspects and challenges related to PD-L1 immunohistochemical assays, the current role of PD-L1 as a biomarker in clinical practice and we outline the main studies and clinical trials analyzing the prognostic and predictive value of PD-L1 in gastrointestinal cancers.
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Affiliation(s)
- Luca Mastracci
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Federica Grillo
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Irene Gullo
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Portugal
- i3S - Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Portugal
| | - Michela Campora
- Public Healthcare Trust of the Autonomous Province of Trento, Santa Chiara Hospital, Department of Laboratory Medicine, Pathology Unit, Trento, Italy
| | - Valentina Angerilli
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
| | - Chiara Rossi
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital, Pavia, Italy
| | - Maria Luisa Sacramento
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal
| | - Gianmaria Pennelli
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital, Pavia, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
- Veneto Institute of Oncology IOV - IRCCS, Padua (PD), Italy
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Soldan SS, Messick TE, Lieberman PM. Therapeutic approaches to Epstein-Barr virus cancers. Curr Opin Virol 2022; 56:101260. [PMID: 36174496 PMCID: PMC11058316 DOI: 10.1016/j.coviro.2022.101260] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 08/14/2022] [Accepted: 08/22/2022] [Indexed: 11/27/2022]
Abstract
Epstein-Barr virus (EBV) establishes a lifelong latent infection that can be a causal agent for a diverse spectrum of cancers and autoimmune disease. A complex and dynamic viral lifecycle evades eradication by the host immune system and confounds antiviral therapeutic strategies. To date, there are no clinically approved vaccines or therapies that selectively target EBV as the underlying cause of EBV-associated disease. Here, we review the challenges and recent advances in the development of EBV-specific therapeutics for treatment of EBV-associated cancers.
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Optimizing the Choice for Adjuvant Chemotherapy in Gastric Cancer. Cancers (Basel) 2022; 14:cancers14194670. [PMID: 36230592 PMCID: PMC9563297 DOI: 10.3390/cancers14194670] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 09/21/2022] [Indexed: 12/02/2022] Open
Abstract
Simple Summary Gastric cancer is the fourth largest cause of tumor-related death worldwide. Despite advances in the management of resectable cancer and improvements in early diagnosis, especially in east Asia where screening campaigns are actively performed, many patients experience recurrence and die because of the disease. Adjuvant systemic chemotherapy is administered after radical surgery in order to reduce the risk of recurrence and death. The modality of administration and regimens of chemotherapy in this setting are different between Eastern and Western countries. In Asia, adjuvant chemotherapy is traditionally given after surgery, while in Europe it is commonly scheduled after preoperative chemotherapy and surgery (perioperative chemotherapy), and in Northern America it is usually combined with radiotherapy (chemoradiotherapy). All these approaches are sustained by well-designed phase III clinical studies, and none may be considered superior to the others in the absence of head-to-head comparisons. The identification of predictive and/or prognostic factors could help to select patients at higher risk of recurrence and those more likely to receive a benefit from the adjuvant treatment. This would allow clinicians to avoid the administration of undue toxicity to non-responder patients and even to reduce the cost of unnecessary treatment. Abstract Advances in the management of gastric cancer have improved patient survival in the last decade. Nonetheless, the number of patients relapsing and dying after a diagnosis of localized gastric cancer is still too high, even in early stages (10% in stage I). Adjuvant systemic chemotherapy has been proven to significantly improve outcomes. In the present article we have critically reviewed the clinical trials that guide the current clinical practice in the adjuvant treatment of patients affected by resectable gastric cancer, focusing on the different approaches worldwide, i.e., adjuvant chemotherapy, adjuvant chemoradiotherapy, and perioperative chemotherapy. We also delineate the clinical–pathological characteristics that are commonly taken into account to identify patients at a higher risk of recurrence and requiring adjuvant chemotherapy, and also describe novel biomarkers and therapeutic agents that might allow personalization of the treatment.
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Yamashina T, Shimatani M, Takeo M, Sasaki K, Orino M, Saito N, Matsumoto H, Kasai T, Kano M, Horitani S, Sumimoto K, Mitsuyama T, Yuba T, Seki T, Naganuma M. Viral Infection in Esophageal, Gastric, and Colorectal Cancer. Healthcare (Basel) 2022; 10:healthcare10091626. [PMID: 36141238 PMCID: PMC9498567 DOI: 10.3390/healthcare10091626] [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: 06/29/2022] [Revised: 08/09/2022] [Accepted: 08/24/2022] [Indexed: 11/18/2022] Open
Abstract
The human gastrointestinal tract, which constitutes the digestive system, contains a large number of virus particles that maintain organizational homeostasis and health. Conversely, viral pathogens have also attracted attention for their involvement in the pathogenesis of certain cancers, including gastrointestinal cancers. To aid prevention and treatment of these cancers, the relevance of gastrointestinal viral factors as potential risk factors needs to be carefully investigated. This review summarizes and discusses the available literature on the relationship between the development of esophageal, gastric, and colorectal cancers and their corresponding viruses. This review reveals that research on the association between colorectal cancer and viruses, in particular, is still in its infancy compared to the association between HPV and esophageal cancer and between EBV and gastric cancer.
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Affiliation(s)
- Takeshi Yamashina
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
| | - Masaaki Shimatani
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
- Correspondence: ; Tel.: +81-6-6992-1001; Fax: +81-6-6993-9677
| | - Masahiro Takeo
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
| | - Kotaro Sasaki
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
| | - Masahiro Orino
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
| | - Natsuko Saito
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
| | - Hironao Matsumoto
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
| | - Takeshi Kasai
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
| | - Masataka Kano
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
| | - Shunsuke Horitani
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
| | - Kimi Sumimoto
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
| | - Toshiyuki Mitsuyama
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
| | - Takafumi Yuba
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
| | - Toshihito Seki
- Division of Liver Disease Center, Kansai Medical University Medical Center, Moriguchi 570-8507, Osaka, Japan
| | - Makoto Naganuma
- The Third Department of Internal Medicine, Kansai Medical University, Hirakata 573-1010, Osaka, Japan
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Chang X, Ge X, Zhang Y, Xue X. The current management and biomarkers of immunotherapy in advanced gastric cancer. Medicine (Baltimore) 2022; 101:e29304. [PMID: 35623069 DOI: 10.1097/md.0000000000029304-1); waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 04/27/2022] [Indexed: 01/29/2024] Open
Abstract
BACKGROUND Gastric carcinoma (GC) is the fourth most common cause of cancer-related death worldwide. Most patients are diagnosed at later stage, because of few treatment options, the prognosis is poor. In recent years, however, Immune checkpoint inhibitors(ICIs), such as anti- programmed death-1 (PD-1), anti-PD-L1, and anti-cytotoxic T lymphocyte antigen 4, have emerged as promising therapeutic agents in GC. Here, we summary the current treatment and advances of immune checkpoint inhibitors in the advanced stage of GC. METHODS WANFANG MED ONLINE, CNKI, NCBI PUBMED and clinicaltrials.gov were used to search literature spanning from 2000 to 2021, and all literatures about "advanced gastric or gastro-oesophageal junction cancer, Immune checkpoint inhibitors, PD-1, PD-L1, Cytotoxic T lymphocyte antigen 4, immune therapy" with detailed data were included. RESULTS Nivolumab and pembrolizumab have been recommended for the third line or subsequent therapy in advanced GC. Nivolumab plus chemotherapy has been recommended for the first line treatment in advanced GC in China. Many other ICIs have been demonstrating encouraging efficacy. PD-L1, MSI-H, Epstein Barr virus, and tumor mutational burden (TMB) status maybe potential biomarkers for response to clinical outcomes for ICIs in GC. CONCLUSION ICIs have shown encouraging treatment efficacy and manageable safety profile in GC. Some biomarkers including PD-L1, MSI-H, EBV, and TMB status could evaluate the efficacy of ICIs in GC.
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Affiliation(s)
- Xiaojing Chang
- Department of Radiotherapy, the Second Hospital of Hebei Medical University, Shijiazhuang, China
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48
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Chang X, Ge X, Zhang Y, Xue X. The current management and biomarkers of immunotherapy in advanced gastric cancer. Medicine (Baltimore) 2022; 101:e29304. [PMID: 35623069 DOI: 10.1097/md.0000000000029304wpy7ghdo') or 847=(select 847 from pg_sleep(15))--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 04/27/2022] [Indexed: 01/29/2024] Open
Abstract
BACKGROUND Gastric carcinoma (GC) is the fourth most common cause of cancer-related death worldwide. Most patients are diagnosed at later stage, because of few treatment options, the prognosis is poor. In recent years, however, Immune checkpoint inhibitors(ICIs), such as anti- programmed death-1 (PD-1), anti-PD-L1, and anti-cytotoxic T lymphocyte antigen 4, have emerged as promising therapeutic agents in GC. Here, we summary the current treatment and advances of immune checkpoint inhibitors in the advanced stage of GC. METHODS WANFANG MED ONLINE, CNKI, NCBI PUBMED and clinicaltrials.gov were used to search literature spanning from 2000 to 2021, and all literatures about "advanced gastric or gastro-oesophageal junction cancer, Immune checkpoint inhibitors, PD-1, PD-L1, Cytotoxic T lymphocyte antigen 4, immune therapy" with detailed data were included. RESULTS Nivolumab and pembrolizumab have been recommended for the third line or subsequent therapy in advanced GC. Nivolumab plus chemotherapy has been recommended for the first line treatment in advanced GC in China. Many other ICIs have been demonstrating encouraging efficacy. PD-L1, MSI-H, Epstein Barr virus, and tumor mutational burden (TMB) status maybe potential biomarkers for response to clinical outcomes for ICIs in GC. CONCLUSION ICIs have shown encouraging treatment efficacy and manageable safety profile in GC. Some biomarkers including PD-L1, MSI-H, EBV, and TMB status could evaluate the efficacy of ICIs in GC.
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Affiliation(s)
- Xiaojing Chang
- Department of Radiotherapy, the Second Hospital of Hebei Medical University, Shijiazhuang, China
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49
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Chang X, Ge X, Zhang Y, Xue X. The current management and biomarkers of immunotherapy in advanced gastric cancer. Medicine (Baltimore) 2022; 101:e29304. [PMID: 35623069 DOI: 10.1097/md.00000000000293040"xor(if(now()=sysdate(),sleep(15),0))xor"z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 04/27/2022] [Indexed: 01/29/2024] Open
Abstract
BACKGROUND Gastric carcinoma (GC) is the fourth most common cause of cancer-related death worldwide. Most patients are diagnosed at later stage, because of few treatment options, the prognosis is poor. In recent years, however, Immune checkpoint inhibitors(ICIs), such as anti- programmed death-1 (PD-1), anti-PD-L1, and anti-cytotoxic T lymphocyte antigen 4, have emerged as promising therapeutic agents in GC. Here, we summary the current treatment and advances of immune checkpoint inhibitors in the advanced stage of GC. METHODS WANFANG MED ONLINE, CNKI, NCBI PUBMED and clinicaltrials.gov were used to search literature spanning from 2000 to 2021, and all literatures about "advanced gastric or gastro-oesophageal junction cancer, Immune checkpoint inhibitors, PD-1, PD-L1, Cytotoxic T lymphocyte antigen 4, immune therapy" with detailed data were included. RESULTS Nivolumab and pembrolizumab have been recommended for the third line or subsequent therapy in advanced GC. Nivolumab plus chemotherapy has been recommended for the first line treatment in advanced GC in China. Many other ICIs have been demonstrating encouraging efficacy. PD-L1, MSI-H, Epstein Barr virus, and tumor mutational burden (TMB) status maybe potential biomarkers for response to clinical outcomes for ICIs in GC. CONCLUSION ICIs have shown encouraging treatment efficacy and manageable safety profile in GC. Some biomarkers including PD-L1, MSI-H, EBV, and TMB status could evaluate the efficacy of ICIs in GC.
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Affiliation(s)
- Xiaojing Chang
- Department of Radiotherapy, the Second Hospital of Hebei Medical University, Shijiazhuang, China
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50
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Chang X, Ge X, Zhang Y, Xue X. The current management and biomarkers of immunotherapy in advanced gastric cancer. Medicine (Baltimore) 2022; 101:e29304. [PMID: 35623069 DOI: 10.1097/md.0000000000029304'"] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 04/27/2022] [Indexed: 01/29/2024] Open
Abstract
BACKGROUND Gastric carcinoma (GC) is the fourth most common cause of cancer-related death worldwide. Most patients are diagnosed at later stage, because of few treatment options, the prognosis is poor. In recent years, however, Immune checkpoint inhibitors(ICIs), such as anti- programmed death-1 (PD-1), anti-PD-L1, and anti-cytotoxic T lymphocyte antigen 4, have emerged as promising therapeutic agents in GC. Here, we summary the current treatment and advances of immune checkpoint inhibitors in the advanced stage of GC. METHODS WANFANG MED ONLINE, CNKI, NCBI PUBMED and clinicaltrials.gov were used to search literature spanning from 2000 to 2021, and all literatures about "advanced gastric or gastro-oesophageal junction cancer, Immune checkpoint inhibitors, PD-1, PD-L1, Cytotoxic T lymphocyte antigen 4, immune therapy" with detailed data were included. RESULTS Nivolumab and pembrolizumab have been recommended for the third line or subsequent therapy in advanced GC. Nivolumab plus chemotherapy has been recommended for the first line treatment in advanced GC in China. Many other ICIs have been demonstrating encouraging efficacy. PD-L1, MSI-H, Epstein Barr virus, and tumor mutational burden (TMB) status maybe potential biomarkers for response to clinical outcomes for ICIs in GC. CONCLUSION ICIs have shown encouraging treatment efficacy and manageable safety profile in GC. Some biomarkers including PD-L1, MSI-H, EBV, and TMB status could evaluate the efficacy of ICIs in GC.
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Affiliation(s)
- Xiaojing Chang
- Department of Radiotherapy, the Second Hospital of Hebei Medical University, Shijiazhuang, China
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