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Tang S, Che X, Wang J, Li C, He X, Hou K, Zhang X, Guo J, Yang B, Li D, Cao L, Qu X, Wang Z, Liu Y. T-bet +CD8 + T cells govern anti-PD-1 responses in microsatellite-stable gastric cancers. Nat Commun 2025; 16:3905. [PMID: 40280928 PMCID: PMC12032036 DOI: 10.1038/s41467-025-58958-1] [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: 04/25/2024] [Accepted: 04/04/2025] [Indexed: 04/29/2025] Open
Abstract
More than 90% of advanced gastric cancers (GC) are microsatellite-stable (MSS). Compared to the high response rate of immune checkpoint inhibitors (ICI) in microsatellite-instability-high (MSI-H) GCs, only 10% of unstratified MSS GCs respond to ICIs. In this study, we apply semi-supervised learning to stratify potential ICI responders in MSS GCs, achieving high accuracy, quantified by an area under the curve of 0.924. Spatial analysis of the tumor microenvironment of ICI-sensitive GCs reveals a high level of T-bet+ CD8 + T cell infiltration in their tumor compartments. T-bet+ CD8 + T cells exhibit superior anti-tumor activity due to their increased ability to infiltrate tumors and secrete cytotoxic molecules. Adoptive transfer of T-bet+ CD8 + T cells boosts anti-tumor immunity and confers susceptibility to ICIs in immune-ignorant MSS GCs in a humanized mouse model. Spatial RNA sequencing suggests a positive-feedback loop between T-bet+ T cells and PD-L1+ tumor cells, which eventually drives T cell exhaustion and can therefore be leveraged for ICI therapy. In summary, our research provides insights into the underlying mechanism of anti-tumor immunity and deepens our understanding of varied ICI responses in MSS GCs.
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Affiliation(s)
- Shiying Tang
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Jinyan Wang
- Department of Immunology, College of Basic Medical Sciences, China Medical University, No. 77, Puhe Road, Shenyang, Liaoning, China
| | - Ce Li
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Xin He
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Kezuo Hou
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Xiaojie Zhang
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Jia Guo
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Bowen Yang
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Danni Li
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Lili Cao
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China.
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China.
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China.
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, No.155, Nanjing Street, Shenyang, Liaoning, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, China Medical University, Shenyang, Liaoning, China.
- Institute of Health Sciences, China Medical University, Shenyang, Liaoning, China.
| | - Yunpeng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China.
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China.
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, 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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Wang L, Sun M, Li J, Wan L, Tan Y, Tian S, Hou Y, Wu L, Peng Z, Hu X, Zhang Q, Huang Z, Han M, Peng S, Pan Y, Ren Y, Zhang M, Chen D, Liu Q, Li X, Qin ZY, Xiang J, Li M, Zhu J, Chen Q, Luo H, Wang S, Wang T, Li F, Bian XW, Wang B. Intestinal Subtype as a Biomarker of Response to Neoadjuvant Immunochemotherapy in Locally Advanced Gastric Adenocarcinoma: Insights from a Prospective Phase II Trial. Clin Cancer Res 2025; 31:74-86. [PMID: 39495175 DOI: 10.1158/1078-0432.ccr-24-2436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/22/2024] [Accepted: 10/31/2024] [Indexed: 11/05/2024]
Abstract
PURPOSE Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma. However, specific biomarkers are still lacking to effectively identify the beneficiary patients for NAIC. PATIENTS AND METHODS A prospective, single-arm, phase II study was conducted to treat locally advanced gastric adenocarcinoma with NAIC (NCT05515796). Correlation between clinicopathologic characteristics and neoadjuvant efficacy was investigated. Bulk RNA sequencing data from 104 samples (from 75 patients in two independent cohorts) and single-cell RNA sequencing data from 105 treatment-naïve gastric adenocarcinomas were comprehensively analyzed to decipher the association of epithelial and microenvironmental characteristics and clinical responses. RESULTS The prespecified primary endpoints were achieved: pathologic complete regression rate was 30%, major pathologic regression rate was 43%, and the regimen was well tolerated. Analysis of baseline clinical-pathologic parameters revealed the intestinal subtype of Lauren's classification as a key feature stratifying patients with increased sensitivity to NAIC. Mechanistically, an increased pool of DNA damage repair-active cancer cells and enrichment of CLEC9A+ dendritic cells in the tumor microenvironment were associated with enhanced responsiveness of the intestinal subtype gastric adenocarcinoma to NAIC. More importantly, an intestinal subtype-specific signature model was constructed by the machine learning algorithm NaiveBayes via integrating the transcriptomic features of both DNA damage repair-active cancer cells and CLEC9A+ dendritic cells, which accurately predicted the efficacy of NAIC in multiple independent gastric adenocarcinoma cohorts. CONCLUSIONS Intestinal subtype is a histologic biomarker of enhanced sensitivity of gastric adenocarcinoma to NAIC. The intestinal subtype-specific signature model is applicable to guide NAIC for patients with locally advanced gastric adenocarcinoma.
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Affiliation(s)
- Lei Wang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Mengting Sun
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Jinyang Li
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Linghong Wan
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Yuting Tan
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- School of Medicine, Chongqing University, Chongqing, P.R. China
| | - Shuoran Tian
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Yongying Hou
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- Department of Pathology, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Linyu Wu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Ziyi Peng
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Xiao Hu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- School of Medicine, Chongqing University, Chongqing, P.R. China
| | - Qihua Zhang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China
| | - Zening Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, P.R. China
| | - Mengyi Han
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Shiyin Peng
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- School of Medicine, Chongqing University, Chongqing, P.R. China
| | - Yuwei Pan
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- School of Medicine, Chongqing University, Chongqing, P.R. China
| | - Yuanfeng Ren
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Mengsi Zhang
- Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Dongfeng Chen
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Qin Liu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Xianfeng Li
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Zhong-Yi Qin
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Junyv Xiang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Mengxia Li
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Jianwu Zhu
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Qiyue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, P.R. China
| | - Huiyan Luo
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China
| | - Shunan Wang
- Department of Radiology, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Tao Wang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Fan Li
- Division of Gastric and Colorectal Surgery, Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Xiu-Wu Bian
- Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Bin Wang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- Jinfeng Laboratory, Chongqing, P.R. China
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Wang M, Huang K, Fan X, Wang J, Jin Y, Zheng ZJ. Access to radiotherapy in improving gastric cancer care quality and equality. COMMUNICATIONS MEDICINE 2024; 4:225. [PMID: 39488624 PMCID: PMC11531536 DOI: 10.1038/s43856-024-00655-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 10/23/2024] [Indexed: 11/04/2024] Open
Abstract
BACKGROUND Quality health services could improve patient outcomes and prognosis. Gastric cancer care was of great disparity across genders. Disparities within radiotherapy units could impact gastric cancer care, potentially exacerbating gender-based inequalities. METHODS We retrieved the disease burden data from Global Burden of Disease 2019. A quality of care index was constructed by applying principal component analysis techniques. The disparity of gastric cancer care across genders was described, and the association of access to radiotherapy with gastric cancer care as well as gender disparity was explored. RESULTS Males receive better quality of gastric cancer care than females, and this gender disparity is widening in middle-low socio-development regions. A positive correlation emerges between the density of radiotherapy facilities and an elevated quality of care, and reduced gender-based disparities. CONCLUSIONS The association between robust radiotherapy access, improved gastric cancer QCI, and reduced gender-based disparities spotlights the imperative of fortifying radiotherapy infrastructure within areas and populations in greatest need.
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Affiliation(s)
- Minmin Wang
- Department of Global Health, School of Public Health, Peking University, Beijing, China
- Institute for Global Health and Development, Peking University, Beijing, China
| | - Kepei Huang
- Department of Global Health, School of Public Health, Peking University, Beijing, China
- Institute for Global Health and Development, Peking University, Beijing, China
| | - Xiaohan Fan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jia Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yinzi Jin
- Department of Global Health, School of Public Health, Peking University, Beijing, China.
- Institute for Global Health and Development, Peking University, Beijing, China.
| | - Zhi-Jie Zheng
- Department of Global Health, School of Public Health, Peking University, Beijing, China
- Institute for Global Health and Development, Peking University, Beijing, China
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Pereira MA, Ramos MFKP, Cardili L, Dias AR, Alves VAF, de Mello ES, Ribeiro U. Prognostic significance of microsatellite instability in patients with resectable gastric cancer. J Gastrointest Surg 2024; 28:1687-1695. [PMID: 39147611 DOI: 10.1016/j.gassur.2024.07.019] [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: 05/08/2024] [Revised: 07/03/2024] [Accepted: 07/26/2024] [Indexed: 08/17/2024]
Abstract
BACKGROUND Microsatellite instability (MSI) gastric cancer (GC) generally has a better prognosis than microsatellite-stable (MSS) GC and has been associated with nonsurvival benefit with the addition of chemotherapy (CMT) compared with surgery alone. However, patients with MSI have distinct clinicopathological characteristics. This study aimed to compare the survival outcomes between patients with MSI GC and those with MSS GC. In addition, this study analyzed the survival outcomes of patients with MSI GC who received CMT. METHODS This study reviewed all patients with GC who underwent curative gastrectomy. Patients were divided into MSI group and the MSS group. Propensity score matching (PSM) was used to match clinicopathological factors. RESULTS Among the 378 patients enrolled, 78 (20.6%) had MSI. Older age (P < .001), subtotal gastrectomy (P = .008), pN0 (P = .020), and earlier pTNM stage (P = .012) were associated with MSI GC. Survival analysis showed better disease-free survival (DFS) and overall survival (OS) of patients in the MSI group (P = .012 and P = .019, respectively). After PSM, 78 patients were matched to each group. All variables assigned to the scores were well matched, and both groups became equivalent. After the matching, the differences in DFS and OS according to MSI/MSS status were estimated to be larger than before (DFS: 63.3% vs 41.4%; P = .002; OS: 65.8% vs 42.5%; P = .002). Regarding patients referred for CMT, there was no difference in DFS and OS between patients with MSI GC who underwent CMT and those who underwent surgery alone (P = .255 and P = .178, respectively). CONCLUSION Even after controlling for clinicopathological characteristics, MSI was identified as a prognostic factor for patient survival. MSI GC showed no significant survival benefit with the addition of CMT.
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Affiliation(s)
- Marina Alessandra Pereira
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil.
| | - Marcus Fernando Kodama Pertille Ramos
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Leonardo Cardili
- Department of Pathology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - André Roncon Dias
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Venancio Avancini Ferreira Alves
- Department of Pathology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Evandro Sobroza de Mello
- Department of Pathology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Ulysses Ribeiro
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
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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: 11] [Impact Index Per Article: 11.0] [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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7
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Yang Z, Zhang R, Liu J, Tian S, Zhang H, Zeng L, Zhang Y, Gao L, Wang M, Shan W, Liu J. The mechanism of RGS5 regulating gastric cancer mismatch repair protein. Mol Carcinog 2024; 63:1750-1767. [PMID: 38860604 DOI: 10.1002/mc.23770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 05/11/2024] [Accepted: 05/24/2024] [Indexed: 06/12/2024]
Abstract
The incidence and mortality rates of gastric cancer (GC) remain alarmingly high worldwide, imposing a substantial healthcare burden. In this study, we utilized data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A 4-gene prognostic model was developed to predict patient prognosis, and its accuracy was validated across multiple datasets. Patients with a low-risk score exhibited improved prognosis, elevated tumor mutation burden, heightened sensitivity to both immunotherapy and conventional chemotherapy. Notably, our investigation revealed that the key gene RGS5 positively modulates the expression of mismatch repair proteins via c-Myc. Furthermore, co-immunoprecipitation (COIP) assays demonstrated the interaction between RGS5 and c-Myc. Additionally, we confirmed that RGS5 regulates c-Myc through the ubiquitin-proteasome pathway. Moreover, RGS5 was identified as a positive regulator of PD-L1 expression and exhibited a negative correlation with the majority of immune cells. These findings underscore the potential of RGS5 as a novel biomarker and therapeutic target in the context of GC.
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Affiliation(s)
- Zhenwei Yang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Intestinal and Colorectal Diseases, Hubei Clinical Center, Wuhan, China
| | - Ranran Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Intestinal and Colorectal Diseases, Hubei Clinical Center, Wuhan, China
| | - Jialong Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Intestinal and Colorectal Diseases, Hubei Clinical Center, Wuhan, China
| | - Sufang Tian
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hailin Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Intestinal and Colorectal Diseases, Hubei Clinical Center, Wuhan, China
| | - Lingxiu Zeng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Intestinal and Colorectal Diseases, Hubei Clinical Center, Wuhan, China
| | - Yangyang Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Intestinal and Colorectal Diseases, Hubei Clinical Center, Wuhan, China
| | - Liping Gao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Intestinal and Colorectal Diseases, Hubei Clinical Center, Wuhan, China
| | - Meng Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Intestinal and Colorectal Diseases, Hubei Clinical Center, Wuhan, China
| | - Wenqing Shan
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Intestinal and Colorectal Diseases, Hubei Clinical Center, Wuhan, China
| | - Jing Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Intestinal and Colorectal Diseases, Hubei Clinical Center, Wuhan, China
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8
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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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9
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Chen X, Zhuang Z, Pen L, Xue J, Zhu H, Zhang L, Wang D. Intratumoral and peritumoral CT-based radiomics for predicting the microsatellite instability in gastric cancer. Abdom Radiol (NY) 2024; 49:1363-1375. [PMID: 38305796 DOI: 10.1007/s00261-023-04165-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/13/2023] [Accepted: 12/14/2023] [Indexed: 02/03/2024]
Abstract
PURPOSE To investigate the value of intratumoral and peritumoral radiomics based on contrast-enhanced computer tomography (CECT) to preoperatively predict microsatellite instability (MSI) status in gastric cancer (GC) patients. METHODS A total of 189 GC patients, including 63 patients with MSI-high (MSI-H) and 126 patients with MSI-low/stable (MSI-L/S), were randomly divided into the training cohort and validation cohort. Intratumoral and 5-mm peritumoral regions' radiomics features were extracted from CECT images. The features were standardized by Z-score, and the Inter- and intraclass correlation coefficient, univariate logistic regression analysis, and least absolute shrinkage and selection operator (LASSO) were applied to select the optimal radiomics features. Radiomics scores (Rad-score) based on intratumoral regions, peritumoral regions, and intratumoral + 5-mm peritumoral regions were calculated by weighting the linear combination of the selected features with their respective coefficients to construct the intratumoral model, peritumoral model, and intratumoral + peritumoral model. Logistic regression was used to establish a combined model by combining clinical characteristics, CT semantic features, and Rad-score of intratumoral and peritumoral regions. RESULTS Eleven radiomics features were selected to establish a radiomics intratumoral + peritumoral model. CT-measured tumor length and tumor location were independent risk factors for MSI status. The established combined model obtained the highest area under the receiver operating characteristic (ROC) curve (AUC) of 0.830 (95% CI, 0.727-0.906) in the validation cohort. The calibration curve and decision curve demonstrated its good model fitness and clinical application value. CONCLUSION The combined model based on intratumoral and peritumoral CECT radiomics features and clinical factors can predict the MSI status of GS with moderate accuracy before surgery, which helps formulate personalized treatment strategies.
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Affiliation(s)
- Xingchi Chen
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Zijian Zhuang
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Lin Pen
- School of Medicine, Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Jing Xue
- School of Medicine, Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Haitao Zhu
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China
| | - Lirong Zhang
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China.
- Institute of Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, 212000, Jiangsu Province, China.
| | - Dongqing Wang
- Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu Province, China.
- Institute of Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, 212000, Jiangsu Province, China.
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Uema R, Hayashi Y, Komori M, Shibukawa N, Hayashi N, Horimoto M, Yamada T, Yamamoto M, Hiyama S, Kinoshita K, Ogiyama H, Yamaguchi S, Egawa S, Kanesaka T, Kato M, Yoshii S, Tsujii Y, Keiichiro H, Shinzaki S, Iijima H, Morii E, Takehara T. Non-Pure Intestinal Phenotype as an Indicator of Progression in Sporadic Nonampullary Duodenal Adenomas: A Multicenter Retrospective Cohort Study. Clin Transl Gastroenterol 2024; 15:e00649. [PMID: 37991249 PMCID: PMC10810609 DOI: 10.14309/ctg.0000000000000649] [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: 01/12/2023] [Accepted: 09/19/2023] [Indexed: 11/23/2023] Open
Abstract
INTRODUCTION We aimed to evaluate the natural course of sporadic nonampullary duodenal adenomas (SNDAs) and determine the risk factors of progression. METHODS We retrospectively analyzed the follow-up outcomes of patients with biopsy-diagnosed SNDA between April 2010 and March 2016 at 13 institutions. All initial biopsy specimens were centrally evaluated. Only those diagnosed with adenomas were included. Mucinous phenotypes were classified into pure intestinal and non-pure intestinal phenotypes. Cumulative incidence rates of carcinoma and tumor enlargement were evaluated. Tumor enlargement was defined as a ≥25% or 5-mm increase in tumor size. RESULTS Overall, 121 lesions were analyzed. Within a median observation period of 32.7 months, 5 lesions were diagnosed as carcinomas; the cumulative 5-year incidence of carcinoma was 9.5%. Male sex ( P = 0.046), initial lesion size ≥10 mm ( P = 0.044), and non-pure intestinal phenotype ( P = 0.019) were significantly associated with progression to carcinoma. Tumor enlargement was observed in 22 lesions, with a cumulative 5-year incidence of 33.9%. Initial lesion size ≥10 mm ( P < 0.001), erythematous lesion ( P = 0.002), high-grade adenoma ( P = 0.002), Ki67 negative ( P = 0.007), and non-pure intestinal phenotype ( P = 0.001) were risk factors of tumor enlargement. In a multivariate analysis, an initial lesion size ≥10 mm ( P = 0.010) and non-pure intestinal phenotype ( P = 0.046) were independent and significant risk factors of tumor enlargement. DISCUSSION Lesion size ≥10 mm and non-pure intestinal phenotype on initial biopsy are risk factors of cancer progression and tumor enlargement in cases with SNDA. Thus, management effectiveness may be improved by focusing on lesion size and the mucinous phenotype.
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Affiliation(s)
- Ryotaro Uema
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yoshito Hayashi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Masato Komori
- Department of Gastroenterology, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Hyogo, Japan
| | - Narihiro Shibukawa
- Department of Gastroenterology, Daini Osaka Police Hospital, Osaka, Osaka, Japan
| | - Noriko Hayashi
- Department of Gastroenterology, Nishinomiya Municipal Central Hospital, Nishinomiya, Hyogo, Japan
| | - Masayoshi Horimoto
- Department of Gastroenterology, Saiseikai Senri Hospital, Suita, Osaka, Japan
| | - Takuya Yamada
- Department of Gastroenterology, Osaka Rosai Hospital, Sakai, Osaka, Japan
| | - Masashi Yamamoto
- Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan
| | - Satoshi Hiyama
- Department of Gastroenterology, Japan Community Health Care Organization Osaka Hospital, Osaka, Osaka, Japan
| | - Kazuo Kinoshita
- Department of Gastroenterology, Otemae Hospital, Osaka, Osaka, Japan
| | - Hideharu Ogiyama
- Department of Gastroenterology, Itami City Hospital, Itami, Hyogo, Japan
| | - Shinjiro Yamaguchi
- Department of Gastroenterology, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan
| | - Satoshi Egawa
- Department of Internal Medicine, Osaka Police Hospital, Osaka, Osaka, Japan
| | - Takashi Kanesaka
- Department of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Osaka, Japan
| | - Minoru Kato
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Shunsuke Yoshii
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yoshiki Tsujii
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Honma Keiichiro
- Department of Pathology, Osaka International Cancer Institute, Osaka, Osaka, Japan
- Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
| | - Shinichiro Shinzaki
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hideki Iijima
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Internal Medicine, Osaka Police Hospital, Osaka, Osaka, Japan
| | - Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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11
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Liu HL, Peng H, Huang CH, Zhou HY, Ge J. Mutational separation and clinical outcomes of TP53 and CDH1 in gastric cancer. World J Gastrointest Surg 2023; 15:2855-2865. [PMID: 38222005 PMCID: PMC10784822 DOI: 10.4240/wjgs.v15.i12.2855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/18/2023] [Accepted: 11/21/2023] [Indexed: 12/27/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is a deadly tumor with the fifth highest occurrence and highest global mortality rates. Owing to its heterogeneity, the underlying mechanism of GC remains unclear, and chemotherapy offers little benefit to individuals. AIM To investigate the clinical outcomes of TP53 and CDH1 mutations in GC. METHODS In this study, 202 gastric adenocarcinoma tumor tissues and their corresponding normal tissues were collected. A total of 490 genes were identified using target capture. Through t-test and Wilcoxon rank-sum test, somatic mutations, microsatellite instability, and clinical statistics, including overall survival, were detected, compared, and calculated. RESULTS The mutation rates of 32 genes, including TP53, SPEN, FAT1, and CDH1 exceeded 10%. TP53 mutations had a slightly lower overall occurrence rate (33%). The TP53 mutation rate was significantly higher in advanced stages (stage III/IV) than that in early stages (stage I/II) (P < 0.05). In contrast, CDH1 mutations were significantly associated with diffuse GC. TP53 is related to poor prognosis of advanced-stage tumors; nevertheless, CDH1 corresponds to a diffuse type of cancer. TP53 is exclusively mutated in CDH1 and is primarily affected by two distinct GC mechanisms. CONCLUSION Different somatic mutation patterns in TP53 and CDH1 indicate two major mechanisms of GC.
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Affiliation(s)
- He-Li Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Huan Peng
- Clinical Nursing Teaching and Research Section, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Chang-Hao Huang
- Teaching and Research Section of Clinical Nursing, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Hai-Yan Zhou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Jie Ge
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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12
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Talari FF, Bozorg A, Zeinali S, Zali M, Mohsenifar Z, Asadzadeh Aghdaei H, Baghaei K. Low incidence of microsatellite instability in gastric cancers and its association with the clinicopathological characteristics: a comparative study. Sci Rep 2023; 13:21743. [PMID: 38065969 PMCID: PMC10709324 DOI: 10.1038/s41598-023-48157-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
Gastric cancer is a complex heterogeneous disease with different molecular subtypes that have clinical implications. It is characterized by high mortality rates and limited effective therapies. Microsatellite instability (MSI) has been recognized as a subgroup with a good prognosis based on TCGA and ACRG categorizations. Besides its prognostic and predictive value, gastric cancers with high MSI exhibit different clinical behaviors. The prevalence of high MSI has been assessed in gastric cancer worldwide, especially in East Asia, but there is a lack of such information in the Middle East. Therefore, this study aimed to investigate the incidence and status of MSI in Iranian gastric cancer patients using 53 samples collected from 2015 to 2020 at Taleghani Hospital Medical Center. DNA from tumoral and normal tissues were extracted and assessed through multiplex-PCR based on five mononucleotide repeats panel. Clinicopathological variables, including age, sex, Lauren classification, lymph node involvement, TNM stage, differentiation, localization, and tumor size, were also analyzed. With 2 males and 2 females, high microsatellite instability represented a small subgroup of almost 7.5% of the samples with a median age of 60.5 years. High microsatellite instability phenotypes were significantly associated with patients aged 68 years and older (p‑value of 0.0015) and lower lymph node involvement (p‑value of 0.0004). Microsatellite instability was also more frequent in females, with distal gastric location, bigger tumor size, and in the intestinal type of gastric cancer rather than the diffuse type.
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Affiliation(s)
| | - Ali Bozorg
- Biotechnology Department, College of Science, University of Tehran, Tehran, Iran.
| | - Sirous Zeinali
- Dr. Zeinali's Medical Genetics Laboratory, Kawsar Human Genetics Research Center, Tehran, Iran
- Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Mohammadreza Zali
- Research Institute for Gastroenterology and Liver Diseases, Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zhale Mohsenifar
- Department of Pathology, School of Medicine, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Research Institute for Gastroenterology and Liver Diseases, Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Research Institute for Gastroenterology and Liver Diseases, Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Wu H, Ma W, Jiang C, Li N, Xu X, Ding Y, Jiang H. Heterogeneity and Adjuvant Therapeutic Approaches in MSI-H/dMMR Resectable Gastric Cancer: Emerging Trends in Immunotherapy. Ann Surg Oncol 2023; 30:8572-8587. [PMID: 37667098 PMCID: PMC10625937 DOI: 10.1245/s10434-023-14103-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 07/24/2023] [Indexed: 09/06/2023]
Abstract
Gastric cancer (GC) remains one of the world's most common and fatal malignant tumors. With a refined understanding of molecular typing in recent years, microsatellite instability (MSI) has become a major molecular typing approach for gastric cancer. MSI is well recognized for its important role during the immunotherapy of advanced GC. However, its value remains unclear in resectable gastric cancer. The reported incidence of microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) in resectable gastric cancer varies widely, with no consensus reached on the value of postoperative adjuvant therapy in patients with MSI-H/dMMR resectable GC. It has been established that MSI-H/dMMR tumor cells can elicit an endogenous immune antitumor response and ubiquitously express immune checkpoint ligands such as PD-1 or PD-L1. On the basis of these considerations, MSI-H/dMMR resectable GCs are responsive to adjuvant immunotherapy, although limited research has hitherto been conducted. In this review, we comprehensively describe the differences in geographic distribution and pathological stages in patients with MSI-H/dMMR with resectable gastric cancer and explore the value of adjuvant chemotherapy and immunotherapy on MSI-H/dMMR to provide a foothold for the individualized treatment of this patient population.
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Affiliation(s)
- Hui Wu
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Wenyuan Ma
- Zhejiang University School of Medicine, Hangzhou, China
| | - Congfa Jiang
- Department of Hematology and Oncology, Ningbo Forth Hospital, Ningbo, China
| | - Ning Li
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xin Xu
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yongfeng Ding
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
| | - Haiping Jiang
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
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14
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Yamamoto G, Ito T, Suzuki O, Kamae N, Kakuta M, Takahashi A, Iuchi K, Arai T, Ishida H, Akagi K. Concordance between microsatellite instability testing and immunohistochemistry for mismatch repair proteins and efficient screening of mismatch repair deficient gastric cancer. Oncol Lett 2023; 26:494. [PMID: 37854865 PMCID: PMC10579988 DOI: 10.3892/ol.2023.14081] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/07/2023] [Indexed: 10/20/2023] Open
Abstract
Microsatellite instability (MSI) testing, an established technique that has gained prominence in recent years for its predictive potential regarding the efficacy of immune checkpoint inhibitors, is used to evaluate DNA mismatch repair (MMR) deficiency (dMMR). As with other methods, the immunohistochemistry (IHC) of MMR proteins is also widely adopted. Although both techniques have been validated, their concordance rate remains unknown, particularly regarding non-colorectal cancer. Therefore, the aim of the present study was to explore and elucidate their concordance in the context of gastric cancer (GC). A total of 489 surgically resected primary GC tissues were analyzed to compare the results yielded by the MSI test and those from IHC. Of 488 GC cases, 56 (11.5%) exhibited a loss of MMR proteins, whereas 52 (10.7%) were classified as high-frequency MSI (MSI-H). The concordance rate between these two categories was 99.2%. The microsatellite markers BAT26 and MONO27 demonstrated 100% sensitivity and 99.5% specificity in detecting dMMR GC. In addition, histopathological analysis revealed that MSI-H was more prevalent in GCs exhibiting coexisting Tub2 and Por1 subtypes. However, four discordant cases were observed. All four cases were microsatellite-stable cases but exhibited loss of MLH1 protein expression with hypermethylation of the MLH1 promoter. The results of the present study highlight that while there is a strong concordance between MSI and IHC testing results for determining dMMR status, IHC testing may offer superior efficacy in detecting dMMR.
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Affiliation(s)
- Gou Yamamoto
- Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama 362-0806, Japan
| | - Tetsuya Ito
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan
| | - Okihide Suzuki
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan
- Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan
| | - Nao Kamae
- Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan
| | - Miho Kakuta
- Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama 362-0806, Japan
| | - Akemi Takahashi
- Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama 362-0806, Japan
| | - Katsuya Iuchi
- Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama 362-0806, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan
- Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan
| | - Kiwamu Akagi
- Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama 362-0806, Japan
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15
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Zhu Y, Wang P, Wang B, Jiang Z, Li Y, Jiang J, Zhong Y, Xue L, Jiang L. Dual-layer spectral-detector CT for predicting microsatellite instability status and prognosis in locally advanced gastric cancer. Insights Imaging 2023; 14:151. [PMID: 37726599 PMCID: PMC10509117 DOI: 10.1186/s13244-023-01490-x] [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: 05/31/2023] [Accepted: 07/31/2023] [Indexed: 09/21/2023] Open
Abstract
OBJECTIVE To construct and validate a prediction model based on dual-layer detector spectral CT (DLCT) and clinico-radiologic features to predict the microsatellite instability (MSI) status of gastric cancer (GC) and to explore the relationship between the prediction results and patient prognosis. METHODS A total of 264 GC patients who underwent preoperative DLCT examination were randomly allocated into the training set (n = 187) and validation set (n = 80). Clinico-radiologic features and DLCT parameters were used to build the clinical and DLCT model through multivariate logistic regression analysis. A combined DLCT parameter (CDLCT) was constructed to predict MSI. A combined prediction model was constructed using multivariate logistic regression analysis by integrating the significant clinico-radiologic features and CDLCT. The Kaplan-Meier survival analysis was used to explore the prognostic significant of the prediction results of the combined model. RESULTS In this study, there were 70 (26.52%) MSI-high (MSI-H) GC patients. Tumor location and CT_N staging were independent risk factors for MSI-H. In the validation set, the area under the curve (AUC) of the clinical model and DLCT model for predicting MSI status was 0.721 and 0.837, respectively. The combined model achieved a high prediction efficacy in the validation set, with AUC, sensitivity, and specificity of 0.879, 78.95%, and 75.4%, respectively. Survival analysis demonstrated that the combined model could stratify GC patients according to recurrence-free survival (p = 0.010). CONCLUSION The combined model provides an efficient tool for predicting the MSI status of GC noninvasively and tumor recurrence risk stratification after surgery. CRITICAL RELEVANCE STATEMENT MSI is an important molecular subtype in gastric cancer (GC). But MSI can only be evaluated using biopsy or postoperative tumor tissues. Our study developed a combined model based on DLCT which could effectively predict MSI preoperatively. Our result also showed that the combined model could stratify patients according to recurrence-free survival. It may be valuable for clinicians in choosing appropriate treatment strategies to avoid tumor recurrence and predicting clinical prognosis in GC. KEY POINTS • Tumor location and CT_N staging were independent predictors for MSI-H in GC. • Quantitative DLCT parameters showed potential in predicting MSI status in GC. • The combined model integrating clinico-radiologic features and CDLCT could improve the predictive performance. • The prediction results could stratify the risk of tumor recurrence after surgery.
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Affiliation(s)
- Yongjian Zhu
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Peng Wang
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Bingzhi Wang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhichao Jiang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ying Li
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jun Jiang
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yuxin Zhong
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Liyan Xue
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Liming Jiang
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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16
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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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17
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Sato Y, Okamoto K, Kawano Y, Kasai A, Kawaguchi T, Sagawa T, Sogabe M, Miyamoto H, Takayama T. Novel Biomarkers of Gastric Cancer: Current Research and Future Perspectives. J Clin Med 2023; 12:4646. [PMID: 37510761 PMCID: PMC10380533 DOI: 10.3390/jcm12144646] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 07/08/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Gastric cancer is a heterogeneous disease with diverse histological and genomic subtypes, making it difficult to demonstrate treatment efficacy in clinical trials. However, recent efforts have been made to identify molecular biomarkers with prognostic and predictive implications to better understand the broad heterogeneity of gastric cancer and develop effective targeted therapies for it. HER2 overexpression, HER2/neu amplification, MSI-H, and PD-L1+ are predictive biomarkers in gastric cancer, and a growing number of clinical trials based on novel biomarkers have demonstrated the efficacy of targeted therapies alone or in combination with conventional chemotherapy. Enrichment design clinical trials of targeted therapies against FGFR2b and claudin 18.2 have demonstrated efficacy in unresectable advanced gastric cancer. Nonetheless, it is essential to continuously validate promising molecular biomarkers and introduce them into clinical practice to optimize treatment selection and improve patient outcomes. In this review, we focused on established (PD-L1, HER2, MSI) and emerging biomarkers (FGFR2, CLDN18.2) in gastric cancer, their clinical significance, detection methods, limitations, and molecular agents that target these biomarkers.
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Affiliation(s)
- Yasushi Sato
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Yutaka Kawano
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Akinari Kasai
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Tomoyuki Kawaguchi
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Tamotsu Sagawa
- Department of Gastroenterology, Hokkaido Cancer Center, Sapporo 060-0042, Japan
| | - Masahiro Sogabe
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
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18
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Wakasugi A, Sasaki A, Okamoto R, Motomura Y. Eldest gastric cancer patient with high microsatellite instability responding to pembrolizumab. Int Cancer Conf J 2023; 12:59-62. [PMID: 36605839 PMCID: PMC9807700 DOI: 10.1007/s13691-022-00581-8] [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: 06/11/2022] [Accepted: 10/01/2022] [Indexed: 11/07/2022] Open
Abstract
Pembrolizumab has been associated with a high tumor response rate among high microsatellite instability (MSI-H) cancer patients. The efficacy and safety of pembrolizumab in the treatment of MSI-H gastric cancer (GC) patients aged ≥ 85 years have not been reported. This study reports the case of an 89-year-old woman diagnosed with stage IIA MSI-H GC based on her chief complaint of abdominal pain. We considered surgery, but it was contraindicated due to the patient's age and cardiovascular comorbidity. Therefore, we administered pembrolizumab after receiving approval from the ethics committee, and no significant adverse events were noted. The tumor was markedly responsive to pembrolizumab, and the computed tomography and endoscopic findings revealed a complete response. This is the first report on the efficacy and safety of pembrolizumab in the treatment of GC in an "oldest old" patient with MSI-H.
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Affiliation(s)
- Akinobu Wakasugi
- Department of Gastroenterology, Tokyo Bay Urayasu Ichikawa Medical Center, 3-4-32 Toudaijima, Urayasu, Chiba 279-0001 Japan
- Department of Gastroenterology, Iizuka Hospital, 3-83 Yoshio-machi, Iizuka, Fukuoka 820-8505 Japan
| | - Akinori Sasaki
- Department of Gastroenterology, Tokyo Bay Urayasu Ichikawa Medical Center, 3-4-32 Toudaijima, Urayasu, Chiba 279-0001 Japan
- Department of Oncology, Tokyo Bay Urayasu Ichikawa Medical Center, 3-4-32 Toudaijima, Urayasu, Chiba 279-0001 Japan
| | - Risa Okamoto
- Department of Gastroenterology, Tokyo Bay Urayasu Ichikawa Medical Center, 3-4-32 Toudaijima, Urayasu, Chiba 279-0001 Japan
| | - Yasuaki Motomura
- Department of Gastroenterology, Tokyo Bay Urayasu Ichikawa Medical Center, 3-4-32 Toudaijima, Urayasu, Chiba 279-0001 Japan
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19
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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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20
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Fanaei K, Salahshourifar I, Ameli F, Esfandbod M, Irani S. High Frequency of Microsatellite Instability among Non-Metastatic Gastric Cancer. Int J Hematol Oncol Stem Cell Res 2022; 16:239-249. [PMID: 36883110 PMCID: PMC9985814 DOI: 10.18502/ijhoscr.v16i4.10882] [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: 06/05/2021] [Accepted: 09/12/2021] [Indexed: 11/05/2022] Open
Abstract
Background: Microsatellite instability (MSI) is considered a key factor in carcinogenesis and a genetic alteration pattern in many types of cancers such as gastric cancer (GC). Although the role of MSI in colorectal cancer (CRC) is well known, its prognostic impact on GC has not been clearly defined. The assessment of MSI in GC has not been documented in the Iranian population yet. Therefore, this study analyzed the association of MSI status with GC in Iranian patients. Materials and Methods: We compared the frequency of MSI at 5 loci from formalin-fixed paraffin-embedded (FFPE) gastrectomy specimens, between metastatic and non-metastatic cases of GC (N = 60). A panel of five quasi-monomorphic markers and a single dinucleotide marker with linker-based fluorescent primers was used. Results: MSI was observed in 46.6% of cases, including MSI-high (H) (33.3%) and MSI-Low (L) (13.3%). Moreover, the most unstable and stable markers in our study were NR-21 and BAT-26 accordingly. MSI-H and MSI were seen more frequently in non-metastatic tumors (p= 0.028 and p= 0.019, respectively). Conclusion: The current study showed MSI status more frequently in non-metastatic GC which may reflect a good prognostic factor in GC like CRC. Although, larger and more comprehensive studies are needed to confirm this statement. A panel consisting of NR-21, BAT-25, and NR-27 mononucleotide markers appears to be reliable and useful markers for detecting MSI in GC in Iranian patients.
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Affiliation(s)
- Khadijeh Fanaei
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Iman Salahshourifar
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Fereshteh Ameli
- Department of Pathology, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Esfandbod
- Department of Hematology and Oncology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Shiva Irani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
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21
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Lee SH, Lee Y, Jang H. Deep learning captures selective features for discrimination of microsatellite instability from pathologic tissue slides of gastric cancer. Int J Cancer 2022; 152:298-307. [DOI: 10.1002/ijc.34251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 08/12/2022] [Accepted: 08/15/2022] [Indexed: 12/24/2022]
Affiliation(s)
- Sung Hak Lee
- Department of Hospital Pathology Seoul St. Mary's Hospital
| | - Yujin Lee
- Department of Hospital Pathology St. Vincent's Hospital
| | - Hyun‐Jong Jang
- Catholic Big Data Integration Center, Department of Physiology, College of Medicine The Catholic University of Korea Seoul South Korea
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22
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Wang Z, Zhang Q, Qi C, Bai Y, Zhao F, Chen H, Li Z, Wang X, Chen M, Gong J, Peng Z, Zhang X, Cai J, Chen S, Zhao X, Shen L, Li J. Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer. J Immunother Cancer 2022; 10:jitc-2022-004703. [PMID: 35705314 PMCID: PMC9204428 DOI: 10.1136/jitc-2022-004703] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/19/2022] [Indexed: 12/13/2022] Open
Abstract
Background Gastrointestinal (GI) cancer is the second most common cancer type with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) phenotype that is expected to respond to immune-checkpoint inhibitors (ICIs). However, approximately half of the patients with dMMR/MSI-H GI cancer derive no benefit from ICIs. We sought to identify the predictors of primary resistance to ICIs in dMMR/MSI-H GI cancer. Methods Three independent cohorts were included: (1) the discovery cohort (65 patients with dMMR/MSI-H GI cancer) with ICI efficacy data and pre-ICIs tissue samples for genomic profile and tumor immune infiltration; (2) the validation cohort (22 patients with dMMR/MSI-H GI cancer) with ICI efficacy data and pre-ICIs plasma samples for genomic profile; and (3) the TCGA (The Cancer Genome Atlas) cohort not receiving ICIs (152 patients with MSI-H GI cancer) with genomic profile and survival data. Results AKT1 and CDH1 mutations were identified as independent predictors of poor progression-free survival (PFS) and primary resistance to ICIs in dMMR/MSI-H GI cancer. We combined these two genes as an immuno-oncology therapy predictor (IOpred), which could recognize 52.4% (11/21) of dMMR/MSI-H patients with primary resistance to ICIs with a positive predictive value (PPV) of 91.7% (11/12). Receiver operating characteristic analysis demonstrated IOpred with a good performance in predicting primary resistance (area under the curve 0.751). Patients with IOpred-Mut (mutant AKT1 or CDH1) GI cancer had significantly shorter PFS (HR=8.36, p<0.001) and overall survival (OS, HR=5.17, p<0.001) than IOpred-WT (wild-type for both AKT1 and CDH1) cases upon ICI treatment. The validation cohort also confirmed the correlation between IOpred-mutation and poorer prognosis (PFS, HR=4.68, p=0.004; OS, HR=15.98, p<0.001) in dMMR/MSI-H patients after ICIs. The PPV of IOpred in identifying primary resistance to ICIs was 80% (4/5) in the validation cohort. Additionally, IOpred-WT patients could be further stratified by tumor mutational burden (TMB), wherein TMB-low patients (TMB ≤26.19 mutations per megabase (Mb)) had a significantly higher primary resistance rate to ICIs (34.8% vs 6.7%, p=0.014) and poorer PFS (HR=3.46, p=0.008) and OS (HR=4.42, p=0.047) than TMB-high patients (TMB >26.19 mutations/Mb). Conclusions IOpred was identified as a powerful predictor of primary resistance to ICIs in dMMR/MSI-H GI cancer, which might serve as a promising biomarker to help guide immunotherapy decision-making.
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Affiliation(s)
- Zhenghang Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Qi Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Changsong Qi
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yuezong Bai
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Feilong Zhao
- Medical Affairs, 3D Medicines Inc, Shanghai, China
| | - Hui Chen
- Medical Affairs, 3D Medicines Inc, Shanghai, China
| | - Zhongwu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xicheng Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Mifen Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jifang Gong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhi Peng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaotian Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jinping Cai
- Medical Affairs, 3D Medicines Inc, Shanghai, China
| | - Shiqing Chen
- Medical Affairs, 3D Medicines Inc, Shanghai, China
| | | | - Lin Shen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jian Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
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23
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A multicenter study on the preoperative prediction of gastric cancer microsatellite instability status based on computed tomography radiomics. Abdom Radiol (NY) 2022; 47:2036-2045. [PMID: 35391567 DOI: 10.1007/s00261-022-03507-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 12/16/2022]
Abstract
PURPOSE To construct and validate a radiomics feature model based on computed tomography (CT) images and clinical characteristics to predict the microsatellite instability (MSI) status of gastric cancer patients before surgery. METHODS We retrospectively collected the upper abdominal or the entire abdominal-enhanced CT scans of 189 gastric cancer patients before surgery. The patients underwent postoperative gastric cancer MSI status testing, and the dates of their radiologic images and clinicopathological data were from January 2015 to August 2021. These 189 patients were divided into a training set (n = 90) and an external validation set (n = 99). The patients were divided by MSI status into the MSI-high (H) arm (30 and 33 patients in the training set and external validation set, respectively) and MSI-low/stable (L/S) arm (60 and 66 patients in the training set and external validation set, respectively). In the training set, the clinical characteristics and tumor radiologic characteristics of the patients were extracted, and the tenfold cross-validation method was used for internal validation of the training set. The external validation set was used to assess its generalized performance. A receiver-operating characteristic (ROC) curve was plotted to assess the model performance, and the area under the curve (AUC) was calculated. RESULTS The AUC of the radiomics model in the training set and external validation set was 0.8228 [95% confidence interval (CI) 0.7355-0.9101] and 0.7603 [95% CI 0.6625-0.8581], respectively, showing that the constructed radiomics model exhibited satisfactory generalization capabilities. The accuracy, sensitivity, and specificity of the training dataset were 0.72, 0.63, and 0.77, respectively. The accuracy, sensitivity, and specificity of the external validation dataset were 0.67, 0.79, and 0.60, respectively. Statistical analysis was carried out on the clinical data, and there was statistical significance for the tumor site and age (p < 0.05). MSI-H gastric cancer was mostly seen in the gastric antrum and older patients. CONCLUSIONS Radiomics markers based on CT images and clinical characteristics have the potential to be a non-invasive auxiliary diagnostic tool for preoperative assessment of gastric cancer MSI status, and they can aid in clinical decision-making and improve patient outcomes.
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24
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Qiu H. Genomic and Immunologic Markers of Intrinsic Resistance to Pembrolizumab Monotherapy in Microsatellite Instability-High Gastric Cancer: Observations from a Prospective Phase II Study. Glob Med Genet 2021; 9:60-62. [PMID: 35707777 PMCID: PMC9192172 DOI: 10.1055/s-0041-1736237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Affiliation(s)
- Haibo Qiu
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
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25
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Lu Z, Chen H, Li S, Gong J, Li J, Zou J, Wu L, Yu J, Han W, Sun H, Jiao X, Zhang X, Peng Z, Lu M, Wang Z, Zhang H, Shen L. Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancer. J Immunother Cancer 2021; 8:jitc-2019-000374. [PMID: 32792358 PMCID: PMC7430454 DOI: 10.1136/jitc-2019-000374] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2020] [Indexed: 12/14/2022] Open
Abstract
Background Despite the great achievements made in immune-checkpoint-blockade (ICB) in cancer therapy, there are no effective predictive biomarkers in gastrointestinal (GI) cancer. Methods This study included 93 metastatic GI patients treated with ICBs. The first cohort comprising 73 GI cancer patients were randomly assigned into discovery (n=44) and validation (n=29) cohorts. Comprehensive genomic profiling was performed on all samples to determine tumor mutational burden (TMB) and copy-number alterations (CNAs). A subset of samples was collected for RNA immune oncology (IO) panel sequencing, microsatellite instability (MSI)/mismatch repair and program death ligand 1 (PD-L1) expression evaluation. In addition, 20 gastric cancer (GC) patients were recruited as the second validation cohort. Results In the first cohort of 73 GI cancer patients, a lower burden of CNA was observed in patients with durable clinical benefit (DCB). In both the discovery (n=44) and validation (n=29) subsets, lower burden of CNA was associated with an improved clinical benefit and better overall survival (OS). Efficacy also correlated with a higher TMB. Of note, a combinatorial biomarker of TMB and CNA may better stratify DCB patients from ICB treatment, which was further confirmed in the second validation cohort of 20 GC patients. Finally, patients with lower burden of CNA revealed increased immune signatures in our cohort and The Cancer Genome Atlas data sets as well. Conclusions Our results suggest that the burden of CNA may have superior predictive value compared with other signatures, including PD-L1, MSI and TMB. The joint biomarker of CNA burden and TMB may better stratify DCB patients, thereby providing a rational choice for GI patients treated with ICBs.
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Affiliation(s)
- Zhihao Lu
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Huan Chen
- Genecast Precision Medicine Technology Institute, Beijing, China
| | - Shuang Li
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jifang Gong
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jianling Zou
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Lihong Wu
- Genecast Precision Medicine Technology Institute, Beijing, China
| | - Jianing Yu
- Genecast Precision Medicine Technology Institute, Beijing, China
| | - Wenbo Han
- Genecast Precision Medicine Technology Institute, Beijing, China
| | - Huaibo Sun
- Genecast Precision Medicine Technology Institute, Beijing, China
| | - Xi Jiao
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaotian Zhang
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ming Lu
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhenghang Wang
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Henghui Zhang
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
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26
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Siebenhüner AR, De Dosso S, Helbling D, Astaras C, Szturz P, Moosmann P, Pederiva S, Winder T, Von Burg P, Borner M. Advanced Gastric Cancer: Current Treatment Landscape and a Future Outlook for Sequential and Personalized Guide: Swiss Expert Statement Article. Oncol Res Treat 2021; 44:485-494. [PMID: 34350899 DOI: 10.1159/000518107] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 05/30/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Gastric cancer is a leading cause of cancer-related deaths worldwide. Several treatment possibilities have been investigated, but only a few show clinically meaningful results. SUMMARY Systemic treatment options for advanced gastric cancer (aGC) have evolved over the recent years, implementing the growing molecular knowledge of this heterogeneous disease. Molecular profiling (at least for HER-2-expression, microsatellite instability status, Epstein-Barr virus expression, and programmed death ligand-1 expression/combined positive score [CPS]) is recommended for all therapy-fit patients prior to the start of a systemic treatment and is crucial for decisions on treatment strategy and drug selection. Various examples like the application of trastuzumab in the HER-2-positive subgroup underline the benefits of this approach starting from the first-line setting. A combination of platinum and fluoropyrimidine remains the first-line chemotherapy backbone in the treatment of advanced gastric cancer. Triplet combinations adding taxanes to the doublet regimen are reserved for certain scenarios. Unfortunately, almost all patients who receive first-line treatment (with or without anti-HER-2 blockade) progress and <70% are eligible for a second-line therapy. The addition of monoclonal antibodies has substantially improved outcomes in this setting. As such, ramucirumab has led to significant and clinically meaningful advancements in the second-line treatment. Furthermore, immuno-oncology with checkpoint inhibition and immune stimulation has evolved in the field of aGC. Recent first-line data show a significant survival benefit in aGC patients with a CPS ≥ 5 under immunochemotherapy. Nonetheless, the impact of immunotherapy combinations and immunochemotherapy remains an area of investigation. Key Message: In this review, we highlight recent improvements in the treatment landscape of advanced gastric cancer, the heterogeneity of this disease, and possible personalized targets.
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Affiliation(s)
- Alexander R Siebenhüner
- Clinic for Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.,Cantonal Hospital Schaffhausen, Schaffhausen, Switzerland
| | - Sara De Dosso
- Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.,Università della Svizzera Italiana, Lugano, Switzerland
| | | | | | - Petr Szturz
- Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | | | | | | | | | - Markus Borner
- ONCOCARE AG Oncology Centre in the Klinik Engeried, Bern, Switzerland
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27
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Huo X, Xiao X, Zhang S, Du X, Li C, Bai Z, Chen Z. Characterization and clinical evaluation of microsatellite instability and loss of heterozygosity in tumor-related genes in gastric cancer. Oncol Lett 2021; 21:430. [PMID: 33868468 PMCID: PMC8045158 DOI: 10.3892/ol.2021.12691] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 02/10/2021] [Indexed: 12/24/2022] Open
Abstract
Microsatellite instability (MSI) detection is widely used in the diagnosis and prognosis evaluation of colorectal cancer. However, for gastric cancer (GC), there is no standard panel of microsatellites (MSs) used in clinical guidance. The present study aimed to identify useful predictors of the clinical features and for the prognosis of GC, based on an investigation of MSI and loss of heterozygosity (LOH) in tumor-related genes. First, from 20 tumor-related genes which were proven to be important to the development of GC, 91 MSs were identified, and PCR amplification, short tandem repeat scanning analysis and TA clone sequencing were used to analyze MSI and LOH in the first set of 90 GC samples. Subsequently, the same method was used to detect the MSI/LOH of the optimized loci in the second set of 136 GC samples. MSI/LOH in the mismatch repair genes was highly consistent with that in oncogenes and tumor suppressor genes, respectively. The length of the core sequence was a main factor for the MSI/LOH rate. The MSI of 12 single loci was significantly associated with lymph node metastasis. The MSI in TP53-1 and the LOH in MGMT-10 were significantly associated with early stages of tumor infiltration depth. The LOH in MGMT-10, PTN-2 and MCC-17 was significantly associated with TNM stage. The LOH in TP53-1 and ERBB2-12 was associated with adenocarcinoma. The MSI/LOH in 6 single loci of 5 tumor-related genes was associated with poor prognosis of GC. The present study demonstrated that the MSI/LOH of loci in tumor-associated genes was associated with 4 clinicopathological characteristics and outcomes of GC. These results may provide potential specific biomarkers for the clinical prediction and treatment of GC.
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Affiliation(s)
- Xueyun Huo
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China
- Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Xiaoqin Xiao
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China
- Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Shuangyue Zhang
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China
- Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Xiaoyan Du
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China
- Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Changlong Li
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China
- Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Zhigang Bai
- Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
- Department of General Surgery, National Clinical Research Center for Digestive Diseases, Beijing 100050, P.R. China
| | - Zhenwen Chen
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China
- Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
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28
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Kwon M, An M, Klempner SJ, Lee H, Kim KM, Sa JK, Cho HJ, Hong JY, Lee T, Min YW, Kim TJ, Min BH, Park WY, Kang WK, Kim KT, Kim ST, Lee J. Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability-High Gastric Cancer. Cancer Discov 2021; 11:2168-2185. [PMID: 33846173 DOI: 10.1158/2159-8290.cd-21-0219] [Citation(s) in RCA: 141] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/28/2021] [Accepted: 04/08/2021] [Indexed: 11/16/2022]
Abstract
Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers and associated with clinical response to anti-PD-1 antibodies. However, 50% of microsatellite instability-high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in patients with advanced MSI-H gastric cancer and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)-derived nonsynonymous mutations correlated with antitumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on-treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. In addition, an increase in PD-1+ CD8+ T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H gastric cancer and may inform development of strategies to enhance responsiveness. SIGNIFICANCE: This study highlights response heterogeneity within MSI-H gastric cancer treated with pembrolizumab monotherapy and underscores the potential for extended baseline and early on-treatment biomarker analyses to identify responders. The observed markers of intrinsic resistance have implications for patient stratification to inform novel combinations among patients with intrinsically resistant features.See related commentary by Fontana and Smyth, p. 2126.This article is highlighted in the In This Issue feature, p. 2113.
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Affiliation(s)
- Minsuk Kwon
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Minae An
- Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Korea
| | - Samuel J Klempner
- Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Hyuk Lee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jason K Sa
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea
| | - Hee Jin Cho
- Innovative Institute for Precision Medicine, Samsung Medical Center, Seoul, Korea
| | - Jung Yong Hong
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Taehyang Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yang Won Min
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Jun Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byung-Hoon Min
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Woong-Yang Park
- Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyu-Tae Kim
- Department of Physiology, Ajou University School of Medicine, Suwon, Korea.
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. .,Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, Korea
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29
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Ghidini M, Petrillo A, Botticelli A, Trapani D, Parisi A, La Salvia A, Sajjadi E, Piciotti R, Fusco N, Khakoo S. How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches. J Clin Med 2021; 10:1412. [PMID: 33915839 PMCID: PMC8037391 DOI: 10.3390/jcm10071412] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/17/2021] [Accepted: 03/22/2021] [Indexed: 02/07/2023] Open
Abstract
Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease.
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Affiliation(s)
- Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | | | - Andrea Botticelli
- Department of Clinical and Molecular Medicine, Sapienza University, 00189 Rome, Italy;
- Medical Oncology (B), Policlinico Umberto I, 00161 Rome, Italy
| | - Dario Trapani
- Division of Early Drug Development for innovative therapies, European Institute of Oncology, IRCCS, 20141 Milan, Italy;
| | - Alessandro Parisi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy;
- Medical Oncology Unit, St. Salvatore Hospital, 67100 L’Aquila, Italy
| | - Anna La Salvia
- Department of Oncology, University Hospital 12 De Octubre, 28041 Madrid, Spain;
| | - Elham Sajjadi
- Division of Pathology, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (E.S.); (R.P.); (N.F.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Roberto Piciotti
- Division of Pathology, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (E.S.); (R.P.); (N.F.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Nicola Fusco
- Division of Pathology, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (E.S.); (R.P.); (N.F.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Shelize Khakoo
- Department of Medicine, Royal Marsden Hospital, London and Surrey, Sutton SM25PT, UK;
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30
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Cai Z, Song H, Fingerhut A, Sun J, Ma J, Zhang L, Li S, Yu C, Zheng M, Zang L. A greater lymph node yield is required during pathological examination in microsatellite instability-high gastric cancer. BMC Cancer 2021; 21:319. [PMID: 33765970 PMCID: PMC7992823 DOI: 10.1186/s12885-021-08044-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 03/15/2021] [Indexed: 02/06/2023] Open
Abstract
Background The impact of microsatellite status on lymph node (LN) yield during lymphadenectomy and pathological examination has never been assessed in gastric cancer (GC). In this study, we aimed to appraise the association between microsatellite instability-high (MSI-H) and LN yield after curative gastrectomy. Methods We retrospectively analyzed 1757 patients with GC undergoing curative gastrectomy and divided them into two groups: MSI-H (n = 185(10.5%)) and microsatellite stability (MSS) (n = 1572(89.5%)), using a five-Bethesda-marker (NR-24, BAT-25, BAT-26, CAT-25, MONO-27) panel. The median LN count and the percentage of specimens with a minimum of 16 LNs (adequate LN ratio) were compared between the two groups. The log odds (LODDS) of positive LN count (PLNC) to negative LN count (NLNC) and the target LN examined threshold (TLNT(x%)) were calculated in both groups. Results Statistically significant differences were found in the median LN count between MSI-H and MSS groups for the complete cohort (30 vs. 28, p = 0.031), for patients undergoing distal gastrectomy (DG) (30 vs. 27, p = 0.002), for stage II patients undergoing DG (34 vs. 28, p = 0.005), and for LN-negative patients undergoing DG (28 vs. 24, p = 0.002). MSI-H was an independent factor for higher total LN count in patients undergoing DG (p = 0.011), but it was not statistically correlated to the adequate LN ratio. Statistically significant differences in PLNC, NLNC and LODDS were found between MSI-H GC and MSS GC (all p < 0.001). The TLNT(90%) for MSI-H and MSS groups were 31 and 25, respectively. TLNT(X%) of MSI-H GC was always higher than that of MSS GC regardless of the given value of X%. Conclusions MSI-H was associated with higher LN yield in patients undergoing gastrectomy for GC. Although MSI-H did not affect the adequacy of LN harvest, we speculate that a greater lymph node yield is required during pathological examination in MSI-H GC.
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Affiliation(s)
- Zhenghao Cai
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, P. R. China.,Shanghai Minimally Invasive Surgery Center, Shanghai, P. R. China
| | - Haiqin Song
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, P. R. China.,Shanghai Minimally Invasive Surgery Center, Shanghai, P. R. China
| | - Abe Fingerhut
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, P. R. China.,Shanghai Minimally Invasive Surgery Center, Shanghai, P. R. China.,Section for Surgical Research, Department of Surgery, Medical University of Graz, Auenbruggerplatz 29, 8036, Graz, Austria
| | - Jing Sun
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, P. R. China.,Shanghai Minimally Invasive Surgery Center, Shanghai, P. R. China
| | - Junjun Ma
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, P. R. China.,Shanghai Minimally Invasive Surgery Center, Shanghai, P. R. China
| | - Luyang Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, P. R. China.,Shanghai Minimally Invasive Surgery Center, Shanghai, P. R. China
| | - Shuchun Li
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, P. R. China.,Shanghai Minimally Invasive Surgery Center, Shanghai, P. R. China
| | - Chaoran Yu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, P. R. China.,Shanghai Minimally Invasive Surgery Center, Shanghai, P. R. China
| | - Minhua Zheng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, P. R. China. .,Shanghai Minimally Invasive Surgery Center, Shanghai, P. R. China.
| | - Lu Zang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, P. R. China. .,Shanghai Minimally Invasive Surgery Center, Shanghai, P. R. China.
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31
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Cai Z, Ma J, Li S, Fingerhut A, Sun J, Zang L, Yan C, Liu W, Zhu Z, Zheng M. Impact of microsatellite status on negative lymph node count and prognostic relevance after curative gastrectomy. J Surg Oncol 2021; 123 Suppl 1:S15-S24. [PMID: 33650696 DOI: 10.1002/jso.26325] [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: 11/20/2020] [Accepted: 11/22/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND OBJECTIVES The impact of microsatellite instability-high (MSI-H) phenotype on lymph node yield after lymphadenectomy has never been discussed in gastric cancer (GC). In this study, we aimed to assess the association of microsatellite status with negative lymph node count (NLNC) as well as its prognostic value. METHODS We retrospectively analyzed 1491 GC patients and divided them into two groups: MSI-HGC (n = 141 [9.5%]) and microsatellite stability (MSSGC ) (n = 1350 [90.5%]). The NLNC and survival data were compared between the two groups. The log odds of positive lymph nodes (LNs) to negative LNs and the target lymph node examined threshold (TLNT) were calculated in both groups. RESULTS A statistically significant difference was found in median NLNC (26 vs. 23, p < .001) between MSI-HGC and MSSGC patients. MSI status was an independent factor for NLNC (p < .001). NLNC showed positive prognostic value for cases with metastatic lymph node (LN+ ) in both MSI-HGC and MSSGC groups. The TLNT(90%) for MSI-HGC and MSSGC were 33 and 26, respectively. CONCLUSIONS MSI-HGC was associated with higher NLNC in GC patients and this was independent of the presence of LN+ . However, more LNs are needed during pathological examination to capture LN+ cases in MSI-HGC.
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Affiliation(s)
- Zhenghao Cai
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Shanghai, China
| | - Junjun Ma
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Shanghai, China
| | - Shuchun Li
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Shanghai, China
| | - Abe Fingerhut
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Shanghai, China.,Department of Surgery, Section for Surgical Research, Medical University of Graz, Graz, Austria
| | - Jing Sun
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Shanghai, China
| | - Lu Zang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Shanghai, China
| | - Chao Yan
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wentao Liu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenggang Zhu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Minhua Zheng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Shanghai, China
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Puliga E, Corso S, Pietrantonio F, Giordano S. Microsatellite instability in Gastric Cancer: Between lights and shadows. Cancer Treat Rev 2021; 95:102175. [PMID: 33721595 DOI: 10.1016/j.ctrv.2021.102175] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 12/11/2022]
Abstract
Gastric cancer (GC) represents an important contributor to the global burden of cancer, being one of the most common and deadly malignancies worldwide. According to TCGA and ACRG classifications, the microsatellite instable (MSI) group represents a significant subset of GCs and is currently in the limelight of many researches due to its favorable survival outcome in resectable stages compared to microsatellite stable tumors. MSI GCs hypermutated phenotype triggers immunosurveillance, making this molecular subgroup a promising candidate for immune checkpoint inhibitors treatment. Conversely, conflicting outcomes have been reported in chemotherapy settings. Due to the clinical relevance of these observations, in this review we report and discuss the molecular, pathological, prognostic, and predictive features of MSI gastric tumors.
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Affiliation(s)
- Elisabetta Puliga
- Department of Oncology, University of Torino, Candiolo, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
| | - Simona Corso
- Department of Oncology, University of Torino, Candiolo, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Silvia Giordano
- Department of Oncology, University of Torino, Candiolo, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
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Wei XL, Xu JY, Wang DS, Chen DL, Ren C, Li JN, Wang F, Wang FH, Xu RH. Baseline lesion number as an efficacy predictive and independent prognostic factor and its joint utility with TMB for PD-1 inhibitor treatment in advanced gastric cancer. Ther Adv Med Oncol 2021; 13:1758835921988996. [PMID: 33613701 PMCID: PMC7871293 DOI: 10.1177/1758835921988996] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 12/22/2020] [Indexed: 12/20/2022] Open
Abstract
Background We previously reported tumor mutation burden (TMB) as a potential prognostic factor for patients with advanced gastric cancer (AGC) receiving immunotherapy. We aimed to comprehensively understand the impact of tumor burden and TMB on efficacy and prognosis in immunotherapy-treated AGC patients. Methods A total of 58 patients with refractory AGC receiving PD-1 inhibitor monotherapy from a phase Ib/II clinical trial (ClinicalTrials.gov identifier: NCT02915432) were retrospectively included. Univariate and multivariate logistical regression analyses and the Cox proportional hazards model were performed for prognostic value of baseline factors. Factors reflecting baseline tumor burden, including baseline lesion number (BLN), the maximum tumor size (MTS) and the sum of target lesion size (SLS) were analyzed. The objective response rate (ORR) and disease control rate (DCR) were compared by Chi-square test. Results In univariate analysis, high BLN was associated with poor median progression-free survival (mPFS) [1.7 months versus 3.4 months; hazard ratio (HR), 2.696, p < 0.05] and median overall survival (mOS) (3.2 months versus 7.6 months; HR, 1.997, p < 0.05), while high TMB was a positive prognostic factor. In multivariable analysis, both BLN and TMB were independent prognostic factors for mOS (BLN: HR, 2.782, p < 0.05; TMB: HR, 0.288, p < 0.05), while MTS or SLS had no association with survival. Better ORR and DCR were observed in the low BLN group (15.4% versus 5.3%, p > 0.05; 86.96% versus 54.29%, p < 0.05). When combining BLN and TMB, the best efficacy and survival were observed in the BLNlowTMBhigh group (ORR: 37.5%, DCR: 62.5%, mPFS and mOS: not reached). The worst efficacy and survival were shown in the BNLhighTMBlow group [ORR: 0% (0/15); DCR: 13.3%; mPFS: 1.7 months; mOS: 2.7 months (all p < 0.05)]. Conclusions BLN, rather than factors regarding baseline tumor size, is perhaps a potential predictor for benefit from immunotherapy and its combination with TMB could further risk-stratify patients with AGC receiving immunotherapy.
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Affiliation(s)
- Xiao-Li Wei
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jian-Ying Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - De-Shen Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Dong-Liang Chen
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chao Ren
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jia-Ning Li
- Department of Clinical Trial Center, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Feng Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, Guangdong Province 510060, China
| | - Feng-Hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, Guangdong Province 510060, China
| | - Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, Guangdong Province 510060, China
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Zhao C, Feng Z, He H, Zang D, Du H, Huang H, Du Y, He J, Zhou Y, Nie Y. Protein expression-based classification of gastric cancer by immunohistochemistry of tissue microarray. PLoS One 2020; 15:e0238836. [PMID: 33095797 PMCID: PMC7584200 DOI: 10.1371/journal.pone.0238836] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 08/25/2020] [Indexed: 12/21/2022] Open
Abstract
Recently, the Cancer Genome Atlas and Asian Cancer Research Group propose two new classifications system of gastric cancer by using multi-platforms of molecular analyses. However, these highly complicated and cost technologies have not yet been translated into full clinical utility. In addition, the clinicians are expected to gain more guidance of treatment for different molecular subtypes. In this study, we developed a panel of gastric cancer patients in population from Southern China using commercially accessible TMA and immunohistochemical technology. A cohort of 259 GC patients was classified into 4 subtypes on the basis of expression of mismatch repair proteins (PMS2, MLH1, MSH2, and MSH6), E-cadherin and p21 protein. We observed that the subtypes presented distinct prognosis. dMMR-like subtype was associated with the best prognosis, and E-cadherin-a subtype was associated with the worst prognosis. Patients with p21-High and p21-Ligh subtypes had intermediate overall survival. In multivariate analysis, the dMMR-like subtype remained an independent prediction power for overall survival in the model. We described a molecular classification of gastric cancers using clinically applicable assay. The biological relevance of the four subtypes was illustrated by significant differences in prognosis. Our molecular classification provided an effective and inexpensive screening tool for improving prognostic models. Nevertheless, our study should be considered preliminary and carries a limited predictive value as a single-center retrospective study.
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Affiliation(s)
- Chong Zhao
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zhiqiang Feng
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Hongzhen He
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Dan Zang
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Hong Du
- Department of Pathology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
| | - Hongli Huang
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yanlei Du
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jie He
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yongjian Zhou
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
- * E-mail: (YN); (YZ)
| | - Yuqiang Nie
- Department of Gastroenterology, Guangzhou First People’s Hospital, Medical School, South China University of Technology, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
- * E-mail: (YN); (YZ)
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Clinicopathologic Characteristics and Long-Term Outcome of Gastric Cancer Patients with Family History: Seven-Year Follow-Up Study for Korean Health Check-Up Subjects. Gastroenterol Res Pract 2020; 2020:4028136. [PMID: 33144855 PMCID: PMC7599414 DOI: 10.1155/2020/4028136] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 08/27/2020] [Accepted: 09/29/2020] [Indexed: 12/24/2022] Open
Abstract
Methods This study was conducted on asymptomatic healthy individuals who underwent upper gastrointestinal endoscopy for the purpose of GC screening. Patients who were diagnosed with GC between October 2003 and December 2013 at Seoul National University Hospital Healthcare System Gangnam Center were identified. Demographic and clinicopathologic characteristics were compared between the groups with and without FHx of GC. Overall survival (OS) and recurrence-free survival (RFS) were assessed as primary outcomes. Results There were no significant differences in tumor characteristics according to FHx of GC. However, preexisting adenoma was more frequent in patients with FHx than in those without FHx (14.5% vs. 6.3%, p = 0.035). The proportion of patients with microsatellite instability (MSI) was also higher in groups with FHx of GC (43.2% vs. 13.2%, p = 0.006). Helicobacter pylori infection rates of patients with FHx of GC tended to be higher although not significant (70.5% vs. 61.3%, p = 0.188). However, OS and RFS at 5 years of the GC patients with FHx were not significantly different from those of patients without FHx. Conclusion Preexisting adenoma and GC with MSI are more common in patients with FHx of GC than in those without. There were no significant differences in the survival rate according to FHx.
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De Souza ALPB. Finding the hot spot: identifying immune sensitive gastrointestinal tumors. Transl Gastroenterol Hepatol 2020; 5:48. [PMID: 33073043 DOI: 10.21037/tgh.2019.12.11] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 12/06/2019] [Indexed: 12/16/2022] Open
Abstract
Although researchers have been trying to harness the immune system for over 100 years, the advent of immune checkpoint blockers (ICB) marks an era of significant clinical outcomes in various metastatic solid tumors, characterized by complete and durable responses. ICBs are monoclonal antibodies that target either of a pair of transmembrane molecules in tumors or T-cells involved in immune evasion. Currently 2 ICBs targeting the checkpoint program death 1 (PD-1), nivolumab and pembrolizumab, and one cytotoxic lymphocyte antigen-4 (CTLA-4) inhibitor (ipilimumab) are approved in gastrointestinal malignancies. We review herein the current evidence on predictive biomarkers for ICB response in gastrointestinal tumors. A review of literature based on the National Cancer Institute list of FDA-approved drugs for neoplasms and FDA-approved therapies at the FDA website was performed. An initial literature review was based on the American Association for Clinical Research meeting 2019, the American Society of Clinical Oncology meeting 2019 and the European Society of Medical Oncology 2019 proceedings. A systematic search of PubMed was performed involving MeSH browser terms such as biomarkers, immunotherapy, gastrointestinal diseases and neoplasms. When appropriate, American and British terms were used in the search. The most relevant predictor of response to ICBs is microsatellite instability (MSI) and the data is strongest for colorectal cancer. At least 3 prospective trials show evidence of PD-L1 as a predictive biomarker for ICB response in gastroesophageal malignancies. At least one prospective trial has described tumor mutational burden high (TMB-H), independent of MSI, as predictive of response in anal and biliary tract carcinomas. DNA Polymerase Epsilon (POLE) or delta (POL-D) mutations have been implicated in a subset of MSS colorectal cancer with TMB-H but this biomarker requires prospective validation. There is evolving data based on retrospective observations that gene alterations predicting acquired resistance and hyper-progression. Ongoing clinical research is assessing the role of the human microbiome and RNA-editing complex mutations as predictive biomarkers of response to ICBs. MSI has the strongest predictive power among current biomarkers for ICB response in gastrointestinal cancers. Data continue to accumulate from ongoing clinical trials and new biomarkers are emerging from pre-clinical studies, suggesting that drug combinations targeting pathways complimentary to the PD-1/PD-L1 axis inhibition will define a robust field of clinical research.
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Fraune C, Burandt E, Simon R, Hube-Magg C, Makrypidi-Fraune G, Kluth M, Büscheck F, Höflmayer D, Blessin NC, Mandelkow T, Li W, Perez D, Izbicki JR, Wilczak W, Sauter G, Schrader J, Neipp M, Mofid H, Daniels T, Isbert C, Clauditz TS, Steurer S. MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes. Ann Surg Oncol 2020; 27:3997-4006. [PMID: 32108923 PMCID: PMC7471097 DOI: 10.1245/s10434-020-08209-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Microsatellite instability (MSI) has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in pancreatic cancer, but data on the possible extent of intratumoral heterogeneity are lacking. METHODS To study MSI heterogeneity in pancreatic cancer, a tissue microarray (TMA) comprising 597 tumors was screened by immunohistochemistry with antibodies for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. RESULTS In six suspicious cases, large section immunohistochemistry and microsatellite analysis (Bethesda panel) resulted in the identification of 4 (0.8%) validated MSI cases out of 480 interpretable pancreatic ductal adenocarcinomas. MSI was absent in 55 adenocarcinomas of the ampulla of Vater and 7 acinar cell carcinomas. MMR deficiency always involved MSH6 loss, in three cases with additional loss of MSH2 expression. Three cancers were MSI-high and one case with isolated MSH6 loss was MSS in PCR analysis. The analysis of 44 cancer-containing tumor blocks revealed that the loss of MMR protein expression was always homogeneous in affected tumors. Automated digital image analysis of CD8 immunostaining demonstrated markedly higher CD8 + tumor infiltrating lymphocytes in tumors with (mean = 685, median = 626) than without (mean = 227; median = 124) MMR deficiency (p < 0.0001), suggesting a role of MSI for immune response. CONCLUSIONS Our data suggest that MSI occurs early in a small subset of ductal adenocarcinomas of the pancreas and that immunohistochemical MMR analysis on limited biopsy or cytology material may be sufficient to estimate MMR status of the entire cancer mass.
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Affiliation(s)
- Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Doris Höflmayer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Niclas Ch Blessin
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tim Mandelkow
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Wenchao Li
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Daniel Perez
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R Izbicki
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Waldemar Wilczak
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jörg Schrader
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- I. Medical Department - Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Neipp
- General, Vascular and Visceral Surgery Clinic, Itzehoe Medical Center, Itzehoe, Germany
| | - Hamid Mofid
- General, Visceral Thoracic and Vascular Surgery Clinic, Regio Clinic Pinneberg, Pinneberg, Germany
| | - Thies Daniels
- General, Visceral and Tumor Sugery Clinic, Albertinen Hospital, Hamburg, Germany
| | - Christoph Isbert
- Department of General, Gastrointestinal and Colorectal Surgery, Amalie Sieveking Hospital, Hamburg, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Harvey JB, Phan LH, Villarreal OE, Bowser JL. CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers. Front Immunol 2020; 11:508. [PMID: 32351498 PMCID: PMC7174602 DOI: 10.3389/fimmu.2020.00508] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 03/05/2020] [Indexed: 02/06/2023] Open
Abstract
CD73, a cell surface 5'nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.
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Affiliation(s)
- Jerry B. Harvey
- Department of Anesthesiology, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Luan H. Phan
- Department of Anesthesiology, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Oscar E. Villarreal
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jessica L. Bowser
- Department of Anesthesiology, The University of Texas Health Science Center at Houston, Houston, TX, United States
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39
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Fraune C, Simon R, Hube-Magg C, Makrypidi-Fraune G, Kähler C, Kluth M, Höflmayer D, Büscheck F, Dum D, Luebke AM, Burandt E, Clauditz TS, Wilczak W, Sauter G, Steurer S. MMR deficiency in urothelial carcinoma of the bladder presents with temporal and spatial homogeneity throughout the tumor mass. Urol Oncol 2020; 38:488-495. [PMID: 32067846 DOI: 10.1016/j.urolonc.2019.12.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 12/06/2019] [Accepted: 12/10/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Microsatellite instability (MSI), a hypermutator phenotype described in many cancers, has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in bladder cancer, but data on the possible extent of intratumoral heterogeneity are lacking. METHODS To study MSI heterogeneity in bladder cancer, a tissue microarray (TMA) comprising 598 muscle-invasive urothelial carcinomas of the bladder was utilized to screen for MSI by immunhistochemistry with antibodies for MLH1, PMS2, MSH2, and MSH6. RESULTS In 9 cases suspicious for MSI, MMR status was further evaluated by large section examination and polymerase chain reaction (PCR)-based analysis of microsatellites ("Bethesda panel") resulting in the identification of 5 validated MSI cases from 448 interpretable cancers (prevalence 1.1%). MMR deficiency always involved PMS2 loss, in 3 cases with additional loss or reduction of MLH1 expression. Four cancers were MSI-high and 1 was MSI-low in the PCR analysis. Parallel sequencing revealed an inactivating MLH1 mutation in 1 tumor but no further known pathogenic MMR gene mutations were found. Immunostaining of all available 72 cancer-containing tissue blocks of the 5 confirmed bladder cancer with MSI including prior and subsequent biopsies showed complete homogeneity of the MMR protein defects and the status of the 4 MMR proteins did not markedly change in sequential resections. In all 4 cases with noninvasive precursor lesions, MSI was also detectable. CONCLUSION These data suggest that MSI occurs early in invasive bladder cancer and immunohistochemical MMR analysis on limited biopsy material is sufficient to estimate MMR status of the entire cancer mass.
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Affiliation(s)
- Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Christian Kähler
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Doris Höflmayer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David Dum
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas M Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Waldemar Wilczak
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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40
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Martinson HA, Mallari D, Richter C, Wu TT, Tiesinga J, Alberts SR, Olnes MJ. Molecular Classification of Gastric Cancer among Alaska Native People. Cancers (Basel) 2020; 12:cancers12010198. [PMID: 31941061 PMCID: PMC7016562 DOI: 10.3390/cancers12010198] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 12/13/2019] [Accepted: 01/07/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is an aggressive and heterogeneous malignancy that often varies in presentation and disease among racial and ethnic groups. The Alaska Native (AN) people have the highest incidence and mortality rates of gastric cancer in North America. This study examines molecular markers in solid tumor samples from eighty-five AN gastric adenocarcinoma patients using next-generation sequencing, immunohistochemistry, and in situ hybridization analysis. AN patients have a low mutation burden with fewer somatic gene mutations in their tumors compared to other populations, with the most common mutation being TP53. Epstein-Barr virus (EBV) was associated with 20% of AN gastric cancers, which is higher than the world average of 10%. The inflammation marker, cyclooxygenase-2 (COX-2), is highly expressed in patients with the lowest survival rates. Mismatch repair deficiency was present in 10% of AN patients and was associated with patients who were female, 50 years or older, gene mutations, and tumors in the distal stomach. Program death-ligand 1 (PD-L1) was expressed in 14% of AN patients who were more likely to have MMR deficiency, EBV-associated gastric cancers, and mutations in the PIK3CA gene, all of which have been linked to clinical response to PD-1 inhibitors. These studies suggest a portion of AN gastric cancer patients could be candidates for immunotherapy. Overall, this study highlights future avenues of investigation for clinical and translational studies, so that we can improve early detection and develop more effective treatments for AN patients.
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Affiliation(s)
- Holly A. Martinson
- WWAMI School of Medical Education, University of Alaska Anchorage, 3211 Providence Drive, Anchorage, AK 99508, USA
- Correspondence: ; Tel.: +1-907-786-4672
| | - Dominic Mallari
- Department of Chemistry, University of Alaska Anchorage, 3211 Providence Drive, Anchorage, AK 99508, USA;
| | - Christine Richter
- Department of Biological Sciences, University of Alaska Anchorage, 3211 Providence Drive, Anchorage, AK 99508, USA;
| | - Tsung-Teh Wu
- Department of Laboratory Medicine and Pathology, Mayo Clinic Cancer Center, 200 First Street SW, Rochester, MN 55905, USA;
| | - James Tiesinga
- Department of Pathology and Clinical Laboratory, Alaska Native Medical Center, 4315 Diplomacy Drive, Anchorage, AK 99508, USA;
| | - Steven R. Alberts
- Medical Oncology, Mayo Clinic Cancer Center, 200 First Street SW, Rochester, MN 55905, USA;
| | - Matthew J. Olnes
- Oncology and Hematology, Alaska Native Medical Center, 4315 Diplomacy Drive, Anchorage, AK 99508, USA;
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High homogeneity of MMR deficiency in ovarian cancer. Gynecol Oncol 2020; 156:669-675. [PMID: 31924330 DOI: 10.1016/j.ygyno.2019.12.031] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 12/19/2019] [Accepted: 12/23/2019] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Mismatch repair (MMR) deficiency and Bethesda panel microsatellite instability (MSI) are increasingly analyzed to identify tumors that might benefit from immune checkpoint inhibitors, but tumor heterogeneity is a potential obstacle for such analyses. In ovarian cancer, data on intratumoral heterogeneity of MMR deficiency/MSI are lacking. METHODS N = 582 ovarian cancers were screened for MMR deficiency by immunohistochemistry (IHC) on a tissue microarray. 10 cases suspect for MMR deficiency were identified among 478 interpretable cancers and repeated IHC on large sections combined with polymerase chain reaction (PCR)-based MSI analysis validated MMR deficiency/MSI in 9 of these tumors. RESULTS MMR deficiency/MSI was predominantly seen in endmetrioid cancers (8 of 35, 23%) and also in 1 of 358 serous carcinomas (0.3%), but was absent in 34 mucinous carcinomas, 23 clear cell carcinomas, 17 malignant mixed Mullerian tumors (carcinosarcomas), and 11 mixed carcinomas. MMR deficiency involed protein loss of PMS2/MLH1 in 6 cases and of MSH2 and/or MSH6 in 3 cases. 7 MMR deficient cancers were MSI-high (all endometrioid), one was MSI-low (endometrioid) and one cancer with unequivocal MMR protein loss exhibited microsatellite stability (serous). MLH1 promotor methylation was observed in 4 of 5 endometrioid cancers with MLH1 protein loss. Immunostaining of all available cancer-containing tissue blocks (n = 114) of tumors with confirmed MMR deficiency/MSI revealed uniform MMR status throughout the entire tumor mass. CONCLUSIONS Our data show that MSI is present in a substantial proportion of endometrioid ovarian cancers but can also occur in other tumor subtypes. MMR deficiency/MSI typically involves the entire tumor mass, suggesting that MMR inactivation occurs early in tumorigenesis in a subset of ovarian cancers.
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High homogeneity of mismatch repair deficiency in advanced prostate cancer. Virchows Arch 2019; 476:745-752. [PMID: 31811435 DOI: 10.1007/s00428-019-02701-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/07/2019] [Accepted: 10/16/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND Recent reports have described favorable response rates for immune checkpoint inhibitors in prostate cancers with microsatellite instability (MSI). However, it is unclear whether MSI affects the entire tumor mass or is distributed heterogeneously, the latter potentially impairing treatment efficiency. METHODS To identify prostate cancers with MSI, 316 advanced prostate cancers were analyzed by immunohistochemistry (IHC) for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6 on a TMA format. RESULTS Out of 200 interpretable cancers, IHC findings were consistent with MSI in 10 tumors. In 9 of these 10 cancers, tissue blocks were available for subsequent large section IHC, confirming MSI in 6 cases, each with combined protein loss of MSH2 and MSH6. One additional tumor with unequivocal loss of MLH1 and PMS2 on the TMA, for which further analyses could not be carried out due to lack of tissue, was also considered to exhibit MSI. In total, 7 of 200 interpretable advanced prostate cancers were found to exhibit MMR deficiency/MSI (3.5%). Subsequent analysis of all available cancer-containing archived tissue blocks (n=114) revealed consistent and homogeneous MMR protein loss in each case. Polymerase chain reaction (PCR)-based analysis using the "Bethesda panel" could be executed in 6 MMR deficient tumors of which 4 were MSI-high and 2 were MSI-low. CONCLUSIONS The absence of intratumoral heterogeneity for the MMR status suggests that MSI occurs early in prostate cancer. It is concluded that MMR analysis on limited biopsy material by IHC is sufficient to estimate the MMR status of the entire cancer mass.
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Cavaliere A, Merz V, Casalino S, Zecchetto C, Simionato F, Salt HL, Contarelli S, Santoro R, Melisi D. Novel Biomarkers for Prediction of Response to Preoperative Systemic Therapies in Gastric Cancer. J Gastric Cancer 2019; 19:375-392. [PMID: 31897341 PMCID: PMC6928085 DOI: 10.5230/jgc.2019.19.e39] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/02/2019] [Accepted: 09/17/2019] [Indexed: 12/13/2022] Open
Abstract
Preoperative chemo- and radiotherapeutic strategies followed by surgery are currently a standard approach for treating locally advanced gastric and esophagogastric junction cancer in Western countries. However, in a large number of cases, the tumor is extremely resistant to these treatments and the patients are exposed to unnecessary toxicity and delayed surgical therapy. The current clinical trials evaluating the combination of preoperative systemic therapies with modern targeted and immunotherapeutic agents represent a unique opportunity for identifying predictive biomarkers of response to select patients that would benefit the most from these treatments. However, it is of utmost importance that these potential biomarkers are corroborated by extensive preclinical and translational research. The aim of this review article is to present the most promising biomarkers of response to classic chemotherapeutic, anti-HER2, antiangiogenic, and immunotherapeutic agents that can be potentially useful for personalized preoperative systemic therapies in gastric cancer patients.
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Affiliation(s)
- Alessandro Cavaliere
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Valeria Merz
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Simona Casalino
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Camilla Zecchetto
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Francesca Simionato
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Hayley Louise Salt
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, Verona, Italy
| | - Serena Contarelli
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, Verona, Italy
| | - Raffaela Santoro
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, Verona, Italy
| | - Davide Melisi
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
- Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, Verona, Italy
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Kwak Y, Seo AN, Lee HE, Lee HS. Tumor immune response and immunotherapy in gastric cancer. J Pathol Transl Med 2019; 54:20-33. [PMID: 31674166 PMCID: PMC6986974 DOI: 10.4132/jptm.2019.10.08] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 10/08/2019] [Indexed: 02/07/2023] Open
Abstract
Remarkable developments in immuno-oncology have changed the landscape of gastric cancer (GC) treatment. Because immunotherapy intervenes with tumor immune response rather than directly targeting tumor cells, it is important to develop a greater understanding of tumor immunity. This review paper summarizes the tumor immune reaction and immune escape mechanisms while focusing on the role of T cells and their co-inhibitory signals, such as the immune checkpoint molecules programmed death-1 and programmed deathligand 1 (PD-L1). This paper also describes past clinical trials of immunotherapy for patients with GC and details their clinical implications. Strong predictive markers are essential to improve response to immunotherapy. Microsatellite instability, Epstein-Barr virus, PD-L1 expression, and tumor mutational burden are now regarded as potent predictive markers for immunotherapy in patients with GC. Novel immunotherapy and combination therapy targeting new immune checkpoint molecules such as lymphocyte-activation gene 3, T cell immunoglobulin, and mucin domain containing-3, and indoleamine 2,3-dioxygenase have been suggested, and trials are ongoing to evaluate their safety and efficacy. Immunotherapy is an important treatment option for patients with GC and has great potential for improving patient outcome, and further research in immuno-oncology should be carried out.
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Affiliation(s)
- Yoonjin Kwak
- Department of Pathology, Seoul National University Hospital, Seoul, Korea.,Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - Hee Eun Lee
- Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Hye Seung Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
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Brar G, Shah MA. The role of pembrolizumab in the treatment of PD-L1 expressing gastric and gastroesophageal junction adenocarcinoma. Therap Adv Gastroenterol 2019; 12:1756284819869767. [PMID: 31516556 PMCID: PMC6724489 DOI: 10.1177/1756284819869767] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 07/22/2019] [Indexed: 02/04/2023] Open
Abstract
Gastric cancer is a leading cause of cancer-related death worldwide. Recent evidence suggests that gastric cancer is a complex and heterogenous disease with emerging subtypes shown to affect response to treatment and survival. Immunotherapy is an advancing field and immune checkpoint inhibitors have become standard treatment options in numerous tumor types. In this review, we discuss the current and evolving use of checkpoint blockade, focusing on the anti-PD-1 inhibitor, pembrolizumab, for use in advanced gastric and gastroesophageal cancers.
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Affiliation(s)
- Gagandeep Brar
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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Lu Z, Zou J, Hu Y, Li S, Zhou T, Gong J, Li J, Zhang X, Zhou J, Lu M, Wang X, Peng Z, Qi C, Li Y, Li J, Li Y, Zou J, Du X, Zhang H, Shen L. Serological Markers Associated With Response to Immune Checkpoint Blockade in Metastatic Gastrointestinal Tract Cancer. JAMA Netw Open 2019; 2:e197621. [PMID: 31339548 PMCID: PMC6659353 DOI: 10.1001/jamanetworkopen.2019.7621] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
IMPORTANCE There are a limited number of predictive biomarkers for hyperprogressive disease (HPD), which is induced by immune checkpoint blockade (ICB) therapy. OBJECTIVE To evaluate the association of biomarkers in serum with the response to ICB therapy in patients with metastatic gastrointestinal tract cancer. DESIGN, SETTING, AND PARTICIPANTS Cohort study in which patients with metastatic gastrointestinal tract cancer treated with ICB were enrolled at the Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China, from August 1, 2015, to July 31, 2017, with the last follow-up date on January 1, 2018. Serum samples were collected at baseline and during the first visit to the clinic after starting treatment. Data analysis was conducted from January 16, 2018, to September 1, 2018. EXPOSURES A total of 59 factors, including cytokines/chemokines, growth factors, and soluble checkpoint-related proteins in serum, were examined by multiplexed bead immunoassays. MAIN OUTCOMES AND MEASURES Tree-based estimators were used to evaluate the importance of serum protein levels to ICB treatment response. Progression-free survival and overall survival analyses were conducted with the Kaplan-Meier method and log-rank test. RESULTS In total, 56 patients were examined. All patients with HPD (5 [8.9%]) had significantly lower mean (SD) levels of serum monocyte chemoattractant protein 1 than patients without HPD at baseline (53.4 [17.3] pg/mL vs 106.4 [48.4] pg/mL; P = .02). All patients with HPD were also identified by lower leukemia inhibitory factor levels (<13.28 pg/mL) and higher cluster of differentiation 152 levels (≥31.81 pg/mL). Among the remaining 51 patients, responders with esophageal squamous cell carcinoma (ESCC) or colorectal cancer (CRC) showed larger decreases in interleukin 1 receptor antagonist levels than nonresponders (ESCC: -55.02% [95% CI, -86.52% to -23.51%] vs 43.44% [95% CI, 11.93% to 74.96%]; P < .001; CRC: -35.82% [95% CI, -67.38% to -4.26%] vs 59.14% [95% CI, -72.34% to 190.6%]; P = .04). Responders with gastric cancer (GC) had larger increases in brain-derived neurotrophic factor levels than nonresponders (44.77% [95% CI, 10.76% to 78.79%] vs -26.2% [95% CI, -58.53% to 6.12%]; P = .003). Furthermore, early decreases in serum interleukin 1 receptor antagonist in patients with metastatic ESCC and CRC were associated with longer progression-free survival (ESCC: not reached vs 2.1 months; hazard ratio, 0.19; 95% CI, 0.04 to 0.95; P = .04; CRC: not reached vs 2.1 months; hazard ratio, 0.06; 95% CI, 0.01 to 0.38; P < .001). Early increases in brain-derived neurotrophic factor levels in patients with metastatic GC were associated with longer progression-free survival (not reached vs 4.2 months; hazard ratio, 0.15; 95% CI, 0.03 to 0.84; P = .03). CONCLUSIONS AND RELEVANCE In this study, baseline serum levels of monocyte chemoattractant protein 1, leukemia inhibitory factor, and cluster of differentiation 152 were associated with hyperprogressive metastatic gastrointestinal cancer among patients receiving ICB. An early decrease in serum interleukin 1 receptor antagonist levels in patients with metastatic ESCC or CRC and an early increase in serum brain-derived neurotrophic factor levels in patients with metastatic GC were better able to identify who would respond to ICB compared with microsatellite stability status or programmed cell death ligand 1 expression.
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Affiliation(s)
- Zhihao Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jianling Zou
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ying Hu
- Genecast Precision Medicine Technology Institute, Beijing, China
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shuang Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Tao Zhou
- Genecast Precision Medicine Technology Institute, Beijing, China
| | - Jifang Gong
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaotian Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jun Zhou
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ming Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Xicheng Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Changsong Qi
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yanyan Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jie Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yan Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jianyin Zou
- Department of Otolaryngology, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Xiao Du
- Genecast Precision Medicine Technology Institute, Beijing, China
| | - Henghui Zhang
- Genecast Precision Medicine Technology Institute, Beijing, China
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
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Martinez-Ciarpaglini C, Fleitas-Kanonnikoff T, Gambardella V, Llorca M, Mongort C, Mengual R, Nieto G, Navarro L, Huerta M, Rosello S, Roda D, Tarazona N, Navarro S, Ribas G, Cervantes A. Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications. ESMO Open 2019; 4:e000470. [PMID: 31231566 PMCID: PMC6555614 DOI: 10.1136/esmoopen-2018-000470] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 02/07/2019] [Accepted: 02/13/2019] [Indexed: 02/06/2023] Open
Abstract
Background The molecular classification of gastric cancer recognises two subtypes prone to immune checkpoint blockade: the microsatellite unstable and the Epstein-Barr virus (EBV)-related tumours. We aim to assess the concordance between immunohistochemistry and PCR for microsatellite status evaluation, and explore the value of microsatellite instability (MSI) and EBV as predictive survival factors. Material and methods We collected 246 consecutively diagnosed gastric cancer cases in all stages and evaluated the microsatellite status using immunohistochemistry for mismatched repair (MMR) proteins and PCR. EBV expression was studied through in situ hybridisation. Results Forty-five (18%) cases presented MSI and 13 (6%) were positive for EBV. MSI was associated with female sex, older age, distal location and distal non-diffuse type of the modified Lauren classification. EBV expression was most frequent in proximal location and proximal non-diffuse type. The sensitivity, specificity, positive predictive value and negative predictive value of immunohistochemistry for the microsatellite study were 91%, 98%, 91% and 98%, respectively. In the multivariate analysis, MSI was an independent predictor of favourable tumour-specific survival (TSS) in stages I–III (MSI: HR: 0.37, 95% CI 0.12 to 0.95, p=0.04). Conclusions The MSI status and the EBV expression should be incorporated in routine pathological report for two reasons. First, MSI defines a different pathological entity with a better outcome. Second, MSI and EBV may be useful biomarkers to identify patients who will respond to immune checkpoint blockade inhibitors. For this purpose, immunohistochemical study for MMR proteins and in situ hybridisation study for EBV evaluation are feasible and cost-effective methods.
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Affiliation(s)
- Carolina Martinez-Ciarpaglini
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Tania Fleitas-Kanonnikoff
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Valentina Gambardella
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Marta Llorca
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Cristina Mongort
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Regina Mengual
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Gema Nieto
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Lara Navarro
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Marisol Huerta
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Susana Rosello
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Desamparados Roda
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Noelia Tarazona
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Samuel Navarro
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Gloria Ribas
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Andrés Cervantes
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
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Haag GM, Czink E, Ahadova A, Schmidt T, Sisic L, Blank S, Heger U, Apostolidis L, Berger AK, Springfeld C, Lasitschka F, Jäger D, Knebel Doeberitz M, Kloor M. Prognostic significance of microsatellite‐instability in gastric and gastroesophageal junction cancer patients undergoing neoadjuvant chemotherapy. Int J Cancer 2019; 144:1697-1703. [DOI: 10.1002/ijc.32030] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 11/19/2018] [Indexed: 12/28/2022]
Affiliation(s)
- Georg Martin Haag
- Department of Medical Oncology, National Center for Tumor DiseasesUniversity Hospital Heidelberg Heidelberg Germany
| | - Elena Czink
- Department of Medical Oncology, National Center for Tumor DiseasesUniversity Hospital Heidelberg Heidelberg Germany
| | - Aysel Ahadova
- Department of Applied Tumor Biology, Institute of PathologyUniversity Hospital Heidelberg Heidelberg Germany
| | - Thomas Schmidt
- Department of SurgeryUniversity Hospital Heidelberg Heidelberg Germany
| | - Leila Sisic
- Department of SurgeryUniversity Hospital Heidelberg Heidelberg Germany
| | - Susanne Blank
- Department of SurgeryUniversity Hospital Heidelberg Heidelberg Germany
| | - Ulrike Heger
- Department of SurgeryUniversity Hospital Heidelberg Heidelberg Germany
| | - Leonidas Apostolidis
- Department of Medical Oncology, National Center for Tumor DiseasesUniversity Hospital Heidelberg Heidelberg Germany
| | - Anne Katrin Berger
- Department of Medical Oncology, National Center for Tumor DiseasesUniversity Hospital Heidelberg Heidelberg Germany
| | - Christoph Springfeld
- Department of Medical Oncology, National Center for Tumor DiseasesUniversity Hospital Heidelberg Heidelberg Germany
| | - Felix Lasitschka
- Institute of PathologyUniversity Hospital Heidelberg Heidelberg Germany
| | - Dirk Jäger
- Department of Medical Oncology, National Center for Tumor DiseasesUniversity Hospital Heidelberg Heidelberg Germany
| | - Magnus Knebel Doeberitz
- Department of Applied Tumor Biology, Institute of PathologyUniversity Hospital Heidelberg Heidelberg Germany
| | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of PathologyUniversity Hospital Heidelberg Heidelberg Germany
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Ratti M, Lampis A, Hahne JC, Passalacqua R, Valeri N. Microsatellite instability in gastric cancer: molecular bases, clinical perspectives, and new treatment approaches. Cell Mol Life Sci 2018; 75:4151-4162. [PMID: 30173350 PMCID: PMC6182336 DOI: 10.1007/s00018-018-2906-9] [Citation(s) in RCA: 163] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 08/13/2018] [Accepted: 08/14/2018] [Indexed: 12/15/2022]
Abstract
Gastric cancer is one of the most aggressive malignancies, with limited treatment options in both locally advanced and metastatic setting, resulting in poor prognosis. Based on genomic characterization, stomach tumour has recently been described as a heterogeneous disease composed by different subtypes, each of them with peculiar molecular aspects and specific clinical behaviour. With an incidence of 22% among all western gastric tumour cases, stomach cancer with microsatellite instability was identified as one of these subgroups. Retrospective studies and limited prospective trials reported differences between gastric cancers with microsatellite stability and those with instability, mainly concerning clinical and pathological features, but also in regard to immunological microenvironment, correlation with prognostic value, and responses to treatment. In particular, gastric cancer with microsatellite instability constitutes a small but relevant subgroup associated with older age, female sex, distal stomach location, and lower number of lymph-node metastases. Emerging data attribute to microsatellite instability status a favourable prognostic meaning, whereas the poor outcomes reported after perioperative chemotherapy administration suggest a detrimental role of cytotoxic drugs in this gastric cancer subgroup. The strong immunogenicity and the widespread expression of immune-checkpoint ligands make microsatellite instability subtype more vulnerable to immunotherapeutic approach, e.g., with anti-PD-L1 and anti-CTLA4 antibodies. Since gastric cancer with microsatellite instability shows specific features and clinical behaviour not overlapping with microsatellite stable disease, microsatellite instability test might be suitable for inclusion in a diagnostic setting for all tumour stages to guarantee the most targeted and effective treatment to every patient.
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Affiliation(s)
- Margherita Ratti
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Division of Oncology, Medical Department, ASST di Cremona, Ospedale di Cremona, Cremona, Italy
| | - Andrea Lampis
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Jens C Hahne
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
| | - Rodolfo Passalacqua
- Division of Oncology, Medical Department, ASST di Cremona, Ospedale di Cremona, Cremona, Italy
| | - Nicola Valeri
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Department of Medicine, The Royal Marsden NHS Foundation Trust, London, UK
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Polom K, Marano L, Marrelli D, De Luca R, Roviello G, Savelli V, Tan P, Roviello F. Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer. Br J Surg 2018; 105:159-167. [PMID: 29091259 DOI: 10.1002/bjs.10663] [Citation(s) in RCA: 195] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 02/03/2017] [Accepted: 07/06/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Several associations between microsatellite instability (MSI) and other clinicopathological factors have been reported in gastric cancer, but the results have been ambiguous. This systematic review and meta-analysis investigated the relationship between MSI and overall survival and clinicopathological characteristics of patients with gastric cancer. METHODS A systematic literature search of the PubMed, Cochrane and Ovid databases until 31 January 2016 was performed in accordance with the PRISMA statement. The articles were screened independently according to PICO (population, intervention, comparator, outcome) eligibility criteria. All eligible articles were evaluated independently by two reviewers for risk of bias according to the Quality In Prognosis Study tool. RESULTS Overall, 48 studies with a total of 18 612 patients were included. MSI was found in 9·2 per cent of patients (1718 of 18 612), and was associated with female sex (odds ratio (OR) 1·57, 95 per cent c.i. 1·31 to 1·89; P < 0·001), older age (OR 1·58, 2·20 to 1·13; P < 0·001), intestinal Laurén histological type (OR 2·23, 1·94 to 2·57; P < 0·001), mid/lower gastric location (OR 0·38, 0·32 to 0·44; P < 0·001), lack of lymph node metastases (OR 0·70, 0·57 to 0·86, P < 0·001) and TNM stage I-II (OR 1·77, 1·47 to 2·13; P < 0·001). The pooled hazard ratio for overall survival of patients with MSI versus those with non-MSI gastric cancer from 21 studies was 0·69 (95 per cent c.i. 0·56 to 0·86; P < 0·001). CONCLUSION MSI in gastric cancer was associated with good overall survival, reflected in several favourable clinicopathological tumour characteristics.
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Affiliation(s)
- K Polom
- Department General Surgery and Surgical Oncology, University of Siena, Siena, Italy
- Department of Surgical Oncology, Medical University of Gdansk, Gdansk, Poland
| | - L Marano
- General, Minimally Invasive and Robotic Surgery, Department of Surgery, San Matteo degli Infermi Hospital, Spoleto, Italy
| | - D Marrelli
- Department General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - R De Luca
- Department of Surgical Oncology, National Cancer Research Centre-Istituto Tumori G. Paolo II, Bari, Italy
| | - G Roviello
- Department of Oncology, Medical Oncology Unit, San Donato Hospital, Arezzo, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - V Savelli
- Department General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - P Tan
- Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Genome Institute of Singapore, Cancer Science Institute of Singapore, National University of Singapore, and Cellular and Molecular Research, National Cancer Centre, Singapore
| | - F Roviello
- Department General Surgery and Surgical Oncology, University of Siena, Siena, Italy
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