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Cammarota A, Woodford R, Smyth EC. Targeting HER2 in Gastroesophageal Cancer: A New Appetite for an Old Plight. Drugs 2025; 85:361-383. [PMID: 39843758 DOI: 10.1007/s40265-024-02132-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/21/2024] [Indexed: 01/24/2025]
Abstract
The incidence of gastroesophageal cancers is rising, driven, in part, by an increasing burden of risk factors of obesity and gastroesophageal reflux. Despite efforts to address these risk factors, and a growing interest in methods of population screening, the bulk of these tumours are unresectable at diagnosis. In this setting, effective systemic treatments are paramount to improve survival and quality of life. Early and accurate identification of oncogenic drivers, such as human epidermal growth factor receptor 2 (HER2), present in 5-30% of gastroesophageal adenocarcinomas (GEAs), is integral to guide choice of therapies due to the clear predictive implications that arise from overexpression of this receptor. After trastuzumab, the first anti-HER2 agent with approved use in HER2-positive GEA, the addition of pembrolizumab to first-line trastuzumab-chemotherapy and trastuzumab deruxtecan in the refractory space have more recently changed practice. Yet, the response to these agents has been vastly different across patients with HER2-positive disease, underpinning the need for reliable biomarkers of response. Emergent data have suggested that levels of HER2 expression on tissue or liquid biopsies may predict response to first-generation HER2 therapies while HER2 heterogeneity, receptor changes, co-occurring molecular alterations and oncogenic genomic and metabolic reprogramming may be implicated in resistance. A robust knowledge of the mechanisms of resistance and response to HER2-directed therapies is necessary to inform novel strategies of HER2-targeting and guide choice combinations with other biomarker-directed therapies, to improve outcomes from a new generation of clinical trials in HER2-positive GEA. Understanding and close examination of previous failures in this space form an important part of this assessment, as does correlative biomarker and translational work pertaining to the role of HER2 and dynamic changes that result through treatment exposure. In this review, we aim to provide an overview of strategies for HER2 targeting, summarising both the successes and disappointments in this therapeutic landscape and discuss existing challenges and future perspectives on development in this highly morbid tumour type.
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Affiliation(s)
- Antonella Cammarota
- Sarah Cannon Research Institute UK, 93 Harley St, London, UK
- Department of Medical Sciences, Humanitas University, Via Rita Levi Montalcini, Pieve Emanuele, Milan, Italy
| | - Rachel Woodford
- Sarah Cannon Research Institute UK, 93 Harley St, London, UK
- National Health and Medical Research Council Clinical Trials Centre (NHMRC CTC), University of Sydney, Parramatta Road, Camperdown, Australia
| | - Elizabeth C Smyth
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
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Cheng J, Cai M, Wang G, Tao K. HER2 becomes a novel survival biomarker for gastric cancer patients: a pooled analysis. Ther Adv Med Oncol 2024; 16:17588359241271913. [PMID: 39281969 PMCID: PMC11401144 DOI: 10.1177/17588359241271913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 07/02/2024] [Indexed: 09/18/2024] Open
Abstract
Background Although anti-HER2 therapies have been widely used against gastric carcinoma, the prognostic significance of HER2 overexpression remains unclear. Previous studies failed to provide convincible evidence due to inconsistent HER2 evaluation criteria and heterogeneous clinical characteristics. Objectives To figure out the prognostic significance of HER2 expression in gastric cancer, we rigorously designed and conducted this study. Design Meta-analysis. Data sources and methods Record retrieval was performed by searching PubMed, Web of Science, Cochrane Library, Embase, ASCO, and ESMO meeting libraries from inception to November 2022. Cohort studies investigating overall survival comparison between HER2-positive and HER2-negative gastric cancer patients were included. Both resectable and advanced cases were separately collected while HER2 evaluation standards should be consistent across eligible studies. Newcastle-Ottawa Scale was used for quality assessment. Overall survival was the only endpoint and effect size was presented by hazard ratio (HR) with its 95% confidence interval. The pooled calculation was conducted on Review Manager 5.4. Results Thirty studies were eligible, including 9945 patients. Eligible studies were mostly high quality (n = 31). Regarding resectable cases (n = 22), HER2-positive groups had significantly worse prognosis than HER2-negative counterparts (HR 1.56, 95%CI 1.32-1.85, p < 0.00001). For HER2-positive patients with advanced gastric cancer (n = 10), HER2 overexpression was also an unfavorable survival indicator (HR 1.70, 95%CI 1.23-2.35, p = 0.001). Potential heterogeneous studies had been eliminated while outcomes remained stable by sensitivity analysis. Subgroup analysis suggested HER2-positive patients had a poorer prognosis in both East Asian (resectable: HR 1.56; advanced: HR 1.32) and non-East Asian countries (HR 1.58; HR 3.27). Conclusion As a novel survival biomarker in gastric cancer, HER2 overexpression indicates unfavorable prognosis among both resectable and advanced patients, irrespective of East Asian or non-East Asian populations. Trial registration PROSPERO (CRD42020168051).
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Affiliation(s)
- Ji Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
| | - Ming Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guobin Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Lim SH, Kim MJ, Lee J, Lim HY, Kang WK, Kim ST. The Impact of Pembrolizumab as a Salvage Therapy Based on HER2 Expression in Advanced Gastric Cancer. Cancers (Basel) 2024; 16:2969. [PMID: 39272827 PMCID: PMC11393848 DOI: 10.3390/cancers16172969] [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: 06/22/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) are used as salvage treatments for advanced gastric cancer (AGC) regardless of HER2 status. This study assessed the efficacy of ICIs based on HER2 expression in AGC patients who received pembrolizumab as salvage monotherapy at Samsung Medical Center from November 2017 to March 2023. HER2 status was determined via immunohistochemistry, and tumor response and survival outcomes were compared accordingly. Among the 113 patients analyzed, with a median age of 61 years and 64.6% being male, 12 patients (10.6%) were HER2-positive, and 101 patients (89.4%) were HER2-negative. Of 92 evaluable patients, none had a complete response. However, 50% of HER2-positive patients had a partial response, compared to 4.9% of HER2-negative patients (p < 0.001). The disease control rate was 70% in HER2-positive and 37.8% in HER2-negative patients (p = 0.086). Median progression-free survival was 5.53 months for HER2-positive patients versus 1.81 months for HER2-negative patients (p = 0.037). Pembrolizumab as a salvage chemotherapy for the treatment of AGC demonstrated superior effectiveness in HER2-positive patients compared with HER2-negative patients.
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Affiliation(s)
- Sung Hee Lim
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Min Jung Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
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Sekmek S, Karahan I, Ucar G, Ceylan F, Bayram D, Seven I, Bölek H, Ürün Y, Yücel KB, Yazici O, Kadioglu A, Karacin C, Canaslan K, Atag E, Demirer S, Erdem GU, Ergun Y, Atak M, Koksal B, Kiran MM, Turkay DO, Civelek B, Yalcin B, Uncu D. Effect of HER2/CEP17 ratio on survival in metastatic HER2-positive gastric cancer, multicenter study. Clin Transl Oncol 2024; 26:1878-1885. [PMID: 38451412 DOI: 10.1007/s12094-024-03410-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 02/12/2024] [Indexed: 03/08/2024]
Abstract
AIM HER2-positive metastatic gastric cancer is still a highly fatal disease despite advances. We aimed to investigate the relationship between HER2/CEP17 ratio and survival in patients with HER2-positive metastatic gastric cancer. METHODS A total of 99 patients from 8 different centers in Turkey were included in the study. Patients with HER2-positive metastatic gastric cancer and whose HER2/CEP17 ratio was examined were included in the study. Patients were divided into two groups according to HER2/CEP17 values, and survival analysis was performed. RESULTS The median age was 64 (24-83) years. There were 74 (74.8%) male and 25 (25.2%) female patients. OS in the high HER2/CEP17 ratio group was 21.97 months (95% CI: 16.36-27.58), and in the low ratio group was 16.17 months (95% CI: 10.95-21.38) (p = 0.015). OS was 17.7 months (95% CI: 7.02-28.37) in the high HER2 gene copy number group and 10.13 months (5.55-14.71) in the group with low copy number (p = 0.03). PFS was 10.94 months (95% CI: 7.55-14.33) in the group with high HER2 gene copy number and 7.56 months (4.62-10.49) in the low copy number group (p = 0.06). CONCLUSION Patients with both high HER2 gene amplification and high HER2/CEP17 ratio had better OS. The PFS of the group with high HER2 gene amplification was also better. To our knowledge, this is the first study in the literature showing that the HER2/CEP17 ratio affects survival in patients with metastatic gastric cancer.
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Affiliation(s)
- Serhat Sekmek
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey.
| | - Irfan Karahan
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Gokhan Ucar
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Furkan Ceylan
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Dogan Bayram
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Ismet Seven
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Hatice Bölek
- Department of Medical Oncology, Ankara University, Ankara, Turkey
| | - Yüksel Ürün
- Department of Medical Oncology, Ankara University, Ankara, Turkey
| | | | - Ozan Yazici
- Department of Medical Oncology, Gazi University, Ankara, Turkey
| | - Ahmet Kadioglu
- Department of Medical Oncology, UHS Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey
| | - Cengiz Karacin
- Department of Medical Oncology, UHS Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey
| | - Kubra Canaslan
- Department of Medical Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Elif Atag
- Department of Medical Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Serhat Demirer
- Department of Medical Oncology, İstanbul Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey
| | - Gokmen Umut Erdem
- Department of Medical Oncology, İstanbul Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey
| | - Yakup Ergun
- Department of Medical Oncology, Antalya City Hospital, Antalya, Turkey
| | - Mehmetcan Atak
- Department of Medical Oncology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Baris Koksal
- Department of Medical Oncology, Hacettepe University, Ankara, Turkey
| | | | | | - Burak Civelek
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Bulent Yalcin
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Dogan Uncu
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
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Mohammed O, Gizaw ST, Degef M. Potential diagnostic, prognostic, and predictive biomarkers of gastric cancer. Health Sci Rep 2024; 7:e2261. [PMID: 39040881 PMCID: PMC11260885 DOI: 10.1002/hsr2.2261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 06/29/2024] [Accepted: 07/04/2024] [Indexed: 07/24/2024] Open
Abstract
Background Gastric cancer (GC), a malignant epithelial tumor, is the fourth leading cause of cancer-related death worldwide. Therapeutic strategies for GC, despite the biggest challenges, can significantly improve survival rates through early detection and effective screening methods. Aim To provide brief information on the necessity of multiple specific diagnostic, prognostic, and predictive markers for GC. Methods This review was conducted using a variety of search engines, including PubMed Central, Scopus, Web of Science, Google Scholar, and others. Results Some potential biomarkers that provide essential information include circulating tumor cells (CTCs), DNA methylation, claudin 18.2, fibroblast growth factor receptor 2 (FGFR2), long noncoding RNAs (lncRNAs), cell-free DNA (cfDNA), microRNAs, and serum pepsinogens. Conclusion Multiple tumor markers are essential for screening, tumor identification, staging, prognostic assessment, and monitoring recurrence after therapy due to the absence of a single tumor indicator for diagnosing, prognosticating, and predicting GC.
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Affiliation(s)
- Ousman Mohammed
- Department of Medical Laboratory SciencesCollege of Medicine and Health Sciences, Wollo UniversityDessieEthiopia
| | - Solomon Tebeje Gizaw
- Department of Medical BiochemistrySchool of Medicine, College of Health Sciences, AAUAddis AbabaEthiopia
| | - Maria Degef
- Department of Medical BiochemistrySchool of Medicine, College of Health Sciences, AAUAddis AbabaEthiopia
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Kuwata T. Molecular classification and intratumoral heterogeneity of gastric adenocarcinoma. Pathol Int 2024; 74:301-316. [PMID: 38651937 PMCID: PMC11551831 DOI: 10.1111/pin.13427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/25/2024] [Accepted: 04/03/2024] [Indexed: 04/25/2024]
Abstract
Gastric cancers frequently harbor striking histological complexity and diversity between lesions as well as within single lesions, known as inter- and intratumoral heterogeneity, respectively. The latest World Health Organization Classification of Tumors designated more than 30 histological subtypes for gastric epithelial tumors, assigning 12 subtypes for gastric adenocarcinoma (GAD). Meanwhile, recent advances in genome-wide analyses have provided molecular aspects to the histological classification of GAD, and consequently revealed different molecular traits underlying these histological subtypes. Moreover, accumulating knowledge of comprehensive molecular profiles has led to establishing molecular classifications of GAD, which are often associated with clinical biomarkers for therapeutics and prognosis. However, most of our knowledge of GAD molecular profiles is based on inter-tumoral heterogeneity, and the molecular profiles underlying intratumoral heterogeneity are yet to be determined. In this review, recently established molecular classifications of GAD are introduced in the aspect of pathological diagnosis and are discussed in the context of intratumoral heterogeneity.
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Affiliation(s)
- Takeshi Kuwata
- Department of Genetic Medicine and ServicesNational Cancer Center Hospital EastKashiwaChibaJapan
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Wakatsuki T, Ishizuka N, Hironaka S, Minashi K, Kadowaki S, Goto M, Shoji H, Hirano H, Nakayama I, Osumi H, Ogura M, Chin K, Yamaguchi K, Takahari D. Exploratory analysis of serum HER2 extracellular domain for HER2 positive gastric cancer treated with SOX plus trastuzumab. Int J Clin Oncol 2024; 29:801-812. [PMID: 38589679 PMCID: PMC11130043 DOI: 10.1007/s10147-024-02509-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 03/06/2024] [Indexed: 04/10/2024]
Abstract
BACKGROUND The aim of this study was to explore the clinical utility of serum HER2 extracellular domain (sHER2 ECD) using data from a clinical trial evaluating trastuzumab combined S-1 plus oxaliplatin (SOX) in HER2 positive gastric cancer. METHODS sHER2 ECD were prospectively measured at baseline and subsequent treatment courses. Based on each quantile point of baseline sHER2 ECD levels and its early changes, patients were divided into two groups and compared clinical outcomes. RESULTS 43 patients were enrolled, and 17 patients (39.5%) were positive for baseline sHER2 ECD. Higher baseline sHER2 ECD levels tended to have lower hazard ratios (HRs). When divided into two groups by baseline sHER2 ECD of 19.1 ng/ml, median progression-free survival (PFS) and overall survival (OS) was longer in the higher group (mPFS: 16.8 vs 8.7 months, p = 0.359. mOS: 35.5 vs 20.6 months, p = 0.270), respectively. After initiation of treatment, sHER2 ECD significantly decreased up until the third cycle. Higher reduction rates of sHER2 ECD within 3 cycles also tended to have lower HRs. When divided into two groups by reduction rate of 42.5%, mPFS and mOS was longer in the higher reduced group (mPFS: 17.2 vs 8.7 months, p = 0.095. mOS: 65.0 vs 17.8 months, p = 0.047), respectively. Furthermore, higher reduction rates could surrogate higher objective response rates (ORR) (ORR: 90% vs 63.2% for 29.5%, p = 0.065. 100% vs 70% for 42.5%, p = 0.085), respectively. CONCLUSIONS Baseline sHER2 ECD levels and its early decline may be useful biomarkers for SOX plus trastuzumab efficacy in HER2 positive gastric cancer.
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Affiliation(s)
- Takeru Wakatsuki
- Department of Gastrointestinal Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan.
| | - Naoki Ishizuka
- Department of Clinical Trial Planning, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shuichi Hironaka
- Clinical Trial Promotion Department, Chiba Cancer Center, Chiba, Japan
- Department of Medical Oncology, Faculty of Medicine, Kyorin University, Tokyo, Japan
| | - Keiko Minashi
- Clinical Trial Promotion Department, Chiba Cancer Center, Chiba, Japan
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Masahiro Goto
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan
| | - Hirokazu Shoji
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hidekazu Hirano
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Izuma Nakayama
- Department of Gastrointestinal Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Hiroki Osumi
- Department of Gastrointestinal Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Mariko Ogura
- Department of Gastrointestinal Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Keisho Chin
- Department of Gastrointestinal Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastrointestinal Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Daisuke Takahari
- Department of Gastrointestinal Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
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Xu J, Gong J, Li M, Kang Y, Ma J, Wang X, Liang X, Qi X, Yu B, Yang J. Gastric cancer patient-derived organoids model for the therapeutic drug screening. Biochim Biophys Acta Gen Subj 2024; 1868:130566. [PMID: 38244703 DOI: 10.1016/j.bbagen.2024.130566] [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: 05/25/2023] [Revised: 12/11/2023] [Accepted: 01/14/2024] [Indexed: 01/22/2024]
Abstract
BACKGROUND Gastric cancer (GC) is a highly heterogeneous disease featuring many various histological and molecular subtypes. Therefore, it is imperative to have well-characterized in vitro models for personalized treatment development. Gastric cancer patient-derived organoids (PDOs), re-capitulating in vivo conditions, exhibit high clinical efficacy in predicting drug sensitivity to facilitate the development of cancer precision medicine. METHODS PDOs were established from surgically resected GC tumor tissues. Histological and molecular characterization of PDOs and primary tissues were performed via IHC and sequencing analysis. We also conducted drug sensitivity tests using PDO cultures with five chemotherapeutic drugs and twenty-two targeted drugs. RESULTS We have successfully constructed a PDOs biobank that included EBV+, intestinal/CIN, diffuse/GS, mixed and Her2+ GC subtypes, and these PDOs captured the pathological and genetic characteristics of corresponding tumors and exhibited different sensitivities to the tested agents. In a clinical case study, we performed an additional drug sensitivity test for a patient who reached an advanced progressive stage after surgery. We discovered that the combination of napabucasin and COTI-2 exhibited a stronger synergistic effect than either drug alone. CONCLUSION PDOs maintained the histological and genetic characteristics of original cancer tissues. PDOs biobank opens up new perspectives for studying cancer cell biology and personalized medicine as a preclinical study platform.
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Affiliation(s)
- Jiao Xu
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Jin Gong
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Mengyang Li
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Ye Kang
- MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Jinrong Ma
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Xi Wang
- Department of Medical Oncology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Xiao Liang
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Xin Qi
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Bixin Yu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Jin Yang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China; Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China; Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
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Nowak KM, Chetty R. Predictive and prognostic biomarkers in gastrointestinal tract tumours. Pathology 2024; 56:205-213. [PMID: 38238239 DOI: 10.1016/j.pathol.2023.12.412] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/28/2023] [Accepted: 12/30/2023] [Indexed: 02/18/2024]
Abstract
Tumours of the gastrointestinal tract represent nearly a quarter of all newly diagnosed tumours diagnosed in 2019. Various treatment modalities for gastrointestinal cancers exist, some of which may be guided by biomarkers. Biomarkers act as gauges of either normal or pathogenic processes or responses to an exposure or intervention. They come in many forms. This review explores established and potential molecular/immunohistochemical (IHC) predictive and prognostic biomarkers of the gastrointestinal tract.
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Affiliation(s)
- Klaudia M Nowak
- Laboratory Medicine Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
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10
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Li F, Yu J, Pan T, Feng H, Li J, Yu B, Fan Z, Sang Q, Chen M, Zang M, Hou J, Wu X, Yu Y, Li Y, Yan C, Zhu Z, Su L, Liu B. BPTF Drives Gastric Cancer Resistance to EGFR Inhibitor by Epigenetically Regulating the C-MYC/PLCG1/Perk Axis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303091. [PMID: 37863665 PMCID: PMC10700682 DOI: 10.1002/advs.202303091] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 08/06/2023] [Indexed: 10/22/2023]
Abstract
Erlotinib, an EGFR tyrosine kinase inhibitor, is used for treating patients with cancer exhibiting EGFR overexpression or mutation. However, the response rate of erlotinib is low among patients with gastric cancer (GC). The findings of this study illustrated that the overexpression of bromodomain PHD finger transcription factor (BPTF) is partially responsible for erlotinib resistance in GC, and the combination of the BPTF inhibitor AU-1 with erlotinib synergistically inhibited tumor growth both in vivo and in vitro. AU-1 inhibited the epigenetic function of BPTF and decreased the transcriptional activity of c-MYC on PLCG1 by attenuating chromosome accessibility of the PLCG1 promoter region, thus decreasing the expression of p-PLCG1 and p-Erk and eventually improving the sensitivity of GC cells to erlotinib. In patient-derived xenograft (PDX) models, AU-1 monotherapy exhibited remarkable tumor-inhibiting activity and is synergistic anti-tumor effects when combined with erlotinib. Altogether, the findings illustrate that BPTF affects the responsiveness of GC to erlotinib by epigenetically regulating the c-MYC/PLCG1/pErk axis, and the combination of BPTF inhibitors and erlotinib is a viable therapeutic approach for GC.
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Affiliation(s)
- Fangyuan Li
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Junxian Yu
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Tao Pan
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Haoran Feng
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Jianfang Li
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Beiqin Yu
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Zhiyuan Fan
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Qingqing Sang
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Mengdi Chen
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Mingde Zang
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
- Department of Gastric Cancer SurgeryFudan University Shanghai Cancer CenterDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Junyi Hou
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Xiongyan Wu
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Yingyan Yu
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Yuan‐Yuan Li
- Shanghai Center for Bioinformation TechnologyShanghai Engineering Research Center of Pharmaceutical Translation & Shanghai Industrial Technology InstituteShanghai202163P. R. China
| | - Chao Yan
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Zhenggang Zhu
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Liping Su
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
| | - Bingya Liu
- Department of General SurgeryShanghai Key Laboratory of Gastric NeoplasmsShanghai Institute of Digestive SurgeryRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025P. R. China
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11
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Yanagimoto Y, Imamura H, Adachi S, Odagiri K, Kawase T, Yamashita M, Takeyama H, Suzuki Y, Ikenaga M, Shimizu J, Tomita N, Dono K. The effect of specimen processing time on HER2 expression in gastric cancer and esophagogastric junction cancer: a single-center retrospective observational study. BMC Cancer 2023; 23:645. [PMID: 37434116 PMCID: PMC10334514 DOI: 10.1186/s12885-023-11148-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 07/04/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND Recent developments in the field of companion diagnosis and molecular-targeting therapeutic agents have helped in developing treatments targeting human epidermal growth factor receptor 2 (HER2) in gastric cancer (GC) and esophagogastric junction cancer (EGJC), and the importance of accurate diagnosis of HER2 expression is increasing. However, the HER2-positivity rate significantly differs among reports in GC and EGJC, and factors that affect HER2-positivity require elucidation. METHODS The present study retrospectively examined factors related to HER2-positivity in a single institution, including age, sex, body mass index, the American Society of Anesthesiologists physical status, tumor information, and surgery information, including time to specimen processing. RESULTS Our study included 165 patients tested for HER2 using GC and EGJC surgery specimens among the 1,320 patients who underwent gastrectomy from January 2007 to June 2022. In total, 35 (21.2%) and 130 (78.8%) patients were HER2-positive and -negative, respectively. Multivariate analysis revealed that intestinal type (odds ratio [OR]: 3.41, 95% confidence interval [CI]: 1.44-8.09, p = 0.005), pM1 (OR: 3.99, 95% CI: 1.51-10.55, p = 0.005), and time to specimen processing of < 120 min (OR: 2.65, 95% CI: 1.01-6.98, p = 0.049) were independent factors that affected HER2-positivity. CONCLUSIONS The outcomes of the present study indicated that intestinal type, pM, and time to specimen processing are important factors affecting HER2-positive rates in GC and EGJC. Therefore, the risk of false-negative HER2 results may be reduced by decreasing the time required to process the resected specimen. Additionally, accurate diagnosis of HER2 expression may increase the opportunity to administer molecular-targeted drugs that can expect therapeutic effects to patients appropriately. TRAIL REGISTRATION Retrospectively registered.
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Affiliation(s)
- Yoshitomo Yanagimoto
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan.
| | - Hiroshi Imamura
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Shiro Adachi
- Department Diagnostic Pathology, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Kazuki Odagiri
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Tomono Kawase
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Masafumi Yamashita
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Hiroshi Takeyama
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Yozo Suzuki
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Masakazu Ikenaga
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Junzo Shimizu
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Naohiro Tomita
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Keizo Dono
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
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12
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Marshall S, Wakatsuki T, Takahari D, Matsushima T, Ishizuka N, Nakayama I, Osumi H, Ogura M, Ichimura T, Shinozaki E, Chin K, Yamaguchi K. Prognostic Factors in Patients with Advanced HER2-Positive Gastric Cancer Treated with Trastuzumab-Based Chemotherapy: a Cohort Study. J Gastrointest Cancer 2023; 54:475-484. [PMID: 35435573 DOI: 10.1007/s12029-022-00815-1] [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] [Accepted: 02/19/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE Prognostic factors for the survival of patients with advanced HER2-positive gastric cancer treated with trastuzumab-based chemotherapy remain controversial. The aim of this study was to identify the clinical factors that predict prognosis in patients with advanced HER2-positive gastric cancer. METHODS We retrospectively reviewed the medical records of HER2-positive gastric cancer patients treated with trastuzumab-based chemotherapy at our institution. Clinical features and laboratory test results that considered prognostic factors were re-examined. Overall survival (OS) was estimated using the Kaplan-Meier method. Univariate analysis was performed with the log-rank test and multivariate analysis was performed using Cox's proportional hazard regression model. RESULTS A total of 133 patients with advanced HER2-positive gastric cancer were enrolled. The median OS in this cohort was 18.7 months. Four prognostic factors: visceral metastasis (lung or liver), levels of hemoglobin (Hb) (< 11.6 g/dl), lactate dehydrogenase (LDH) (> 222 mg/dl), and C-reactive protein (CRP) (> 0.14 mg/dl), were identified as independent prognostic factors. The patients were placed into three groups according to their number of prognostic factors. These included low (0, 1), moderate (2, 3), and high (4) risk factors. The OS was separated into three categories with a median OS of 32.0, 18.7, and 10.1 months, respectively. Compared to the low-risk group, hazard ratios for the moderate- and high-risk groups were 1.75 and 3.49, respectively. CONCLUSION Visceral metastasis and abnormal Hb, LDH, and CRP levels were associated with unfavorable OS. These findings may be beneficial for the management of advanced HER2-positive gastric cancer treated with trastuzumab-based chemotherapy.
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Affiliation(s)
- Shoko Marshall
- Department of Medicine, Tokyo Women's Medical University Medical Center East, Tokyo, Japan
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Takeru Wakatsuki
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
| | - Daisuke Takahari
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Tomohiro Matsushima
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
- Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan
| | - Naoki Ishizuka
- Department of Clinical Trial Planning and Management, Clinical Research & Medical Development Center, Tokyo, Japan
| | - Izuma Nakayama
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Hiroki Osumi
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Mariko Ogura
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Takashi Ichimura
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Eiji Shinozaki
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Keisho Chin
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
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13
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Gao X, Zhao L, Zhang N, Han W, Liu K, Yan J, Chen L, Pan Y, Li R, Li W, Zhang H, Li H, Wang S, Gao X, Niu P, Wang W, Ji G, Zhao Q, Lu Y, Li Z, Shang L, Liang H, Wu K, Deng J, Chen Y, Nie Y. Impact of HER2 on prognosis and benefit from adjuvant chemotherapy in stage II/III gastric cancer patients: a multicenter observational study. Int J Surg 2023; 109:1330-1341. [PMID: 37037586 PMCID: PMC10389606 DOI: 10.1097/js9.0000000000000370] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 03/16/2023] [Indexed: 04/12/2023]
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) is a well-developed therapeutic target in breast and gastric cancer (GC). However, the impact of HER2 on survival and benefit from fluorouracil-based adjuvant chemotherapy remains unclear in patients with GC. MATERIALS AND METHODS This multicenter cohort study involved 5622 consecutive stage II/III GC patients. HER2 expression was assessed prospectively via immunohistochemistry (IHC). The staining intensity was graded on a scale of 0 to 3+. An IHC score of 2+or 3+was defined as high expression, and a score of 3+was defined as overexpression. RESULTS HER2 overexpression was independently associated with a lower 5-year overall survival (OS) in stage II [hazard ratio (HR), 2.10; 95% CI: 1.41-3.11], but not in stage III GC (HR, 1.00; 95% CI, 0.82-1.20). Further analysis revealed that stage II patients with high HER2 expression showed a poorer response to chemotherapy than stage II patients with low HER2 expression ( Pinteraction =0.024). The HRs for 5-year OS were 0.51 (95% CI, 0.38-0.70) for stage II patients with low HER2 expression, 0.58 (95% CI, 0.51-0.66) for stage III patients with low HER2 expression, 1.13 (95% CI, 0.61-2.09) for stage II patients with high HER2 expression, and 0.47 (95% CI, 0.36-0.61) for stage III patients with high HER2 expression. CONCLUSIONS Fluorouracil-based adjuvant chemotherapy is insufficient for stage II GC patients with high HER2 expression, indicating that prospective trials are required to validate alternative HER2-targeted adjuvant therapies in the individuals above.
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Affiliation(s)
- Xianchun Gao
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
- Department of Health Statistics, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health
| | - Lulu Zhao
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Nannan Zhang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer
- Key Laboratory of Cancer Prevention and Therapy
- Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China
| | - Weili Han
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Kun Liu
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Junya Yan
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Ling Chen
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi’an
| | - Yan Pan
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Renlong Li
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Wenjiao Li
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Haohao Zhang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Hongwei Li
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Shibo Wang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Xiaoliang Gao
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Penghui Niu
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Wanqing Wang
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Gang Ji
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Qingchuan Zhao
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Yuanyuan Lu
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Zengshan Li
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi’an
| | - Lei Shang
- Department of Health Statistics, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health
| | - Han Liang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer
- Key Laboratory of Cancer Prevention and Therapy
- Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China
| | - Kaichun Wu
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
| | - Jingyu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer
- Key Laboratory of Cancer Prevention and Therapy
- Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China
| | - Yingtai Chen
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases
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Arigami T, Matsushita D, Okubo K, Shimonosono M, Sasaki K, Tsuruda Y, Kita Y, Tanabe K, Mori S, Yanagita S, Uenosono Y, Nakajo A, Kurahara H, Ohtsuka T. A prognostic scoring system for conversion surgery after trastuzumab-based chemotherapy for human epidermal growth factor receptor 2-positive advanced gastric cancer. Surg Today 2022; 52:1721-1730. [PMID: 35543754 PMCID: PMC9700637 DOI: 10.1007/s00595-022-02515-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/15/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE To investigate the clinical indications and prognostic significance of surgical interventions after chemotherapy using trastuzumab-containing regimens for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC). METHODS A total of 146 patients with AGC who underwent chemotherapy were enrolled in this retrospective study. Tumors with an immunohistochemistry (IHC) score of 3 + or an IHC score of 2 + plus fluorescence in situ hybridization positivity were defined as HER2-positive AGC. We devised a scoring system for predicting prognosis associated with conversion surgery. RESULTS Thirty-three patients received trastuzumab-based chemotherapy for HER2-positive tumors. Multivariate analyses identified advanced age, peritoneal dissemination, histologically undifferentiated tumors, and tumor response of progressive disease as independent prognostic factors for a worse prognosis. Twelve patients with HER2-positive AGC underwent conversion surgery. The conversion surgery group of patients with HER2-positive AGC had a better prognosis than the chemotherapy-alone group. A prognostic scoring system based on age, peritoneal dissemination, and histological type was significantly correlated with the presence or absence of conversion surgery and the prognosis of patients with HER2-positive AGC. CONCLUSIONS Our scoring system has the clinical potential to predict prognosis associated with conversion surgery after trastuzumab-containing chemotherapy for patients with HER2-positive AGC.
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Affiliation(s)
- Takaaki Arigami
- Department of Onco-Biological Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
| | - Daisuke Matsushita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Keishi Okubo
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Masataka Shimonosono
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Ken Sasaki
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Yusuke Tsuruda
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Yoshiaki Kita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kan Tanabe
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Shinichiro Mori
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Shigehiro Yanagita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Yoshikazu Uenosono
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Akihiro Nakajo
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Hiroshi Kurahara
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Takao Ohtsuka
- Department of Onco-Biological Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan
- Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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15
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Identification of a Biomarker Combination for Survival Stratification in pStage II/III Gastric Cancer after Curative Resection. Cancers (Basel) 2022; 14:cancers14184427. [PMID: 36139587 PMCID: PMC9497152 DOI: 10.3390/cancers14184427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/07/2022] [Accepted: 09/09/2022] [Indexed: 11/29/2022] Open
Abstract
Simple Summary Gastric cancer (GC) is the fifth most common cancer worldwide and the fourth most common cause of cancer-related deaths, with a high frequency of recurrence and metastasis, and a poor prognosis. This study presents a novel combination of four proteins (PDGFRB, INHBA, MMP11, and galectin-10) in GC tissues that have been identified as useful survival stratification markers in patients with pStage II/III GC after curative resection by quantitative polymerase chain reaction (qPCR), proteomic analysis, and immunohistochemistry (IHC). Abstract Background: We sought to identify an optimal combination of survival risk stratification markers in patients with pathological (p) stage II/III gastric cancer (GC) after curative resection. Methods: We measured the expression levels of 127 genes in pStage II/III GC tissues of two patient cohorts by quantitative polymerase chain reaction (qPCR) and the expression of 1756 proteins between two prognosis (good and poor) groups by proteomic analysis to identify candidate survival stratification markers. Further, immunohistochemistry (IHC) using tumor microarrays (TMAs) in another cohort of patients was performed to identify an optimal biomarker combination for survival stratification in GC patients. Results: secreted protein acidic and rich in cysteine (SPARC), erb-b2 receptor tyrosine kinase 2 (ERBB2), inhibin subunit beta A (INHBA), matrix metallopeptidase-11 (MMP11), tumor protein p53 (TP53), and platelet-derived growth factor receptor-beta (PDGFRB) were identified as candidate biomarkers from qPCR analysis, and SPARC and galectin-10 were obtained from the proteomic analysis. The combination of PDGFRB, INHBA, MMP11, and galectin-10 was identified as the optimal combination of survival risk stratification markers. Conclusions: A combination of four proteins in GC tissues may serve as useful survival risk stratification markers in patients with pStage II/III GC following curative resection. Our results may facilitate future multicenter prospective clinical trials.
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16
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Ghojazadeh M, Somi MH, Naseri A, Salehi-Pourmehr H, Hassannezhad S, Hajikamanaj Olia A, Kafshdouz L, Nikniaz Z. Systematic Review and Meta-analysis of TP53, HER2/ERBB2, KRAS, APC, and PIK3CA Genes Expression Pattern in Gastric Cancer. Middle East J Dig Dis 2022; 14:335-345. [PMID: 36619267 PMCID: PMC9489438 DOI: 10.34172/mejdd.2022.292] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 05/19/2022] [Indexed: 11/06/2022] Open
Abstract
Background: With a global prevalence of about 10%, gastric cancer is among the most prevalent cancers. Currently, there has been an ongoing trend toward investigating genetic disruptions in different cancers because they can be used as a target-specific therapy. We aimed to systemically review some gene expression patterns in gastric cancer. Methods: The current systematic review was designed and executed in 2020. Scopus, PubMed, Cochrane Library, Google Scholar, web of knowledge, and Science Direct were searched for relevant studies. A manual search of articles (hand searching), reference exploring, checking for grey literature, and seeking expert opinion were also done. Results: In this review, 65 studies were included, and the expression pattern of HER2/ ERBB2, ER1/Erb1/EGFR, PIK3CA, APC, KRAS, ARID1A, TP53, FGFR2 and MET was investigated. TP53, APC, KRAS, and PIK3CA mutation cumulative frequency were 24.8 (I2=95.05, Q value=525.53, df=26, P<0.001), 7.2 (I2=89.79, Q value=48.99, df=5, P<0.001), 7.8 (I2=93.60, Q value=140.71, df=9, P=0.001) and 8.6 (I2=80.78, Q value=525.53, df=9, P<0.001) percent, respectively. Overexpression was investigated for HER1/ Erb1/EGFR, PIK3CA, APC, KRAS, ARID1A, TP53, CCND1, FGFR2, MET and MYC. The frequency of TP53 and HER2/ERBB2 were 43.1 (I2=84.06, Q value=58.09, df=9, P<0.001) and 20.8 (I2=93.61, Q value=234.89, df=15, P<0.001) percent, respectively. Conclusion: More research is encouraged to investigate the genes for which we could not perform a meta-analysis.
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Affiliation(s)
- Morteza Ghojazadeh
- Research Center for Evidence-based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Somi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirreza Naseri
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hanieh Salehi-Pourmehr
- Research Center for Evidence-based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sina Hassannezhad
- Research Center for Evidence-based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arash Hajikamanaj Olia
- Research Center for Evidence-based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Kafshdouz
- Genetic Department, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zeinab Nikniaz
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran,Corresponding Author: Zeinab Nikniaz, PhD Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Tel:+98 4133367473 Fax:+984133367473
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17
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Gastric cancer biomarker analysis in patients treated with different adjuvant chemotherapy regimens within SAMIT, a phase III randomized controlled trial. Sci Rep 2022; 12:8509. [PMID: 35595817 PMCID: PMC9123164 DOI: 10.1038/s41598-022-12439-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 03/23/2022] [Indexed: 12/23/2022] Open
Abstract
Biomarkers for selecting gastric cancer (GC) patients likely to benefit from sequential paclitaxel treatment followed by fluorinated-pyrimidine-based adjuvant chemotherapy (sequential paclitaxel) were investigated using tissue samples of patients recruited into SAMIT, a phase III randomized controlled trial. Total RNA was extracted from 556 GC resection samples. The expression of 105 genes was quantified using real-time PCR. Genes predicting the benefit of sequential paclitaxel on overall survival, disease-free survival, and cumulative incidence of relapse were identified based on the ranking of p-values associated with the interaction between the biomarker and sequential paclitaxel or monotherapy groups. Low VSNL1 and CD44 expression predicted the benefit of sequential paclitaxel treatment for all three endpoints. Patients with combined low expression of both genes benefitted most from sequential paclitaxel therapy (hazard ratio = 0.48 [95% confidence interval, 0.30-0.78]; p < 0.01; interaction p-value < 0.01). This is the first study to identify VSNL1 and CD44 RNA expression levels as biomarkers for selecting GC patients that are likely to benefit from sequential paclitaxel treatment followed by fluorinated-pyrimidine-based adjuvant chemotherapy. Our findings may facilitate clinical trials on biomarker-oriented postoperative adjuvant chemotherapy for patients with locally advanced GC.
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Su H, Ren W, Zhang D. Research progress on exosomal proteins as diagnostic markers of gastric cancer (review article). Clin Exp Med 2022; 23:203-218. [DOI: 10.1007/s10238-022-00793-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 01/04/2022] [Indexed: 12/20/2022]
Abstract
AbstractGastric cancer (GC) is one of the most common types of tumors and the most common cause of cancer mortality worldwide. The diagnosis of GC is critical to its prevention and treatment. Available tumor markers are the crucial step for GC diagnosis. Recent studies have shown that proteins in exosomes are potential diagnostic and prognostic markers for GC. Exosomes, secreted by cells, are cup-shaped with a diameter of 30–150 nm under the electron microscope. They are also surrounded by lipid bilayers and are widely found in various body fluids. Exosomes contain proteins, lipids and nucleic acid. The examination of exosomal proteins has the advantages of quickness, easy sampling, and low pain and cost, as compared with the routine inspection method of GC, which may lead to marked developments in GC diagnosis. This article summarized the exosomal proteins with a diagnostic and prognostic potential in GC, as well as exosomal proteins involved in GC progression.
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Tazawa H, Suzuki T, Saito A, Ishikawa A, Komo T, Sada H, Shimada N, Hadano N, Onoe T, Sudo T, Shimizu Y, Kuraoka K, Tashiro H. Utility of TMPRSS4 as a Prognostic Biomarker and Potential Therapeutic Target in Patients with Gastric Cancer. J Gastrointest Surg 2022; 26:305-313. [PMID: 34379296 PMCID: PMC8821072 DOI: 10.1007/s11605-021-05101-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/14/2021] [Indexed: 01/31/2023]
Abstract
BACKGROUND Transmembrane serine protease 4 (TMPRSS4) belongs to the family of type II transmembrane serine proteases that are known to be upregulated in many malignant tumors. However, there is a paucity of studies documenting the clinical impact and biological effects of TMPRSS4 on gastric cancer (GC) patients who underwent surgery. METHODS Tissues samples were obtained from 105 patients with GC who underwent gastrectomy followed by adjuvant chemotherapy, excluding those at stage I. The expression of TMPRSS4 was examined through immunohistochemical analysis. The association between TMPRSS4 expression and clinico-pathological features as well as prognosis was assessed. Moreover, the effects of TMPRSS4 expression on cell migration and sensitivity to 5-FU were investigated. RESULTS The expression rate of TMPRSS4 was 56.3% (59/105) in GC cases. The expression of TMPRSS4 was positively correlated with the depth of tumor (T) and venous (V) invasion. The 5-year overall survival (OS) and recurrence-free survival (RFS) rates of the TMPRSS4-positive group was significantly lower than that of the TMPRSS4-negative group (p=0.0001 and p=0.005, respectively). Especially, there was significant differences in OS and RFS of patients with stage III cancer between the two groups (p=0.0064 and 0.012, respectively). Multivariate analysis demonstrated that TMPRSS4 expression and the stage of cancer were crucial prognostic factors for RFS. TMPRSS4-silenced GC cells exhibited increased sensitivity to 5-FU when compared with the non-specific control siRNA-transfected cells. CONCLUSION TMPRSS4 can be considered as a potential prognostic biomarker, especially for stage III, and a promising therapeutic target for GC.
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Affiliation(s)
- Hirofumi Tazawa
- Department of Surgery, Kure Medical Center・Chugoku Cancer Center, 737-0023, 3-1, Kure, Hiroshima, Japan.
| | - Takahisa Suzuki
- Department of Surgery, Kure Medical Center・Chugoku Cancer Center, 737-0023, 3-1, Kure, Hiroshima, Japan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biochemical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Akihisa Saito
- Department of Diagnostic Pathology, Kure Medical Center・Chugoku Cancer Center, Kure, Hiroshima, Japan
| | - Akira Ishikawa
- Department of Diagnostic Pathology, Kure Medical Center・Chugoku Cancer Center, Kure, Hiroshima, Japan
| | - Toshiaki Komo
- Department of Surgery, Kure Medical Center・Chugoku Cancer Center, 737-0023, 3-1, Kure, Hiroshima, Japan
| | - Haruki Sada
- Department of Surgery, Kure Medical Center・Chugoku Cancer Center, 737-0023, 3-1, Kure, Hiroshima, Japan
| | - Norimitsu Shimada
- Department of Surgery, Kure Medical Center・Chugoku Cancer Center, 737-0023, 3-1, Kure, Hiroshima, Japan
| | - Naoto Hadano
- Department of Surgery, Kure Medical Center・Chugoku Cancer Center, 737-0023, 3-1, Kure, Hiroshima, Japan
| | - Takashi Onoe
- Department of Surgery, Kure Medical Center・Chugoku Cancer Center, 737-0023, 3-1, Kure, Hiroshima, Japan
| | - Takeshi Sudo
- Department of Surgery, Kure Medical Center・Chugoku Cancer Center, 737-0023, 3-1, Kure, Hiroshima, Japan
| | - Yosuke Shimizu
- Department of Surgery, Kure Medical Center・Chugoku Cancer Center, 737-0023, 3-1, Kure, Hiroshima, Japan
| | - Kazuya Kuraoka
- Department of Diagnostic Pathology, Kure Medical Center・Chugoku Cancer Center, Kure, Hiroshima, Japan
| | - Hirotaka Tashiro
- Department of Surgery, Kure Medical Center・Chugoku Cancer Center, 737-0023, 3-1, Kure, Hiroshima, Japan.
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biochemical and Health Sciences, Hiroshima University, Hiroshima, Japan.
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20
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Cao B, Wang Q, Fu XL, Wei GD, Zhao L, Zhang PJ, Li D, Zhang HQ, Zhang Q. The efficacy and safety of neoadjuvant nimotuzumab for gastric cancer: A meta-analysis of randomized controlled studies. Medicine (Baltimore) 2021; 100:e27709. [PMID: 34918627 PMCID: PMC8677901 DOI: 10.1097/md.0000000000027709] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 10/20/2021] [Indexed: 01/05/2023] Open
Abstract
INTRODUCTION The efficacy of neoadjuvant nimotuzumab for gastric cancer remained controversial. We conducted a systematic review and meta-analysis to explore the efficacy of neoadjuvant nimotuzumab plus chemotherapy vs chemotherapy for gastric cancer. METHODS We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through May 2019, and included randomized controlled trials assessing the efficacy of neoadjuvant nimotuzumab plus chemotherapy vs chemotherapy for gastric cancer. This meta-analysis was performed using the random-effect model. RESULTS Four randomized controlled trials were included in the meta-analysis. There were 128 patients included in intervention group and 131 patients included in control group. Overall, compared with chemotherapy for gastric cancer, neoadjuvant nimotuzumab plus chemotherapy showed no substantial influence on response rate (risk ratio [RR] = 1.22; 95% CI = 0.78-1.89; P = .38), disease control rate (RR = 2.22; 95% confidence interval [CI] = 0.32-15.40; P = .42), rash (RR = 1.26; 95% CI = 0.96-1.66; P = .10), neutropenia (RR = 1.26; 95% CI = 0.96-1.66; P = .10), anemia (RR = 1.08; 95% CI = 0.62-1.89; P = .78), or nausea (RR = 1.19; 95% CI = 0.96-1.48; P = .12), but might improve the incidence of vomiting (RR = 1.60; 95% CI = 1.03-2.50; P = .04). CONCLUSIONS Neoadjuvant nimotuzumab might provide no additional benefits to the treatment of gastric cancer.
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Affiliation(s)
- Bin Cao
- Department of the Third General Surgery, Baoding First Central Hospital, Baoding Key Laboratory of Gastrointestinal Diagnosis and Treatment, China
| | - Qian Wang
- Department of the Third General Surgery, Baoding First Central Hospital, Baoding Key Laboratory of Gastrointestinal Diagnosis and Treatment, China
| | - Xiao-li Fu
- Department of Geriatrics, Baoding First Central Hospital, China
| | - Guo-dong Wei
- Department of the Third General Surgery, Baoding First Central Hospital, Baoding Key Laboratory of Gastrointestinal Diagnosis and Treatment, China
| | - Long Zhao
- Department of the Third General Surgery, Baoding First Central Hospital, Baoding Key Laboratory of Gastrointestinal Diagnosis and Treatment, China
| | - Pei-jun Zhang
- Department of the Third General Surgery, Baoding First Central Hospital, Baoding Key Laboratory of Gastrointestinal Diagnosis and Treatment, China
| | | | - Hui-qing Zhang
- Department of the Third General Surgery, Baoding First Central Hospital, Baoding Key Laboratory of Gastrointestinal Diagnosis and Treatment, China
| | - Qi Zhang
- Department of Geriatrics, Baoding First Central Hospital, China
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21
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Zhu H, Liu X. Advances of Tumorigenesis, Diagnosis at Early Stage, and Cellular Immunotherapy in Gastrointestinal Malignancies. Front Oncol 2021; 11:666340. [PMID: 34434889 PMCID: PMC8381364 DOI: 10.3389/fonc.2021.666340] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 07/19/2021] [Indexed: 01/10/2023] Open
Abstract
Globally, in 2018, 4.8 million new patients have a diagnosis of gastrointestinal (GI) cancers, while 3.4 million people died of such disorders. GI malignancies are tightly relevant to 26% of the world-wide cancer incidence and occupies 35% of all cancer-associated deaths. In this article, we principally investigated molecular and cellular mechanisms of tumorigenesis in five major GI cancers occurring at esophagus, stomach, liver, pancreas, and colorectal region that illustrate high morbidity in Eastern and Western countries. Moreover, through this investigation, we not only emphasize importance of the tumor microenvironment in development and treatment of malignant tumors but also identify significance of M2PK, miRNAs, ctDNAs, circRNAs, and CTCs in early detection of GI cancers, as well as systematically evaluate contribution of personalized precision medicine including cellular immunotherapy, new antigen and vaccine therapy, and oncolytic virotherapy in treatment of GI cancers.
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Affiliation(s)
- Haipeng Zhu
- Precision and Personalized Cancer Treatment Center, Division of Cancer Diagnosis & Therapy, Ciming Boao International Hospital, Boao Lecheng International Medical Tourism Pilot Zone, Qionghai, China.,Stem Cell and Biotherapy Technology Research Center, Xinxiang Medical College, Xinxiang, China
| | - Xiaojun Liu
- Division of Cellular & Biomedical Science, Ciming Boao International Hospital, Boao Lecheng International Medical Tourism Pilot Zone, Qionghai, China
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22
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De Lorenzo S, Garajova I, Stefanini B, Tovoli F. Targeted therapies for gallbladder cancer: an overview of agents in preclinical and clinical development. Expert Opin Investig Drugs 2021; 30:759-772. [PMID: 33966562 DOI: 10.1080/13543784.2021.1928636] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Gallbladder cancer (GC) is a rare malignancy with a dismal prognosis. When diagnosed early enough, it can be cured by surgical removal. Unfortunately, only few GC patients can be amenable to surgery, though, with a high relapse rate. Conventional chemotherapy remains the golden standard for unresectable or metastatic GC, both in the first and second-line settings, even if leading to a fair outcome improvement.Areas covered: In recent years, according to the concept of 'precision medicine', new potential molecular targets have been examined. We provided a general outline of the current first- and second-line chemotherapies. New therapeutic possibilities are also reviewed, particularly HER2, EGFR, VEGF, TKI, MEK and BRAF inhibitors, and immunotherapy. Furthermore, published clinical trials are utilized to analyze the principal drug effectiveness in GC.Expert opinion: GC is characterized by vast cancer heterogeneity and individual's efficacy to different drugs. The ongoing trials have the potentiality of reshaping the landscape of systemic treatments for GC in the very next years. Nowadays, amongst therapeutic combinations, the addition of ICIs to chemotherapy has yielded encouraging results needing confirmation. In the next future, systematic implementation of gene profiling and further explorations of combination therapies will likely change the treatment scenario.
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Affiliation(s)
| | - Ingrid Garajova
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Bernardo Stefanini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
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23
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Chang Y, Roy S, Pan Z. Store-Operated Calcium Channels as Drug Target in Gastroesophageal Cancers. Front Pharmacol 2021; 12:668730. [PMID: 34012400 PMCID: PMC8126661 DOI: 10.3389/fphar.2021.668730] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 04/12/2021] [Indexed: 12/24/2022] Open
Abstract
Gastroesophageal cancers, including tumors occurring in esophagus and stomach, usually have poor prognosis and lack effective chemotherapeutic drugs for treatment. The association between dysregulated store-operated calcium entry (SOCE), a key intracellular Ca2+ signaling pathway and gastroesophageal cancers are emerging. This review summarizes the recent advances in understanding the contribution of SOCE-mediated intracellular Ca2+ signaling to gastroesophageal cancers. It assesses the pathophysiological role of each component in SOCE machinery, such as Orais and STIMs in the cancer cell proliferation, migration, and invasion as well as stemness maintenance. Lastly, it discusses efforts towards development of more specific and potent SOCE inhibitors, which may be a new set of chemotherapeutic drugs appearing at the horizon, to provide either targeted therapy or adjuvant treatment to overcome drug resistance for gastroesophageal cancers.
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Affiliation(s)
- Yan Chang
- College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, United States
| | - Souvik Roy
- Department of Mathematics, The University of Texas at Arlington, Arlington, TX, United States
| | - Zui Pan
- College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, United States
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24
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Lau DK, Athauda A, Chau I. Neoadjuvant and adjuvant multimodality therapies in resectable esophagogastric adenocarcinoma. Expert Opin Pharmacother 2021; 22:1429-1441. [PMID: 33688789 DOI: 10.1080/14656566.2021.1900823] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: Gastric and esophageal adenocarcinoma is a leading cause of cancer-related death globally. Surgery is the cornerstone modality for cure where feasible. Clinical studies over the past two decades have provided evidence for the use of perioperative chemotherapy and chemoradiotherapy to improve patient outcomes. However, there remains no global consensus in the optimal use of these therapies.Areas covered: In this review, the authors summarize the latest evidence for perioperative multimodality therapy in resectable esophagogastric adenocarcinoma including the use of combination chemotherapy and targeted therapy containing regimens. In addition, the authors discuss some of the clinical and molecular biomarkers, such as PET imaging and microsatellite instability which can inform future practice and further clinical investigation.Expert opinion: A multimodal approach has been proven to improve survival outcomes over surgery alone. Whilst there is no global standard of care for multi-modality therapies in resectable OG cancer, clinical trials are refining the use of chemotherapy and radiotherapy in the neoadjuvant and adjuvant settings. Further investigation is on-going to further optimize therapy and the integration of molecular targeted agents.
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Affiliation(s)
- David K Lau
- GI and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton and London, UK
| | - Avani Athauda
- GI and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton and London, UK
| | - Ian Chau
- GI and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton and London, UK
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25
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A global and physical mechanism of gastric cancer formation and progression. J Theor Biol 2021; 520:110643. [PMID: 33636204 DOI: 10.1016/j.jtbi.2021.110643] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 12/26/2020] [Accepted: 02/11/2021] [Indexed: 12/17/2022]
Abstract
Gastric cancer is regarded as a major health issue for human being nowadays. The Helicobacter pylori (H. pylori) infection has been found to accelerate the development of gastritis and gastric cancer. Significant efforts have been made towards the understanding of the biology of gastric cancer on both genetic and epigenetic levels. However the physical mechanism behind the gastric cancer formation is still elusive. In this study, we constructed a model for investigating gastric cancer formation by explored the gastric cancer landscape and the flow flux. We uncovered three stable state attractors on the landscape: normal, gastritis and gastric cancer. The definition of each attractor is based on the biological function and gene expression levels. The global stabilities and the switching processes were quantified through the barrier heights and dominant kinetic paths. To investigate the underlying mechanism of the process from normal through the gastritis to the gastric cancer caused by genetic or epigenetic factors, we simulate the oncogenesis of gastric cancer through changes of several gene regulation strengths and H. pylori infection. The simulated results can illustrate the developmental and metastasis process of gastric cancer. Different H. pylori infection degrees accelerating the process from gastritis to gastric cancer can be quantified. Then we applied global sensitivity analysis, one key gene and four key regulations were found. These results are consist with the experimental results and can be used to design the polygenic anti-cancer agents through multiple key genes or regulations. The landscape approach provides a physical and simple strategy for analyzing gastric cancer in a systematic and quantitative way. It also offers new insight into treatment strategy for gastric cancer by adjusting relevant polygenic genes and regulations.
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26
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Watanabe M, Kuwata T, Setsuda A, Tokunaga M, Kaito A, Sugita S, Tonouchi A, Kinoshita T, Nagino M. Molecular and pathological analyses of gastric stump cancer by next-generation sequencing and immunohistochemistry. Sci Rep 2021; 11:4165. [PMID: 33603111 PMCID: PMC7892542 DOI: 10.1038/s41598-021-83711-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 02/02/2021] [Indexed: 11/11/2022] Open
Abstract
Gastric stump cancer (GSC) has distinct clinicopathological characteristics from primary gastric cancer. However, the detailed molecular and pathological characteristics of GSC remain to be clarified because of its rarity. In this study, a set of tissue microarrays from 89 GSC patients was analysed by immunohistochemistry and in situ hybridisation. Programmed death ligand 1 (PD-L1) was expressed in 98.9% of tumour-infiltrating immune cells (TIICs) and 6.7% of tumour cells (TCs). Epstein-Barr virus (EBV) was detected in 18 patients (20.2%). Overexpression of human epidermal growth factor receptor 2 and deficiency of mismatch repair (MMR) protein expression were observed in 5.6% and 1.1% of cases, respectively. Moreover, we used next-generation sequencing to determine the gene mutation profiles of a subset of the 50 most recent patients. The most frequently mutated genes were TP53 (42.0%) followed by SMAD4 (18.0%) and PTEN (16.0%), all of which are tumour suppressor genes. A high frequency of PD-L1 expression in TIICs and a high EBV infection rate suggest immune checkpoint inhibitors for treatment of GSC despite a relatively low frequency of deficient MMR gene expression. Other molecular characteristics such as PTEN and SMAD4 mutations might be considered to develop new treatment strategies.
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Affiliation(s)
- Masahiro Watanabe
- Department of Gastric Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8650, Japan
| | - Takeshi Kuwata
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
- Department of Genetic Medicine and Services, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
| | - Ayumi Setsuda
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Masanori Tokunaga
- Department of Gastric Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Akio Kaito
- Department of Gastric Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Shizuki Sugita
- Department of Gastric Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8650, Japan
| | - Akiko Tonouchi
- Department of Gastric Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Takahiro Kinoshita
- Department of Gastric Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Masato Nagino
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8650, Japan
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Felismino TC, de Oliveira ACF, Alves ACF, da Costa Junior WL, Coimbra FJF, de Souza Begnami MDF, Riechelmann RP, de Jesus VHF, de Mello CAL. Primary Tumor Location Is a Predictor of Poor Prognosis in Patients with Locally Advanced Esophagogastric Cancer Treated with Perioperative Chemotherapy. J Gastrointest Cancer 2021; 51:484-490. [PMID: 31179509 DOI: 10.1007/s12029-019-00258-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Esophagogastric cancer (EGC) is a leading neoplasm worldwide. Perioperative chemotherapy (periCT) is currently a standard of care for most patients (pts). Prevalence of esophagogastric junction (EGJ) tumors is increasing over the last years. METHODS The aim of this study was to retrospectively search for prognostic factors in pts. with locally advanced EGC treated with periCT. Three-year overall survival (OS) and Event-Free Survival (EFS) were main end-points. HER-2 positive tumors were defined by immunohistochemistry or FISH. RESULTS Between June/2007 and November/2015, 128 pts. started periCT for esophagogastric junction (EGJ) or gastric adenocarcinoma (GC). Median age was 59.5 y and 64% were male. Primary site was EGJ in 27% and 65% were cN+. Diffuse subtype was seen in 42%. Ninety-seven pts. were assessed for HER-2; 14 (14.4%) were positive. After median follow-up time of 45 m, 48 deaths occurred. The 3-year OS and EFS rate was 61.3% and 51.2%, respectively. Main prognostic factors were: AJCC ypT3-T4yN1-N3 (HR 6.75 p 0.002) and EGJ primary (HR 2.64, p 0.004). Overall HER-2 was not prognostic. Still, a difference in 3-year OS was observed for GC/HER2+ compared to EGJ/HER2+ (88.9% versus 20%, p = 0.002). This difference is greater for 3-year EFS with no patient with EGJ/HER2+ free-of-event against 62.5% for GC/HER+ (p = 0.011). CONCLUSION In our analysis, pathological staging and primary site were main prognostic factors. Moreover, a small group of EGJ/HER2+ had very poor survival.
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Affiliation(s)
- Tiago Cordeiro Felismino
- Medical Oncology Department, AC Camargo Cancer Center, Rua Professor Antônio Prudente 211, Liberdade, São Paulo, SP CEP: 01509-010, Brazil.
| | - Audrey Cabral Ferreira de Oliveira
- Medical Oncology Department, AC Camargo Cancer Center, Rua Professor Antônio Prudente 211, Liberdade, São Paulo, SP CEP: 01509-010, Brazil
| | - Ana Caroline Fonseca Alves
- Medical Oncology Department, AC Camargo Cancer Center, Rua Professor Antônio Prudente 211, Liberdade, São Paulo, SP CEP: 01509-010, Brazil
| | | | | | | | - Rachel P Riechelmann
- Medical Oncology Department, AC Camargo Cancer Center, Rua Professor Antônio Prudente 211, Liberdade, São Paulo, SP CEP: 01509-010, Brazil
| | - Victor Hugo Fonseca de Jesus
- Medical Oncology Department, AC Camargo Cancer Center, Rua Professor Antônio Prudente 211, Liberdade, São Paulo, SP CEP: 01509-010, Brazil
| | - Celso Abdon Lopes de Mello
- Medical Oncology Department, AC Camargo Cancer Center, Rua Professor Antônio Prudente 211, Liberdade, São Paulo, SP CEP: 01509-010, Brazil
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Rivera F, Izquierdo-Manuel M, García-Alfonso P, Martínez de Castro E, Gallego J, Limón ML, Alsina M, López L, Galán M, Falcó E, Manzano JL, González E, Muñoz-Unceta N, López C, Aranda E, Fernández E, Jorge M, Jiménez-Fonseca P. Perioperative trastuzumab, capecitabine and oxaliplatin in patients with HER2-positive resectable gastric or gastro-oesophageal junction adenocarcinoma: NEOHX phase II trial. Eur J Cancer 2021; 145:158-167. [PMID: 33485079 DOI: 10.1016/j.ejca.2020.12.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/30/2020] [Accepted: 12/02/2020] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Perioperative chemotherapy improves overall survival (OS) and disease-free survival (DFS) compared with surgery alone in patients with resectable gastric adenocarcinoma (GA) or gastro-oesophageal junction adenocarcinoma (GEJA). The addition of trastuzumab to chemotherapy improves outcomes in patients with HER2-positive advanced gastric cancer (GC), and we aimed to explore its role in the perioperative setting. MATERIAL AND METHODS This Spanish, multicentre, open-label phase II trial evaluated the efficacy and toxicity of perioperative capecitabine, oxaliplatin and trastuzumab (XELOX-T) in patients with HER2-positive resectable GA or GEJA. The primary end-point was 18-months DFS; and secondary end-points included pathological complete response (pCR) rate, R0 resection rate, OS and toxicity (NCT01130337). RESULTS Thirty-six patients were included. After three cycles of preoperative treatment, 14 patients (38% of the intention-to-treat population) had partial response and 18 (50%) had stable disease. Surgery was performed in 31 patients: 28 (90%) had R0 resection, three (9.6%) had a pCR and three (9.6%) died due to surgical complications. A total of 24 patients received post-operative XELOX-T, 22 of whom completed trastuzumab maintenance. Main grade III/IV toxicities included diarrhoea (33%), nausea and vomiting (8%). After a median follow-up of 24.1 months, 18-month DFS was 71% (95% confidence interval [CI], 53-83%); and an update after 102 months of follow-up showed a median OS of 79.9 months and a 60-month OS of 58% (95% CI, 40-73%). CONCLUSIONS These data suggest that perioperative XELOX-T in patients with HER2-positive GA and GEJA is feasible and active. Further investigation in randomised studies is warranted.
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Affiliation(s)
- Fernando Rivera
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
| | | | - Pilar García-Alfonso
- Medical Oncology Department, Hospital Universitario Gregorio Marañón, Madrid, Spain.
| | - Eva Martínez de Castro
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
| | - Javier Gallego
- Medical Oncology Department, Hospital General Universitario de Elche, Alicante, Spain.
| | - María Luisa Limón
- Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
| | - María Alsina
- Medical Oncology Department, Hospital Universitari Vall d'Hebron and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
| | - Luis López
- Medical Oncology Department, Hospital Universitario Virgen de la Salud, Toledo, Spain.
| | - Maica Galán
- Medical Oncology Department, Institut Catala d'Oncologia (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.
| | - Esther Falcó
- Medical Oncology Department, Hospital Universitario Sont Llatzer, Palma de Mallorca, Spain.
| | - José Luis Manzano
- Medical Oncology Department, Institut Catala d'Oncologia (ICO), Hospital Universitario Germans Trias i Pujol, Badalona, Spain.
| | - Encarna González
- Medical Oncology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain.
| | - Nerea Muñoz-Unceta
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
| | - Carlos López
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
| | - Enrique Aranda
- Medical Oncology Department, Hospital Universitario Reina Sofía, IMIBIC, UCO, Córdoba, Spain.
| | - Eva Fernández
- Medical Oncology Department, Hospital Universitario de Valme, Sevilla, Spain.
| | - Mónica Jorge
- Medical Oncology Department, Hospital Xeral Cies, Vigo, Spain.
| | - Paula Jiménez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.
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Duarte HO, Rodrigues JG, Gomes C, Hensbergen PJ, Ederveen ALH, de Ru AH, Mereiter S, Polónia A, Fernandes E, Ferreira JA, van Veelen PA, Santos LL, Wuhrer M, Gomes J, Reis CA. ST6Gal1 targets the ectodomain of ErbB2 in a site-specific manner and regulates gastric cancer cell sensitivity to trastuzumab. Oncogene 2021; 40:3719-3733. [PMID: 33947960 PMCID: PMC8154592 DOI: 10.1038/s41388-021-01801-w] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 03/22/2021] [Accepted: 04/14/2021] [Indexed: 02/03/2023]
Abstract
The clinical performance of the therapeutic monoclonal antibody trastuzumab in the treatment of ErbB2-positive unresectable gastric cancer (GC) is severely hampered by the emergence of molecular resistance. Trastuzumab's target epitope is localized within the extracellular domain of the oncogenic cell surface receptor tyrosine kinase (RTK) ErbB2, which is known to undergo extensive N-linked glycosylation. However, the site-specific glycan repertoire of ErbB2, as well as the detailed molecular mechanisms through which specific aberrant glycan signatures functionally impact the malignant features of ErbB2-addicted GC cells, including the acquisition of trastuzumab resistance, remain elusive. Here, we demonstrate that ErbB2 is modified with both α2,6- and α2,3-sialylated glycan structures in GC clinical specimens. In-depth mass spectrometry-based glycomic and glycoproteomic analysis of ErbB2's ectodomain disclosed a site-specific glycosylation profile in GC cells, in which the ST6Gal1 sialyltransferase specifically targets ErbB2 N-glycosylation sites occurring within the receptor's trastuzumab-binding domain. Abrogation of ST6Gal1 expression reshaped the cellular and ErbB2-specific glycomes, expanded the cellular half-life of the ErbB2 receptor, and sensitized ErbB2-dependent GC cells to trastuzumab-induced cytotoxicity through the stabilization of ErbB dimers at the cell membrane, and the decreased activation of both ErbB2 and EGFR RTKs. Overall, our data demonstrates that ST6Gal1-mediated aberrant α2,6-sialylation actively tunes the resistance of ErbB2-driven GC cells to trastuzumab.
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Affiliation(s)
- Henrique O. Duarte
- grid.5808.50000 0001 1503 7226i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal ,grid.5808.50000 0001 1503 7226IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal ,grid.5808.50000 0001 1503 7226ICBAS—Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
| | - Joana G. Rodrigues
- grid.5808.50000 0001 1503 7226i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal ,grid.5808.50000 0001 1503 7226IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal ,grid.5808.50000 0001 1503 7226ICBAS—Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
| | - Catarina Gomes
- grid.5808.50000 0001 1503 7226i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal ,grid.5808.50000 0001 1503 7226IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Paul J. Hensbergen
- grid.10419.3d0000000089452978Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, The Netherlands
| | - Agnes L. Hipgrave Ederveen
- grid.10419.3d0000000089452978Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, The Netherlands
| | - Arnoud H. de Ru
- grid.10419.3d0000000089452978Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, The Netherlands
| | - Stefan Mereiter
- grid.5808.50000 0001 1503 7226i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal ,grid.5808.50000 0001 1503 7226IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal ,grid.4299.60000 0001 2169 3852Present Address: IMBA, Institute of Molecular Biotechnology, Austrian Academy of Sciences, Vienna, Austria
| | - António Polónia
- grid.5808.50000 0001 1503 7226i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal ,grid.5808.50000 0001 1503 7226IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal ,grid.5808.50000 0001 1503 7226IPATIMUP Diagnostics, Department of Pathology, IPATIMUP, University of Porto, Porto, Portugal
| | - Elisabete Fernandes
- grid.418711.a0000 0004 0631 0608Experimental Pathology and Therapeutics Group, IPO-Porto Research Center, Portuguese Institute of Oncology, Porto, Portugal
| | - José A. Ferreira
- grid.418711.a0000 0004 0631 0608Experimental Pathology and Therapeutics Group, IPO-Porto Research Center, Portuguese Institute of Oncology, Porto, Portugal
| | - Peter A. van Veelen
- grid.10419.3d0000000089452978Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, The Netherlands
| | - Lúcio L. Santos
- grid.418711.a0000 0004 0631 0608Experimental Pathology and Therapeutics Group, IPO-Porto Research Center, Portuguese Institute of Oncology, Porto, Portugal ,grid.418711.a0000 0004 0631 0608Department of Surgical Oncology, Portuguese Institute of Oncology, Porto, Portugal
| | - Manfred Wuhrer
- grid.10419.3d0000000089452978Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, The Netherlands
| | - Joana Gomes
- grid.5808.50000 0001 1503 7226i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal ,grid.5808.50000 0001 1503 7226IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - Celso A. Reis
- grid.5808.50000 0001 1503 7226i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal ,grid.5808.50000 0001 1503 7226IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal ,grid.5808.50000 0001 1503 7226ICBAS—Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal ,grid.5808.50000 0001 1503 7226Faculty of Medicine, University of Porto, Porto, Portugal
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Xin L, Tang F, Song B, Yang M, Zhang J. Objective Quantitation of EGFR Protein Levels using Quantitative Dot Blot Method for the Prognosis of Gastric Cancer Patients. J Gastric Cancer 2021; 21:335-351. [PMID: 35079437 PMCID: PMC8753283 DOI: 10.5230/jgc.2021.21.e32] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/21/2021] [Accepted: 10/28/2021] [Indexed: 11/23/2022] Open
Abstract
Purpose An underlying factor for the failure of several clinical trials of anti-epidermal growth factor receptor (EGFR) therapies is the lack of an effective method to identify patients who overexpress EGFR protein. The quantitative dot blot method (QDB) was used to measure EGFR protein levels objectively, absolutely, and quantitatively. Its feasibility was evaluated for the prognosis of overall survival (OS) of patients with gastric cancer. Materials and Methods Slices of 2×5 μm from formalin-fixed paraffin-embedded gastric cancer specimens were used to extract total tissue lysates for QDB measurement. Absolutely quantitated EGFR protein levels were used for the Kaplan-Meier OS analysis. Results EGFR protein levels ranged from 0 to 772.6 pmol/g (n=246) for all gastric cancer patients. A poor correlation was observed between quantitated EGFR levels and immunohistochemistry scores with ρ=0.024 and P=0.717 in Spearman's correlation analysis. EGFR was identified as an independent negative prognostic biomarker for gastric cancer patients only through absolute quantitation, with a hazard ratio of 1.92 (95% confidence interval, 1.05–3.53; P=0.034) in multivariate Cox regression OS analysis. A cutoff of 208 pmol/g was proposed to stratify patients with a 3-year survival probability of 44% for patients with EGFR levels above the cutoff versus 68% for those below the cutoff based on Kaplan-Meier OS analysis (log rank test, P=0.002). Conclusions A QDB-based assay was developed for gastric cancer specimens to measure EGFR protein levels absolutely, quantitatively, and objectively. This assay should facilitate clinical trials aimed at evaluation of anti-EGFR therapies retrospectively and prospectively for gastric cancer.
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Affiliation(s)
- Lei Xin
- Department of Gastrointestinal Surgery, Yantaishan Hospital, Yantai, China
| | - Fangrong Tang
- Yantai Quanticision Diagnostics, Inc. (Division of Quanticision Diagnostics, Inc. of USA), Yantai, China
| | - Bo Song
- Department of Gastroenterology, Yantaishan Hospital, Yantai, China
| | - Maozhou Yang
- Yantai Quanticision Diagnostics, Inc. (Division of Quanticision Diagnostics, Inc. of USA), Yantai, China
| | - Jiandi Zhang
- Yantai Quanticision Diagnostics, Inc. (Division of Quanticision Diagnostics, Inc. of USA), Yantai, China
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31
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Maron SB, Xu J, Janjigian YY. Targeting EGFR in Esophagogastric Cancer. Front Oncol 2020; 10:553876. [PMID: 33364187 PMCID: PMC7753114 DOI: 10.3389/fonc.2020.553876] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 11/05/2020] [Indexed: 12/24/2022] Open
Abstract
Esophagogastric cancer (EGC) remains a major cause of cancer-related mortality. Overall survival in the metastatic setting remains poor, with few molecular targeted approaches having been successfully incorporated into routine care to-date: only first line anti-HER2 therapy in ERBB2-expressing tumors, second line anti-VEGFR2 therapy with ramucirumab in unselected patients, and pembrolizumab in PD-L1 expressing or MSI-H patients. EGFR inhibitors were extensively studied in EGC, including phase III trials with cetuximab (EXPAND), panitumumab (REAL3), and gefitinib (COG). All three trials were conducted in unselected populations, and therefore, failed to demonstrate clinical benefit. Here, we review previous attempts at targeting EGFR in EGC and potential future biomarkers for targeting this pathway in patients with EGFR-amplified tumors.
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Affiliation(s)
- Steven B Maron
- Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - James Xu
- Computer Engineering Program, Columbia University, New York, NY, United States
| | - Yelena Y Janjigian
- Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
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32
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Nakamura Y, Sasaki A, Yukami H, Jogo T, Kawazoe A, Kuboki Y, Taniguchi H, Yamashita R, Kuwata T, Ozawa M, Nakamura M, Yoshino T, Shitara K. Emergence of Concurrent Multiple EGFR Mutations and MET Amplification in a Patient With EGFR-Amplified Advanced Gastric Cancer Treated With Cetuximab. JCO Precis Oncol 2020; 4:2000263. [PMID: 33283138 DOI: 10.1200/po.20.00263] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/20/2020] [Indexed: 12/19/2022] Open
Affiliation(s)
- Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.,Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Akinori Sasaki
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Hiroki Yukami
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Tomoko Jogo
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Akihito Kawazoe
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Yasutoshi Kuboki
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Hiroya Taniguchi
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.,Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Riu Yamashita
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan
| | - Takeshi Kuwata
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Miho Ozawa
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Maho Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
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Zhou Q, Lan X, Li N, Yuan D, Zhang J. Analysis of Prognostic Factors and Design of Prognosis Model for Patients with Stage IV Gastric Cancer Following First-Line Palliative Chemotherapy. Cancer Manag Res 2020; 12:10461-10468. [PMID: 33122945 PMCID: PMC7588669 DOI: 10.2147/cmar.s263320] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 09/14/2020] [Indexed: 01/13/2023] Open
Abstract
Background This study was to investigate the prognostic factors of patients with advanced gastric cancer and described a sample model to better differentiate the patients who could better benefit from palliative chemotherapy. Patients and Methods In this retrospective study, 112 gastric cancer patients at stage IV following first-line chemotherapy were enrolled from July 2013 to September 2019. The clinical factors including age, sex, ECOG, pathologic types, metastatic sites, blood indexes, response of first-line chemotherapy, and survival were collected. The treatment responses were evaluated using the response evaluation criteria in solid tumors (RECIST). The survival curves were drawn by the Kaplan–Meier method, and the independent prognostic factors of overall survival (OS) were analyzed by Cox proportional hazards regression model. Results In this study, the median overall survival (mOS) of gastric cancer patients was 10.5 months, the disease remission rate (PR) was 21.4%, and the disease control rate (DCR) was 86.6%. Multivariate analysis identified 5 independent prognostic factors: peritoneal metastasis [P = 0.002; hazard risk (HR), 2.394; 95% CI 1.394–4.113], hemoglobin <90g/L [P = 0.001; hazard risk (HR), 2.674; 95% CI 1.536–4.655], LDH ≥225 U/L [P = 0.033; hazard risk (HR), 1.818; 95% CI 1.409–3.150], and 3 times higher level of CEA [P = 0.006; hazard risk (HR), 2.123; 95% CI 1.238–3.640] along with CA199 [P = 0.005; hazard risk (HR), 2.544; 95% CI 1.332–4.856] than upper limit of normal. Based on the obtained data, a prognostic index was constructed, dividing the patients into three risk groups: low (n = 67), intermediate (n = 35), and high-risk group (n = 10). The mOS for low, intermediate, and high-risk groups was 13.9 months (95% CI 10.7–17.1), 8.1 months (95% CI 5.7–10.4), and 3.9 months (95% CI 2.6–5.3), respectively, whereas the 1-year survival rate was 56.4%, 20.0%, and 0.0%, respectively (P < 0.001). Conclusion This model should facilitate the prediction of treatment outcomes and then individualized treatment of advanced gastric cancer patients.
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Affiliation(s)
- Qiyin Zhou
- Department of Oncology, Chengdu Seventh People Hospital (Chengdu Tumorous Disease Quality Control Center), Chengdu 610000, People's Republic of China
| | - Xi Lan
- Department of Oncology, Chengdu Seventh People Hospital (Chengdu Tumorous Disease Quality Control Center), Chengdu 610000, People's Republic of China
| | - Ni Li
- Department of Oncology, Chengdu Seventh People Hospital (Chengdu Tumorous Disease Quality Control Center), Chengdu 610000, People's Republic of China
| | - Daozu Yuan
- Department of Oncology, Chengdu Seventh People Hospital (Chengdu Tumorous Disease Quality Control Center), Chengdu 610000, People's Republic of China
| | - Jiliang Zhang
- Department of Oncology, Chengdu Seventh People Hospital (Chengdu Tumorous Disease Quality Control Center), Chengdu 610000, People's Republic of China
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Sun LF, Yang K, Wang YG, Liu YX, Hou PX, Lu ZH, Chen XL, Zhang WH, Zhou ZG, Mo XM, Hu JK. The Role of HER2 in Self-Renewal, Invasion, and Tumorigenicity of Gastric Cancer Stem Cells. Front Oncol 2020; 10:1608. [PMID: 32974199 PMCID: PMC7472958 DOI: 10.3389/fonc.2020.01608] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 07/24/2020] [Indexed: 02/05/2023] Open
Abstract
Background Deregulation of HER2 expression could affect the biological characteristics of gastric cancer cells and treatment option for gastric cancer patients. This research aims to investigate the impact of HER2 on biological characteristics of gastric cancer stem cells (GCSCs) and prognosis of gastric cancer patients. Methods HER2 knockdown in GCSCs were constructed by lentivirus transfection. Alterations of proliferation, self-renewal, invasion, migration, colony formation, and tumorigenicity of GCSCs were examined. The changes of gene expressions after HER2 interference in GCSCs were detected by gene microarray. The impact of concentration of serum HER2 and expression of HER2 in tumor tissues on survival of 213 gastric cancer patients was also analyzed. Results Down-regulation of HER2 decreased the self-renewal, colony formation, migration, invasion, proliferation, and chemotherapy resistance of GCSCs. However, the tumorigenicity of GCSCs in vivo was increased after down-regulation of HER2. The results of gene microarray showed that HER2 gene might regulate the signal transduction of mTOR, Jak-STAT, and other signal pathways and affect the biological characteristics of GCSCs. Furthermore, survival analyses indicated that patients with high concentration of HER2 in serum had a favorable overall survival. However, there was no significant correlation between expression of HER2 in tumor tissue and overall survival. Conclusion Interference of HER2 in GCSCs decreased the capacity of self-renewal, proliferation, colony formation, chemotherapy resistance, invasion, and migration but might increase the tumorigenicity in vivo. Patients with high concentration of HER2 in serum seemed to have a favorable prognosis.
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Affiliation(s)
- Li-Fei Sun
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Kun Yang
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Yi-Gao Wang
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yu-Xin Liu
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Pei-Xian Hou
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Zheng-Hao Lu
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Xiao-Long Chen
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Wei-Han Zhang
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Zong-Guang Zhou
- Department of Gastrointestinal Surgery and Laboratory of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Xian-Ming Mo
- Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Jian-Kun Hu
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
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Hara H, Ozawa S, Ninomiya Y, Yamamoto M, Ogimi M, Nabeshima K, Nakamura K, Kajiwara H, Nakamura N, Sato Y. Prognostic significance of vasohibin-1 and vasohibin-2 immunohistochemical expression in gastric cancer. Surg Today 2020; 50:1530-1543. [PMID: 32494966 DOI: 10.1007/s00595-020-02040-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 04/27/2020] [Indexed: 12/17/2022]
Abstract
PURPOSE It was recently identified that the vasohibin family may regulate angiogenesis through suppression by the vasohibin-1 gene and promotion by the vasohibin-2 gene. We assessed vasohibin expression in gastric cancer patients and its effect on their prognosis. METHODS We evaluated vasohibin immunohistochemical expression in 210 patients with gastric cancer, who underwent radical surgery. The patients were divided first into a vasohibin-1-positive group and a vasohibin-1-negative group, and then into groups with high or low vasohibin-2 expression, to allow us to investigate the clinicopathological factors of prognosis retrospectively. RESULTS There were 139 patients in the vasohibin-1-positive group and 71 patients in the vasohibin-1-negative group, among which there were and 108 with high vasohibin-2 expression and 102 with low vasohibin-2 expression. Vasohibin-1 was associated with Ly (P = 0.003) and pT (P = 0.037), whereas vasohibin-2 was associated with Ly (P < 0.001), V (P < 0.001) and pStage (P < 0.001). Overall, cancer-specific and relapse-free survival rates were lower in the vasohibin-1-positive (P = 0.034, P < 0.001, P = 0.002, respectively) and high vasohibin-2 expression (P = 0.004, P = 0.003, P < 0.001, respectively) groups. Multivariate analysis revealed that vasohibin-1 expression was associated with cancer-specific (P = 0.014, hazard ratio [HR] 4.454) and relapse-free (P = 0.035, HR 2.557) survival and vasohibin-2 expression tended to influence relapse-free survival (P = 0.051, HR 2.061). Grouping patients by vasohibin expression status combinations showed correlation among their expressions (P = 0.005). Overall, cancer-specific and relapse-free survival rates were lowest in the vasohibin-1-positive and high vasohibin-2 expression group. CONCLUSION Our findings demonstrate that vasohibin-1 and vasohibin-2 could be novel biomarkers for predicting gastric cancer prognosis.
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Affiliation(s)
- Hitoshi Hara
- Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1143, Japan
| | - Soji Ozawa
- Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1143, Japan.
| | - Yamato Ninomiya
- Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1143, Japan
| | - Miho Yamamoto
- Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1143, Japan
| | - Mika Ogimi
- Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1143, Japan
| | - Kazuhito Nabeshima
- Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1143, Japan
| | - Kenji Nakamura
- Department of Gastroenterological Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1143, Japan
| | - Hiroshi Kajiwara
- Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1143, Japan
| | - Naoya Nakamura
- Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1143, Japan
| | - Yasufumi Sato
- Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-9575, Japan
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Feng L, Du J, Yao C, Jiang Z, Li T, Zhang Q, Guo X, Yu M, Xia H, Shi L, Jia J, Tong Y, Ju L, Liu J, Lou J, Lemos B. Ribosomal DNA copy number is associated with P53 status and levels of heavy metals in gastrectomy specimens from gastric cancer patients. ENVIRONMENT INTERNATIONAL 2020; 138:105593. [PMID: 32120062 DOI: 10.1016/j.envint.2020.105593] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 02/15/2020] [Accepted: 02/18/2020] [Indexed: 06/10/2023]
Abstract
The ribosomal DNA (rDNA) can act as a sensor and responder of cancer-associated stress. Here we investigated rDNA copy number in gastric cancers and its association with existing biomarkers and metals exposure. This study was performed on paired tumor and adjacent normal tissues obtained from 65 gastric cancer patients who underwent gastrectomy. Immunohistochemistry was used to assess HER-2, E-cadherin, EGFR, CK (pan), CK20, CK7, TopoⅡ, CAM5.2, P53, and Ki-67 expression. Inductively coupled plasma mass spectrometry (ICP-MS) was used to detect the concentrations of 17 metals in gastric tissues. rDNA copy number was detected by qPCR in genomic DNA isolated from tissue samples. Associations between the expression of existing markers, metal concentrations, and rDNA copy number were evaluated. Within patients with gastric cancer, the copy number of the 45S rDNA components (18S, 5.8S, 28S) and the 5S rDNA in tumor tissues were significantly higher than those in adjacent normal tissues, whereas mitochondrial DNA (mtDNA) copy number was significantly lower in tumor tissues than that in adjacent normal tissues. Further analysis revealed that the increase in 18S, 5.8S, and 28S rDNA copy number in tumor tissues was diminished in the context of EGFR and P53 loss. Moreover, analysis of metals revealed particularly high concentrations of As, Cd, Cr, Cu and Fe in the gastric tissues of these patients. Intriguingly, rDNA copy number variation across individuals was correlated with the concentrations of some metals. The rDNA was amplified in tumor tissues of gastric cancer patients, and its amplification may be associated with metals exposure. The expression of EGFR and P53 may influence rDNA copy number, with diminished amplification of the rDNA in cancers that were negative for these biomarkers. Our observation further our understanding of rDNA copy number in gastric cancer and its potential as a simple and useful marker in gastric cancer monitoring.
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Affiliation(s)
- Lingfang Feng
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Jing Du
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, Hangzhou, China; People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Chunji Yao
- Institute of Hygiene, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Zhaoqiang Jiang
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Tao Li
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Quan Zhang
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, China
| | - Xinnian Guo
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Min Yu
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Hailing Xia
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Li Shi
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Junlin Jia
- Center for Biostatistics, Bioinformatics and Big Data, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yan Tong
- Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Li Ju
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Jiaqi Liu
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China
| | - Jianlin Lou
- Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China; Hangzhou Medical College, Hangzhou, China.
| | - Bernardo Lemos
- Department of Environmental Health, Harvard University T.H. Chan School of Public Health, Boston, USA
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Roy AC, Shapiro J, Burge M, Karapetis CS, Pavlakis N, Segelov E, Chau I, Lordick F, Chen LT, Barbour A, Tebbutt N, Price T. Management of early-stage gastro-esophageal cancers: expert perspectives from the Australasian Gastrointestinal Trials Group (AGITG) with invited international faculty. Expert Rev Anticancer Ther 2020; 20:305-324. [PMID: 32202178 DOI: 10.1080/14737140.2020.1746185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Introduction: A multimodal approach in operable early-stage oesophago-gastric (OG) cancer has evolved in the last decade, leading to improvement in overall outcomes.Areas covered: A review of the published literature and conference abstracts was undertaken on the topic of optimal adjunctive chemotherapy or chemoradiotherapy in early-stage OG cancers. This review article focuses on the current evidence pertaining to neoadjuvant and perioperative strategies in curable OG cancers including the evolving landscape of immunotherapy and targeted drugs in this setting.Expert commentary: Adjunctive therapies in the form of preoperative chemo-radiotherapy (CRT) or chemotherapy and perioperative chemotherapy over surgery alone improve outcomes in patients with operable OG cancer. Although there are variations in practice around the world, a multi-disciplinary approach to patient care is of paramount importance. Immunotherapy and on treatment functional imaging are two examples of emerging strategies to improve the outcome for early-stage patients. A better understanding of the molecular biology of this disease may help overcome the problem of tumor heterogeneity and enable more rationally designed and targeted therapeutic interventions in the future.
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Affiliation(s)
- Amitesh C Roy
- Flinders Centre for Innovation in Cancer, Flinders University, Bedford Park, Australia
| | | | - Matt Burge
- Department of Cancer Care Services, Royal Brisbane Hospital, University Of Queensland, Herston, Australia
| | - Christos S Karapetis
- Flinders Centre for Innovation in Cancer, Flinders University, Bedford Park, Australia
| | - Nick Pavlakis
- Department of Medical Oncology, Royal North Shore Hospital, Sydney, Australia
| | - Eva Segelov
- Department of Medical Oncology, Monash University and Monash Health, Melbourne, Australia
| | - Ian Chau
- Department of Medical Oncology, Royal Marsden Hospital, Institute of Cancer Research, Surrey, London, UK
| | - Florian Lordick
- Leipzig University Medical Centre, University Cancer Centre Leipzig, Leipzig, Germany
| | - Li-Tong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Andrew Barbour
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Australia
| | - Niall Tebbutt
- Department of Medical Oncology, Austin Health, Heidelberg, Australia
| | - Tim Price
- Queen Elizabeth Hospital, University of Adelaide, Adelaide, Australia
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39
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Ku GY, Ilson DH. Cancer of the Esophagus. ABELOFF'S CLINICAL ONCOLOGY 2020:1174-1196.e6. [DOI: 10.1016/b978-0-323-47674-4.00071-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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40
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MUC4-ErbB2 Oncogenic Complex: Binding studies using Microscale Thermophoresis. Sci Rep 2019; 9:16678. [PMID: 31723153 PMCID: PMC6853952 DOI: 10.1038/s41598-019-53099-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 10/27/2019] [Indexed: 02/06/2023] Open
Abstract
The MUC4 membrane-bound mucin is a large O-glycoprotein involved in epithelial homeostasis. At the cancer cell surface MUC4 interacts with ErbB2 receptor via EGF domains to promote cell proliferation and migration. MUC4 is highly regarded as a therapeutic target in pancreatic cancer as it is not expressed in healthy pancreas, while it is neoexpressed in early preneoplastic stages (PanINs). However, the association/dissociation constant of MUC4-ErbB2 complex is unknown. Protein-protein interactions (PPIs) have become a major area of research in the past years and the characterization of their interactions, especially by biophysical methods, is intensively used in drug discovery. To characterize the MUC4-ErbB2 interaction, we used MicroScale Thermophoresis (MST), a powerful method for quantitative protein interaction analysis under challenging conditions. We worked with CHO cell lysates containing either the transmembrane β subunit of MUC4 (MUC4β) or a truncated mutant encompassing only the EGF domains (MUC4EGF3+1+2). MST studies have led to the characterization of equilibrium dissociation constants (Kd) for MUC4β-ErbB2 (7–25 nM) and MUC4EGF3+1+2/ErbB2 (65–79 nM) complexes. This work provides new information regarding the MUC4-ErbB2 interaction at the biophysical level and also confirms that the presence of the three EGF domains of MUC4 is sufficient to provide efficient interaction. This technological approach will be very useful in the future to validate small molecule binding affinities targeting MUC4-ErbB2 complex for drug discovery development in cancer. It will also be of high interest for the other known membrane mucins forming oncogenic complexes with ErbBs at the cancer cell surface.
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Liu F, Ren C, Jin Y, Xi S, He C, Wang F, Wang Z, Xu RH, Wang F. Assessment of two different HER2 scoring systems and clinical relevance for colorectal cancer. Virchows Arch 2019; 476:391-398. [PMID: 31720832 PMCID: PMC7085476 DOI: 10.1007/s00428-019-02668-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 08/28/2019] [Accepted: 09/10/2019] [Indexed: 12/24/2022]
Abstract
Although the positivity of human epidermal growth factor receptor 2 (HER2) is low in colorectal cancer (CRC), anti-HER2 is becoming a new target therapy in metastatic colorectal cancer (mCRC). However, assessment of the HER2 scoring system was still not established in CRC. The purpose of our study was to evaluate HER2 status and its correlation with clinicopathological characteristics and survival according to the HER2 diagnostic criteria for gastroesophageal adenocarcinoma (GEA criteria) and the HERACLES diagnostic criteria (HERACLES criteria) in a large cohort of Chinese CRC patients. The HER2 positivity was 2.9% (43/1490) and 2.6% (39/1490) in CRCs based on the GEA criteria and the HERACLES criteria, and 3.7% (9/243) in mCRC according to both criteria. HER2 status was associated with primary tumor location (P = 0.037), regional lymph node metastasis (P = 0.035), and TNM stage (P = 0.022) in CRCs based on the HERACLES criteria. No such association was found based on the GEA criteria. Furthermore, HER2 positive only presented in patients with RAS gene wild type (P = 0.001). Significant difference was only observed between the HER2-positive and HER2-negative groups in terms of disease-free survival for stage II-III CRCs (P = 0.048) according to the HERACLES criteria, but not based on the GEA criteria. Our findings suggest that the frequency of HER2 overexpression or amplification was low in Chinese CRC patients, and provide a rationale for further evaluation of HER2 in CRC based on the HERACLES criteria and the HER2 diagnostic criteria for gastroesophageal adenocarcinoma.
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Affiliation(s)
- Furong Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Chao Ren
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Ying Jin
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Shaoyan Xi
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Caiyun He
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Fang Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Zixian Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Rui-Hua Xu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Feng Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China. .,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.
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42
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Yoshikawa T, Aoyama T, Sakamaki K, Oshima T, Lin J, Zhang S, Sapari NS, Soong R, Tan I, Chan XB, Bottomley D, Hewitt LC, Arai T, Teh BT, Epstein D, Ogata T, Kameda Y, Miyagi Y, Tsuburaya A, Morita S, Grabsch HI, Tan P. Comprehensive biomarker analyses identifies HER2, EGFR, MET RNA expression and thymidylate synthase 5'UTR SNP as predictors of benefit from S-1 adjuvant chemotherapy in Japanese patients with stage II/III gastric cancer. J Cancer 2019; 10:5130-5138. [PMID: 31602266 PMCID: PMC6775596 DOI: 10.7150/jca.34741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Accepted: 06/25/2019] [Indexed: 12/14/2022] Open
Abstract
Purpose: A comprehensive molecular analysis was conducted to identify prognostic and predictive markers for adjuvant S-1 chemotherapy in stage II/III Japanese gastric cancer (GC) patients and to evaluate their potential suitability for alternative cytotoxic or targeted drugs. Experimental Design: We investigated genetic polymorphisms of enzymes potentially involved in 5-fluoruracil (5-FU) metabolism as well as platinum resistance, previously identified genomic subtypes potentially predicting 5-FU benefit, and mRNA expression levels of receptor tyrosine kinases and KRAS as potential treatment targets in a single institution cohort of 252 stage II/III GC patients treated with or without S-1 after D2 gastrectomy. Results: 88% and 62% GC had a potentially 5-FU sensitive phenotype by SNP analyses of TS 3'UTR, and TS 5'UTR, respectively. 24%, 46%, 40%, 5%, and 44% GC had a potentially platinum sensitive phenotype by SNP analyses of GSTP1, ERCC1 rs11615, ERCC1 rs3212986, ERCC2, and XRCC1, respectively. High HER2, EGFR, FGFR2, or MET mRNA expression was observed in 49%, 66%, 72%, and 54% GC, respectively. High HER2 expression was the only significant prognosticator (HR=3.912, 95%CI: 1.706-8.973, p=0.0005). High HER2 (p=0.031), low EGFR (p=0.124), high MET (p=0.165) RNA expression, and TS 5'UTR subtype 2R/2R, 2R/3C, or 3C (p=0.058) were significant independent predictors for S-1 resistance. Conclusions: The present study suggests that platinum-based or RTK targeted agents could be alternative treatment options for a substantial subgroup of Japanese GC patients currently treated with S-1. HER2, EGFR, MET, and TS 5'UTR SNP appear to be promising predictive markers for S-1 resistance warranting validation in an independent GC series.
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Affiliation(s)
- Takaki Yoshikawa
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan.,Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Toru Aoyama
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Kentaro Sakamaki
- Department of Biostatistics and Epidemiology, Yokohama City University, Yokohama, Japan
| | - Takasi Oshima
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Joyce Lin
- Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore
| | - Shenli Zhang
- Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore
| | - Nur Sabrina Sapari
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Richie Soong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Iain Tan
- Department of Pathology, National University of Singapore, Singapore, Singapore
| | - Xiu Bin Chan
- Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore
| | - Dan Bottomley
- Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Lindsay C Hewitt
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, NL
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan
| | - Bin Tean Teh
- Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore
| | - David Epstein
- Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore
| | - Takashi Ogata
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Yoichi Kameda
- Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan
| | - Yohei Miyagi
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Akira Tsuburaya
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Heike I Grabsch
- Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.,Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, NL
| | - Patrick Tan
- Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.,Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
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Sun GK, Tang LJ, Zhou JD, Xu ZJ, Yang L, Yuan Q, Ma JC, Liu XH, Lin J, Qian J, Yao DM. DOK6 promoter methylation serves as a potential biomarker affecting prognosis in de novo acute myeloid leukemia. Cancer Med 2019; 8:6393-6402. [PMID: 31486300 PMCID: PMC6797566 DOI: 10.1002/cam4.2540] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 08/14/2019] [Accepted: 08/22/2019] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Downstream of tyrosine kinase 6 (DOK6), which is specifically expressed in the nervous system, was previously recognized as an adapter only in neurite outgrowth. Recent studies also demonstrated the potential role of DOK6 in solid tumors such as gastric cancer and breast cancer. However, previous studies of DOK6 have not dealt with its roles in myeloid malignancies. Herein, we verified the promoter methylation status of DOK6 and further explored its clinical implication in de novo acute myeloid leukemia (AML). METHODS A total of 100 newly diagnosed adult AML patients were involved in the current study. DOK6 expression and methylation were detected by real-time qPCR and methylation-specific PCR (MSP), respectively. Bisulfite sequencing PCR (BSP) was performed to assess the methylation density of the DOK6 promoter. RESULTS Downstream of tyrosine kinase 6 promoter methylation was significantly increased in AML patients compared to controls (P = .037), whereas DOK6 expression significantly decreased in AML patients (P < .001). The expression of DOK6 was markedly up-regulated after treated by 5-aza-2'-deoxycytidine (5-aza-dC) in THP-1 cell lines. The methylation status of the DOK6 promoter was associated with French-American-British classifications (P = .037). There was no significant correlation existed between DOK6 expression and its promoter methylation (R = .077, P = .635). Interestingly, of whole-AML and non-APL AML patients, both have a tendency pertaining to the DOK6 methylation group and a significantly longer overall survival (OS) than the DOK6 unmethylation group (P = .042 and .036, respectively). CONCLUSION Our study suggested that DOK6 promoter hypermethylation was a common molecular event in de novo AML patients. Remarkably, DOK6 promoter methylation could serve as an independent and integrated prognostic biomarker not only in non-APL AML patients but also in AML patients who are less than 60 years old.
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Affiliation(s)
- Guo-Kang Sun
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Li-Juan Tang
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Jing-Dong Zhou
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Zi-Jun Xu
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Lan Yang
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Qian Yuan
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Ji-Chun Ma
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Xing-Hui Liu
- Department of Clinical Laboratory, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, China
| | - Jiang Lin
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Jun Qian
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.,Department of Hematology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Dong-Ming Yao
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.,The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
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Choi RSY, Lai WYX, Lee LTC, Wong WLC, Pei XM, Tsang HF, Leung JJ, Cho WCS, Chu MKM, Wong EYL, Wong SCC. Current and future molecular diagnostics of gastric cancer. Expert Rev Mol Diagn 2019; 19:863-874. [PMID: 31448971 DOI: 10.1080/14737159.2019.1660645] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Introduction: Gastric cancer (GC) is the fifth most common cancer and confers the second-highest mortality among other cancers. Improving the survival rates of GC patients requires prompt and accurate diagnosis and effective treatment which is often preceded by the poorly understood pathogenic mechanisms. Area covered: This literature review aims to summarize current understanding of genetic and molecular alterations that promote carcinogenesis including (1) activation of oncogenes, (2) overexpression of growth factors, receptors and matrix metalloproteinases, (3) inactivation of tumor suppressor genes, DNA repair genes, and cell adhesion molecules and (4) alterations of cell-cycle regulators that regulate biological characteristics of cancer cells. Moreover, the significance of molecular biomarkers such as micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) and advanced molecular techniques including droplet digital polymerase chain reaction (ddPCR), quantitative PCR (qPCR) and next-generation sequencing (NGS) are also discussed. Expert opinion: A GC-specific panel of biomarkers based on the NGS or ddPCR has the potential for diagnosis, prognosis, and monitoring treatment response in GC patients. Despite the requirements for validation in larger population in clinical studies, race-specific differences in the gene panel have also to be examined by performing the clinical trials in subjects with different races.
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Affiliation(s)
- Rachel Sin-Yu Choi
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Wing Yin Xenia Lai
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Lok Ting Claire Lee
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Wing Lam Christa Wong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Xiao Meng Pei
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Hin Fung Tsang
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Joel Johnson Leung
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - William Chi Shing Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital , Kowloon , Hong Kong Special Administrative Region, China
| | - Man Kee Maggie Chu
- Division of Life Science, The Hong Kong University of Science and Technology , Clear Water Bay , Hong Kong Special Administrative Region, China
| | - Elaine Yue Ling Wong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Sze Chuen Cesar Wong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
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Saad MI, Rose-John S, Jenkins BJ. ADAM17: An Emerging Therapeutic Target for Lung Cancer. Cancers (Basel) 2019; 11:E1218. [PMID: 31438559 PMCID: PMC6769596 DOI: 10.3390/cancers11091218] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/07/2019] [Accepted: 08/17/2019] [Indexed: 12/23/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality, which histologically is classified into small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancer diagnoses, with the majority of patients presenting with lung adenocarcinoma (LAC). KRAS mutations are a major driver of LAC, and are closely related to cigarette smoking, unlike mutations in the epidermal growth factor receptor (EGFR) which arise in never-smokers. Although the past two decades have seen fundamental progress in the treatment and diagnosis of NSCLC, NSCLC still is predominantly diagnosed at an advanced stage when therapeutic interventions are mostly palliative. A disintegrin and metalloproteinase 17 (ADAM17), also known as tumour necrosis factor-α (TNFα)-converting enzyme (TACE), is responsible for the protease-driven shedding of more than 70 membrane-tethered cytokines, growth factors and cell surface receptors. Among these, the soluble interleukin-6 receptor (sIL-6R), which drives pro-inflammatory and pro-tumourigenic IL-6 trans-signaling, along with several EGFR family ligands, are the best characterised. This large repertoire of substrates processed by ADAM17 places it as a pivotal orchestrator of a myriad of physiological and pathological processes associated with the initiation and/or progression of cancer, such as cell proliferation, survival, regeneration, differentiation and inflammation. In this review, we discuss recent research implicating ADAM17 as a key player in the development of LAC, and highlight the potential of ADAM17 inhibition as a promising therapeutic strategy to tackle this deadly malignancy.
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Affiliation(s)
- Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria 3168, Australia
| | - Stefan Rose-John
- Institute of Biochemistry, Christian-Albrechts-University, D-24098 Kiel, Germany
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria 3168, Australia.
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Zubarayev M, Min EK, Son T. Clinical and molecular prognostic markers of survival after surgery for gastric cancer: tumor-node-metastasis staging system and beyond. Transl Gastroenterol Hepatol 2019; 4:59. [PMID: 31559340 DOI: 10.21037/tgh.2019.08.05] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 07/30/2019] [Indexed: 12/12/2022] Open
Abstract
For accurately predicting prognosis and for effectively describing cancer states at a certain point during treatment to other care providers and patients, various staging systems have been utilized in gastric cancer. Among these, the UICC/AJCC tumor-node-metastasis (TNM) staging system is most widely used. However, even within the same substage, gastric cancers can vary substantially in regards to prognosis after treatment. For more accurate and individualized prognostication, staging systems have been found to benefit from including molecular markers and genomic subtypes, in addition to clinicopathological parameters, such as age, sex, tumor size, tumor location, Lauren classification, number of lymph nodes resected, extent of surgical resection, lymphovascular invasion, and adjuvant chemotherapy. In this review article, we review and summarize relevant biomarkers for gastric cancer that can be incorporated into the current anatomy-based TNM staging system, as well as results from validation studies thereof.
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Affiliation(s)
- Mykola Zubarayev
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.,GI laparoscopic & Robotic Surgery, National Cancer Institute, Kiev, Ukraine
| | - Eun-Ki Min
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Taeil Son
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.,Gastric Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea
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Benli Yavuz B, Koç M, Kozacıoğlu S, Kanyılmaz G, Aktan M. Prognostic importance of PTEN, EGFR, HER-2, and IGF-1R in gastric cancer patients treated with postoperative chemoradiation. Turk J Med Sci 2019; 49:1025-1032. [PMID: 31318186 PMCID: PMC7018360 DOI: 10.3906/sag-1802-34] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background/aim This study aimed to describe the prognostic importance of epidermal growth factor (EGFR), phosphatase and tensin homolog (PTEN), human EGF receptor-2 (HER-2), and insulin-like growth factor 1 receptor (IGF-1R) in gastric cancer patients treated with postoperative chemoradiation therapy. Materials and methods Sixty-nine patients treated with adjuvant chemoradiation therapy were retrospectively evaluated. Tumor samples were stained immunohistochemically. Results All patients were treated with 3D conformal radiation therapy with concomitant and adjuvant chemotherapy. Perineural invasion (PNI) (P = 0.042), prechemoradiation therapy albumin levels below 3.5 mg/dL (P = 0.011), and EGFR positivity (P = 0.008) had negative effects on overall survival (OS). The median OS was 26 months for patients with PNI (+), 34.9 months for those with PNI (–), 19.5 months for those with albumin levels below 3.5 mg/dL, and 33.2 months for those with albumin levels above 3.5 mg/dL. IGF-1R (+) (P = 0.035) and history of cigarette smoking (P = 0.033) were observed to have a statistically significantly negative effect on disease-free survival (DFS). The median DFS was 29.2 months for IGF-1R (+) patients, 37.9 months for those with IGF-1R (-), and 26.3 and 40.59 months for smokers and nonsmokers, respectively. Conclusion IGF-1R and EGFR may be used for patient selection in future prospective studies that evaluate the prognostic importance of these receptors.
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Affiliation(s)
- Berrin Benli Yavuz
- Department of Radiation Oncology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Mehmet Koç
- Department of Radiation Oncology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Sümeyye Kozacıoğlu
- Department of Pathology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Gül Kanyılmaz
- Department of Radiation Oncology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Meryem Aktan
- Department of Radiation Oncology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
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Kim H, Seo S, Kim K, Park YH, An M, Baik H, Choi C, Oh S. Prognostic significance of Human epidermal growth factor receptor-2 expression in patients with resectable gastric adenocarcinoma. World J Surg Oncol 2019; 17:122. [PMID: 31296222 PMCID: PMC6624940 DOI: 10.1186/s12957-019-1652-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 06/19/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The purpose of this study was to investigate the correlation between human epidermal growth factor receptor 2 (HER2) overexpression and clinicopathologic factors and overall survival rate in patients who underwent curative gastrectomy for gastric adenocarcinoma. METHODS Among patients who underwent curative gastrectomy for gastric adenocarcinoma at Inje University Paik Hospital from January 2012 to December 2015, 782 patients underwent an immunohistochemical analysis to evaluate HER2 expression levels. Clinicopathologic records that were collected from a gastric cancer database were retrospectively reviewed to identify clinicopathologic factors and survival rates of the patients. RESULTS HER2 overexpression was detected in 166 patients (21.2%). There was a statistically significant correlation between HER2 expression level and sex (p = 0.013), histologic differentiation (p < 0.001), Lauren classification (p < 0.001), and T pathologic stage (p = 0.022). There were no statistically significant relationships between HER2 expression level and overall 5-year survival rate (p = 0.775) and overall 5-year survival rate of gastric adenocarcinoma classified according to the TNM stage (stage I: p = 0.756, stage II: p = 0.571, stage III: p = 0.704). The HER2 expression level was not affected by the overall 5-year survival rate in the uni- and multivariate analyses. CONCLUSIONS In this study, the HER2 overexpression rate in gastric adenocarcinoma was 21.2% and was observed in well- and moderately differentiated types according to histologic differentiation, intestinal type according to the Lauren classification, male, and low T stage. There was no correlation between HER2 expression level and overall 5-year survival rate, and HER2 expression level was not associated with independent prognostic factors.
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Affiliation(s)
- Hyeongbin Kim
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
| | - SangHyuk Seo
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
| | - KwangHee Kim
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea.
| | - Yo-Han Park
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
| | - MinSung An
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
| | - HyungJoo Baik
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
| | - ChangSoo Choi
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
| | - SangHoon Oh
- Department of Surgery, Busan Paik Hospital, Inje University, Bokgiro 75, Busanjin-gu, Busan, Republic of Korea
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Assessment of EGFR and ERBB2 (HER2) in Gastric and Gastroesophageal Carcinomas: EGFR Amplification is Associated With a Worse Prognosis in Early Stage and Well to Moderately Differentiated Carcinoma. Appl Immunohistochem Mol Morphol 2019; 26:374-382. [PMID: 27753660 DOI: 10.1097/pai.0000000000000437] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epidermal growth factor receptor 1 (EGFR) and erb-b2 receptor tyrosine kinase 2 (ERBB2/HER2) are frequently dysregulated in human cancers. We analyzed EGFR and ERBB2 status in 105 gastric and gastroesophageal junction carcinoma and their clinicopathologic features. For EGFR, 92 (88%) tumors were scored as 0, 2 (2%) as 1+, 7 (7%) as 2+, and 4 (3%) as 3+ by immunohistochemistry (IHC) and 4 (4%) tumors showed EGFR amplification by fluorescence in situ hybridization (FISH). For ERBB2, 90 (86%) tumors were scored as 0, 4 (4%) as 1+, 6 (6%) as 2+, and 5 (5%) as 3+ by IHC and 12 (12%) showed ERBB2 amplification by FISH. The concordance rate between IHC and FISH of EGFR was 98.1% (P<0.001) and of ERBB2 was 93.3% (P<0.001). Most tumors with ERBB2 amplification were tubular adenocarcinoma (N=11, P=0.02) and Lauren intestinal type (N=12, P=0.016). There was no statistically significant difference between EGFR amplification and tumor classification. EGFR amplification had significant impact on overall survival in certain subgroups: early stages (stages I and II) (P<0.001), well to moderately differentiated tumors (P=0.001), and fewer regional lymph node metastasis (pN1) (P=0.001). ERBB2 status had little predictive value on overall survival. In conclusion, this study showed ERBB2 amplification was significantly observed in tubular adenocarcinoma and Lauren intestinal-type carcinoma. The IHC scoring criteria for ERBB2 can be applied to EGFR. EGFR amplification had associated with poor prognosis in early, well to moderately differentiated carcinoma.
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van den Ende T, Ter Veer E, Mali RMA, van Berge Henegouwen MI, Hulshof MCCM, van Oijen MGH, van Laarhoven HWM. Prognostic and Predictive Factors for the Curative Treatment of Esophageal and Gastric Cancer in Randomized Controlled Trials: A Systematic Review and Meta-Analysis. Cancers (Basel) 2019; 11:E530. [PMID: 31013858 PMCID: PMC6521055 DOI: 10.3390/cancers11040530] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 04/05/2019] [Accepted: 04/09/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND An overview of promising prognostic variables and predictive subgroups concerning the curative treatment of esophageal and gastric cancer from randomized controlled trials (RCTs) is lacking. Therefore, we conducted a systematic review and meta-analysis. METHODS PubMed, EMBASE, CENTRAL, and ASCO/ESMO conferences were searched up to March 2019 for RCTs on the curative treatment of esophageal or gastric cancer with data on prognostic and/or predictive factors for overall survival. Prognostic factors were deemed potentially clinically relevant according to the following criteria; (1) statistically significant (p < 0.05) in a multivariate analysis, (2) reported in at least 250 patients, and (3) p < 0.05, in ≥ 33% of the total number of patients in RCTs reporting this factor. Predictive factors were potentially clinically-relevant if (1) the p-value for interaction between subgroups was <0.20 and (2) the hazard ratio in one of the subgroups was significant (p < 0.05). RESULTS For gastric cancer, 39 RCTs were identified (n = 13,530 patients) and, for esophageal cancer, 33 RCTs were identified (n = 8618 patients). In total, we identified 23 potentially clinically relevant prognostic factors for gastric cancer and 16 for esophageal cancer. There were 15 potentially clinically relevant predictive factors for gastric cancer and 10 for esophageal cancer. CONCLUSION The identified prognostic and predictive factors can be included and analyzed in future RCTs and be of guidance for nomograms. Further validation should be performed in large patient cohorts.
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Affiliation(s)
- Tom van den Ende
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Emil Ter Veer
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Rosa M A Mali
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Mark I van Berge Henegouwen
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Maarten C C M Hulshof
- Department of Radiotherapy, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC), location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Martijn G H van Oijen
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Hanneke W M van Laarhoven
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
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