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Belle CJ, Lonie JM, Brosda S, Barbour AP. Tumour microenvironment influences response to treatment in oesophageal adenocarcinoma. Front Immunol 2023; 14:1330635. [PMID: 38155973 PMCID: PMC10753779 DOI: 10.3389/fimmu.2023.1330635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 11/30/2023] [Indexed: 12/30/2023] Open
Abstract
The poor treatment response of oesophageal adenocarcinoma (OAC) leads to low survival rates. Its increasing incidence makes finding more effective treatment a priority. Recent treatment improvements can be attributed to the inclusion of the tumour microenvironment (TME) and immune infiltrates in treatment decisions. OAC TME is largely immunosuppressed and reflects treatment resistance as patients with inflamed TME have better outcomes. Priming the tumour with the appropriate neoadjuvant chemoradiotherapy treatment could lead to higher immune infiltrations and higher expression of immune checkpoints, such as PD-1/PDL-1, CTLA4 or emerging new targets: LAG-3, TIM-3, TIGIT or ICOS. Multiple trials support the addition of immune checkpoint inhibitors to the current standard of care. However, results vary, supporting the need for better response biomarkers based on TME composition. This review explores what is known about OAC TME, the clinical significance of the various cell populations infiltrating it and the emerging therapeutical combination with a focus on immune checkpoints inhibitors.
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Affiliation(s)
- Clemence J. Belle
- Surgical Oncology Group, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
| | - James M. Lonie
- Surgical Oncology Group, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Sandra Brosda
- Surgical Oncology Group, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Andrew P. Barbour
- Surgical Oncology Group, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
- Department of Surgery, Princess Alexandra Hospital, Brisbane, QLD, Australia
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Lu M, Wu Y, Zhang Y, Yu Y, Wang S, Su X. Immunotherapeutic strategy in the management of gastric cancer: molecular profiles, current practice, and ongoing trials. J Egypt Natl Canc Inst 2023; 35:32. [PMID: 37779128 DOI: 10.1186/s43046-023-00192-1] [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] [Received: 08/25/2023] [Accepted: 09/15/2023] [Indexed: 10/03/2023] Open
Abstract
Gastric cancer (GC) is the one of the most commonly solid cancer worldwide. Although under the aggressive treatment, the poor clinical outcomes of patients with GCs have not been improved. Current studies emphasized that targeting therapies or immune response-based therapeutic strategy may be a potential approach to improve the clinical outcomes. Moreover, accumulative evidence has reported the increasing expression of PD-L1 expression in GC cells and highlighted its role in the tumor progression. Currently, great development has been established in the immune checkpoint inhibitors (ICIs) and further changed the clinical practice of GC treatment and prognosis. In addition, the combination therapies with targeting therapy or traditional therapies are expected to push the development of immunotherapies. In our present review, we predominantly focus on the biomarkers and molecular profiles for immunotherapies in GCs and highlight the role and administration of ICIs-based immunotherapeutic strategies against the GCs.
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Affiliation(s)
- Mengxiao Lu
- Department of Gastrointestinal Minimally Invasive Surgery, The Affiliated People's Hospital of Ningbo University, Ningbo, China.
| | - Yingjie Wu
- Department of Gastrointestinal Minimally Invasive Surgery, The Affiliated People's Hospital of Ningbo University, Ningbo, China
| | - Yixin Zhang
- Department of Gastrointestinal Minimally Invasive Surgery, The Affiliated People's Hospital of Ningbo University, Ningbo, China
| | - Yu Yu
- Department of Gastrointestinal Minimally Invasive Surgery, The Affiliated People's Hospital of Ningbo University, Ningbo, China
| | | | - Xiaobao Su
- Department of Gastrointestinal Minimally Invasive Surgery, The Affiliated People's Hospital of Ningbo University, Ningbo, China
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Noori M, Yousefi AM, Zali MR, Bashash D. Predictive value of PD-L1 expression in response to immune checkpoint inhibitors for esophageal cancer treatment: A systematic review and meta-analysis. Front Oncol 2022; 12:1021859. [PMID: 36591463 PMCID: PMC9798008 DOI: 10.3389/fonc.2022.1021859] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 11/10/2022] [Indexed: 12/23/2022] Open
Abstract
Background Programmed death-ligand-1 (PD-L1) molecule is a well-known predictive biomarker for the efficacy of immune checkpoint inhibitors (ICIs) in several cancers. Present systematic review and meta-analysis aimed at investigating the role of PD-L1 in predicting the effectiveness of programmed death-1 (PD-1)/PD-L1 inhibitors in patients suffering from esophageal cancer. Methods We searched PubMed, Scopus, Web of Science, and EMBASE databases as of March 25, 2022, for retrieving the potential relevant randomized controlled trials (RCTs). The pooled hazard ratios (HR) and the corresponding 95% confidence intervals (95%CIs) were calculated for the outcomes of overall survival (OS) and progression-free survival (PFS). The primary objective was to investigate the association between PD-1/PD-L1 inhibitors vs. control agents and treatment efficacy in terms of OS in patients with esophageal tumor expressing different values of PD-L1 based on combined-positive score (CPS) and tumor proportion score (TPS). The secondary outcome was the pooled risk of PFS. Results Eleven studies with a total of 5,418 participants were included. While there was no difference in the OS of CPS<1 patients in the intervention and the control group, patients bearing esophageal tumors with a CPS≥1 (HR 0.65, 0.56-0.74) treated by ICIs showed a significant improvement in OS relative to the control agents. Accordingly, patients with CPS<5 (HR 0.75, 0.58-0.98), CPS≥5 (HR 0.64, 0.53-0.77), CPS<10 (HR 0.86, 0.76-0.98), and CPS≥10 (HR 0.65, 0.56-0.75) had improved OS; however, a significant longer OS was observed in cases who expressed higher values of CPS=10 (p=0.018). In terms of TPS, a significant greater benefit in prolonging the OS came from TPS≥1% PD-L1 expressing tumors in comparison to TPS<1% tumors, suggesting this cut-off as another predictor of PD-1/PD-L1 inhibitors efficacy. Notably, in the subgroup analysis when the cut-off value of CPS=10 or TPS=1% was selected, Nivolumab was the best ICI that improved the survival of PD-L1 positive patients. In patients with negative PD-L1 expression, Toripalimib is the only ICI which could prolong the OS of patients with the cut-off value of CPS=10. Conclusion Among patients suffering from esophageal cancer, PD-L1 CPS=10 and TPS=1% expression thresholds seem to be predictive of a lower rate of mortality when PD-1/PD-L1 inhibitors are administrated; however, further large-scale trials are required for confirming the findings of the present study.
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Affiliation(s)
- Maryam Noori
- Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Amir-Mohammad Yousefi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran,*Correspondence: Davood Bashash, ;
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Haque E, Esmail A, Muhsen I, Salah H, Abdelrahim M. Recent Trends and Advancements in the Diagnosis and Management of Gastric Cancer. Cancers (Basel) 2022; 14:5615. [PMID: 36428707 PMCID: PMC9688354 DOI: 10.3390/cancers14225615] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/10/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022] Open
Abstract
Gastric cancer is an enigmatic malignancy that has recently been shown to be increasing in incidence globally. There has been recent progress in emerging technologies for the diagnosis and treatment of the disease. Improvements in non-invasive diagnostic techniques with serological tests and biomarkers have led to decreased use of invasive procedures such as endoscopy. A multidisciplinary approach is used to treat gastric cancer, with recent significant advancements in systemic therapies used in combination with cytotoxic chemotherapies. New therapeutic targets have been identified and clinical trials are taking place to assess their efficacy and safety. In this review, we provide an overview of the current and emerging treatment strategies and diagnostic techniques for gastric cancer.
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Affiliation(s)
- Emaan Haque
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Abdullah Esmail
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA
| | - Ibrahim Muhsen
- Section of Hematology and Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Haneen Salah
- Department of Pathology, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA
- Cockrell Center for Advanced Therapeutic Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA
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Zhao Y, Bai Y, Shen M, Li Y. Therapeutic strategies for gastric cancer targeting immune cells: Future directions. Front Immunol 2022; 13:992762. [PMID: 36225938 PMCID: PMC9549957 DOI: 10.3389/fimmu.2022.992762] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Gastric cancer (GC) is a malignancy with a high incidence and mortality, and the emergence of immunotherapy has brought survival benefits to GC patients. Compared with traditional therapy, immunotherapy has the advantages of durable response, long-term survival benefits, and lower toxicity. Therefore, targeted immune cells are the most promising therapeutic strategy in the field of oncology. In this review, we introduce the role and significance of each immune cell in the tumor microenvironment of GC and summarize the current landscape of immunotherapy in GC, which includes immune checkpoint inhibitors, adoptive cell therapy (ACT), dendritic cell (DC) vaccines, reduction of M2 tumor-associated macrophages (M2 TAMs), N2 tumor-associated neutrophils (N2 TANs), myeloid-derived suppressor cells (MDSCs), effector regulatory T cells (eTregs), and regulatory B cells (Bregs) in the tumor microenvironment and reprogram TAMs and TANs into tumor killer cells. The most widely used immunotherapy strategies are the immune checkpoint inhibitor programmed cell death 1/programmed death-ligand 1 (PD-1/PD-L1) antibody, cytotoxic T lymphocyte–associated protein 4 (CTLA-4) antibody, and chimeric antigen receptor T (CAR-T) in ACT, and these therapeutic strategies have significant anti-tumor efficacy in solid tumors and hematological tumors. Targeting other immune cells provides a new direction for the immunotherapy of GC despite the relatively weak clinical data, which have been confirmed to restore or enhance anti-tumor immune function in preclinical studies and some treatment strategies have entered the clinical trial stage, and it is expected that more and more effective immune cell–based therapeutic methods will be developed and applied.
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Affiliation(s)
- Yan Zhao
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yuansong Bai
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Meili Shen
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, China
- *Correspondence: Yapeng Li, ; Meili Shen,
| | - Yapeng Li
- The National and Local Joint Engineering Laboratory for Synthesis Technology of High Performance Polymer, College of Chemistry, Jilin University, Changchun, China
- *Correspondence: Yapeng Li, ; Meili Shen,
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Xavier CB, Lopes CDH, Harada G, Peres EDB, Katz A, Jardim DL. Cardiovascular toxicity following immune checkpoint inhibitors: A systematic review and meta-analysis. Transl Oncol 2022; 19:101383. [PMID: 35248919 PMCID: PMC8898968 DOI: 10.1016/j.tranon.2022.101383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/10/2022] [Accepted: 02/23/2022] [Indexed: 10/26/2022] Open
Abstract
BACKGROUND Immune checkpoint inhibitors may be associated with multiple immune-related toxicities. Cardiovascular adverse effects are underreported in clinical trials. METHODS We conducted a systematic review and meta-analysis to evaluate cardiovascular adverse effects incidence among patients with solid tumors receiving immune checkpoint inhibitors in randomized clinical trials and the relative risk of presenting these effects compared to placebo or best supportive care. The search was conducted through MEDLINE, Embase, and Scopus databases from January 1st, 2010 until July 1st, 2020. Outcomes were reported following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. RESULTS 57 randomized clinical trials including 12,118 patients were included. All grade CV AEs incidence rate was 8.32% (95% CI = 6.35%-10.53%). When only grade 3-5 CV AEs were considered, ICIs were significantly associated with increased risk than placebo or BSC (RR = 1.36; 95% CI = 1.06-1.73; p = 0.01). CONCLUSION This meta-analysis corroborates the hypothesis of increased CV risk related to immune checkpoint inhibitors.
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Key Words
- Adverse effects, BSC
- Best supportive care, CTCAE
- Cardiovascular toxicity
- Cardiovascular, FAERS
- Checkpoint blockade
- Common toxicity criteria, CTLA-4
- Cytotoxic t-lymphocyte-associated antigen 4, CV
- Immune checkpoint inhibitors
- Immune checkpoint inhibitors, PRISMA
- Meta-analysis, abbreviations, AES
- Preferred Reporting Items for Systematic Reviews and Meta-analyses, RCTs
- U.S. food and drug administration adverse events reporting system, ICIS
- programmed cell death ligand 1, RR
- programmed cell death protein 1, PD-L1
- randomized clinical trials, PD-1
- relative risk
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Affiliation(s)
| | | | | | | | - Artur Katz
- Oncology Center - Hospital Sírio-Libanês, São Paulo, Brazil
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Identification of SCN7A as the key gene associated with tumor mutation burden in gastric cancer. BMC Gastroenterol 2022; 22:45. [PMID: 35123417 PMCID: PMC8817579 DOI: 10.1186/s12876-022-02112-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 01/21/2022] [Indexed: 12/24/2022] Open
Abstract
Objective Previous studies have shown that tumor mutation burden (TMB) in cancer is associated with prognosis. The purpose of this study is to identify TMB related genes in gastric cancer (GC) and to explore their prognostic value. Methods In our research, weighted gene coexpression network analysis (WGCNA) algorithm was used to cluster the most relevant TMB modules in the Cancer Genome Atlas (TCGA) database. Limma package was used to screen the differentially expressed genes, and the intersection was identified as hub genes. We used gene expression profiling interactive analysis (GEPIA) and survival algorithm to analyze the clinical characteristics and prognosis of hub genes in tumor and normal tissue samples of TCGA and Gene Expression Omnibus cohort respectively. We also used CIBERSORT algorithm to calculate the proportion of 22 tumor immune cells in the high and low expression subgroups of hub genes. In addition, we used gene set enrichment analysis (GSEA) to predict the biological function of hub genes. P < 0.05 was considered statistically significant. Results In the TCGA cohort, TMB was significantly correlated with the clinical features of GC (P < 0.05). Through WGCNA and differential gene analysis, we identified SCN7A as the hub gene (P < 0.05, |log2fc|> 1, and mm > 0.8). We found that the expression of SCN7A in tumor tissues was lower than that in normal tissues, and its expression level was also related to overall survival rate and tumor stage. GSEA analysis showed that SCN7A low expression group was enriched with "DNA replication", "base extension repair" and "proteasome" gene sets in GC. In addition, we found that there were significant differences in the infiltration degree of 7 kinds of immune cells between the two groups. Conclusion TMB can indicate the prognosis of gastric cancer. SCN7A is a hub gene associated with TMB, and its low expression is associated with better prognosis. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02112-4.
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Advances in clinical immunotherapy for gastric cancer. Biochim Biophys Acta Rev Cancer 2021; 1876:188615. [PMID: 34403771 DOI: 10.1016/j.bbcan.2021.188615] [Citation(s) in RCA: 203] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 07/14/2021] [Accepted: 08/12/2021] [Indexed: 12/26/2022]
Abstract
Gastric cancer (GC) is one of the most malignant human cancers with increasing incidence worldwide, ranking among the top five malignant tumors worldwide in terms of incidence and mortality. The clinical efficacy of conventional therapies is limited, and the median overall survival (mOS) for advanced-stage gastric cancer is only about 8 months. Emerging as one of breakthroughs for cancer therapy, immunotherapy has become an effective treatment modality after surgery, chemotherapy, radiotherapy, and targeted therapy. In this review, we have summarized the progresses of clinical development of immunotherapies for gastric cancer. Major advances with immune checkpoint inhibitors (ICIs) have started to change the clinical practice for gastric cancer treatment and prognosis. Additionally, combination therapies with other modalities, such as targeted therapies, are expected to push immunotherapies to front-line. In this review, the efficacy of ICIs and targeted therapy alone or combination with existing therapies gastric cancer treatment was described and the predictive value of biomarkers for immunotherapies in gastric cancer treatment is also discussed.
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9
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Zeng Z, Yang B, Liao Z. Progress and prospects of immune checkpoint inhibitors in advanced gastric cancer. Future Oncol 2021; 17:1553-1569. [PMID: 33397136 DOI: 10.2217/fon-2020-0829] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Gastric cancer, a digestive malignancy, is the sixth most frequent cancer and the second leading cause of tumor-related deaths worldwide. The emergence and advancement of immunotherapeutic agents has brought significant survival benefits for patients with gastric cancer and increasingly challenged the conventional therapy pattern involving chemotherapy and target drugs. Furthermore, these breakthroughs have paved the way for immunotherapy, especially with immune checkpoint inhibitors, which act by blocking specific signaling pathways, in particular the CTLA4 pathway and the PD-1/PD-L1 pathway. In this review, we summarize the current trials of immune checkpoint inhibitors in GC and their predictive biomarkers, and discuss their present limitations.
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Affiliation(s)
- Zhu Zeng
- Department of Abdominal Oncology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China
| | - Biao Yang
- Department of Gastroenterology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China
| | - Zhengyin Liao
- Department of Abdominal Oncology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China
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10
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Abstract
PURPOSE OF REVIEW Immunotherapy and tumor microenvironment have been at the forefront of cancer research over the past several decades. Here, we will review the role of immunotherapy in advanced gastroesophageal cancers including targeted antibodies, immunomodulating agents, vaccines, oncolytic virus therapy, and adoptive immunotherapy, and discuss the future direction for immunotherapy in this population. RECENT FINDINGS Targeted antibodies are already standard-of-care. An anti-PD-1 monoclonal antibody is currently FDA approved for second-line treatment of locally advanced or metastatic ESCC, as well as beyond second-line treatment of advanced G/GEJ cancers, and recent data suggests it may be considered in first-line treatment of advanced G/GEJ cancers. Combination therapies such as immunotherapy plus chemotherapy and/or radiotherapy, vaccines, oncolytic viral therapy, and adoptive immunotherapy in varying combinations are currently under active investigation. Several trials are ongoing and are hoped to reach more efficacious and individualized treatment options in advanced gastroesophageal cancer, where novel treatment options are desperately needed.
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11
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Bai R, Chen N, Liang T, Li L, Lv Z, Lv X, Cui J. Novel Frontiers of Treatment for Advanced Gastric or Gastroesophageal Junction Cancer (GC/GEJC): Will Immunotherapy Be a Future Direction? Front Oncol 2020; 10:912. [PMID: 32793461 PMCID: PMC7386300 DOI: 10.3389/fonc.2020.00912] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 05/11/2020] [Indexed: 12/19/2022] Open
Abstract
Considering the limited progress of chemotherapy and targeted therapy in improving the generally disappointing outcomes of advanced gastric or gastroesophageal junction cancer (GC/GEJC), immunotherapies have been gradually developed and advanced into novel frontiers of treatment for advanced GC/GEJC. Nevertheless, the response to immunotherapy was not always satisfactory, and the emergence of resistance was unavoidable. These factors prompt the development of different combination therapies and predictive and prognostic biomarkers of efficacy to improve the outcomes of patients with advanced GC/GEJC and to overcome drug resistance. This article discusses the advances of immune monotherapy, multiple current and ongoing clinical trials of immune combination therapy, immune-related adverse events, and various biomarkers in GC/GEJC.
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Affiliation(s)
- Rilan Bai
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Naifei Chen
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Tingting Liang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Lingyu Li
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Zheng Lv
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Xiaomin Lv
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Jiuwei Cui
- Cancer Center, The First Hospital of Jilin University, Changchun, China
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12
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Abstract
This review summarizes completed and ongoing studies evaluating the activity of immune checkpoint inhibitors in esophagogastric cancer.
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Affiliation(s)
- Geoffrey Y Ku
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, Room 1035, New York, NY 10065, USA.
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13
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Gastric Cancer in Young Adults: A Different Clinical Entity from Carcinogenesis to Prognosis. Gastroenterol Res Pract 2020; 2020:9512707. [PMID: 32190044 PMCID: PMC7071806 DOI: 10.1155/2020/9512707] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 02/13/2020] [Indexed: 02/07/2023] Open
Abstract
Approximately 5.0% of gastric cancer (GC) patients are diagnosed before the age of 40 and are not candidates for screening programs in most countries and regions. The incidence of gastric cancer in young adults (GCYA) has declined over time in most countries except in the United States. Genetic alterations, environmental factors, and lifestyle may predispose some young adults to GC. According to molecular classifications, the cancer of most GCYA patients belongs to the genomically stable or microsatellite stable/epithelial-mesenchymal transition subtype, with the common genetic aberrations being mutations in CDH1. What characterizes GCYA are a higher prevalence in females, more aggressive tumor behaviors, diagnosis at advanced stages, fewer comorbidities and being better treatment candidates, and a similar or better survival outcome when compared with older patients. Considering the greater loss of life-years in younger patients, lowering the incidence of GC and diagnosing at a relatively early stage are the two most effective ways to decrease GC mortality. To achieve these goals, the low awareness of GCYA among general people, policy-makers, clinicians, and researchers should be changed.
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Zhao Q, Cao L, Guan L, Bie L, Wang S, Xie B, Chen X, Shen X, Cao F. Immunotherapy for gastric cancer: dilemmas and prospect. Brief Funct Genomics 2018; 18:107-112. [PMID: 30388190 DOI: 10.1093/bfgp/ely019] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Affiliation(s)
| | - Liang Cao
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lulu Guan
- Zhengzhou University, Zhengzhou, China
| | - Liangyu Bie
- Department of Internal Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Saiqi Wang
- Department of Internal Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Bojian Xie
- Department of Surgical Oncology, Taizhou Hospital, Wenzhou Medical University, Taizhou, China
| | - Xiaobing Chen
- Department of Internal Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaokun Shen
- Department of Surgical Oncology, Taizhou Hospital, Wenzhou Medical University, Taizhou, China
| | - Feiling Cao
- Department of Surgical Oncology, Taizhou Hospital, Wenzhou Medical University, Taizhou, China
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15
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Abstract
Despite major breakthroughs in the field of personalized medicine, gastric cancer (GC) remains a clinically challenging disease, characterized by scarce effective treatment options and the lack of reliable molecular tools for the prediction of patient outcome and response to therapy. The pronounced molecular heterogeneity that dictates the phenotypical aggressiveness of gastric neoplasms severely limits the antitumor efficacy of targeted agents brought to clinical trials, and constitutes a favorable setting for the emergence of refractory tumors exhibiting multidrug resistance. We will review the most recent advances in our understanding of GC biology, which are underlying the development and clinical testing of novel targeted therapeutic agents. We will also emphasize how their efficacy and acquired resistance relate to the aberrant molecular signatures that drive gastric malignancy.
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Affiliation(s)
- Henrique O Duarte
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,ICBAS - Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - Joana Gomes
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
| | - José C Machado
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Celso A Reis
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,ICBAS - Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.,Faculty of Medicine of the University of Porto, Porto, Portugal
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Gkolfinopoulos S, Papamichael D, Papadimitriou K, Papanastasopoulos P, Vassiliou V, Kountourakis P. Advances in molecular, genetic and immune signatures of gastric cancer: Are we ready to apply them in our patients' decision making? World J Gastrointest Oncol 2018; 10:172-183. [PMID: 30079143 PMCID: PMC6068857 DOI: 10.4251/wjgo.v10.i7.172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/16/2018] [Accepted: 06/13/2018] [Indexed: 02/05/2023] Open
Abstract
In the last few years we have witnessed a vast expansion of our knowledge regarding the molecular and genetic profile of gastric cancer. The molecular subtypes described have shed light on the pathogenesis of the disease, thus prompting the development of new therapeutic strategies and favoring a more individualized approach for treatment. Most of the clinical trials for so called targeted therapies could be considered, at best, partially successful. In addition, checkpoint inhibitors have recently been added to our armamentarium in later stages of the disease, and combinations with chemotherapy and targeted agents are currently under development. In view of the rapid advances of molecular oncology, a new challenge for the clinical oncologist arises: The appropriate patient selection for each new therapy, which can be made possible only through the implementation of predictive biomarkers in our therapy decision making.
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Battaglin F, Naseem M, Puccini A, Lenz HJ. Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions. Cancer Cell Int 2018; 18:99. [PMID: 30008616 PMCID: PMC6042434 DOI: 10.1186/s12935-018-0594-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 06/28/2018] [Indexed: 12/12/2022] Open
Abstract
Gastro-esophageal adenocarcinomas (GEA) represent a severe global health burden and despite improvements in the multimodality treatment of these malignancies the prognosis of patients remains poor. HER2 overexpression/amplification has been the first predictive biomarker approved in clinical practice to guide patient selection for targeted treatment with trastuzumab in advanced gastric and gastro-esophageal junction cancers. More recently, immunotherapy has been approved for the treatment of GEA and PD-L1 expression is now a biomarker required for the administration of pembrolizumab in these diseases. Significant progress has been made in recent years in dissecting the genomic makeup of GEA in order to identify distinct molecular subtypes linked to distinct patterns of molecular alterations. GEA have been found to be highly heterogeneous malignances, representing a challenge for biomarkers discovery and targeted treatment development. The current review focuses on an overview of established and novel promising biomarkers in GEA, covering recent molecular classifications from TCGA and ACRG. Main elements of molecular heterogeneity are discussed, as well as emerging mechanisms of primary and secondary resistance to HER2 targeted treatment and recent biomarker-driven trials. Future perspectives on the role of epigenetics, miRNA/lncRNA and liquid biopsy, and patient-derived xenograft models as a new platform for molecular-targeted drug discovery in GEA are presented. Our knowledge on the genomic landscape of GEA continues to evolve, uncovering the high heterogeneity and deep complexity of these tumors. The availability of new technologies and the identification of promising novel biomarker will be critical to optimize targeted treatment development in a setting where therapeutic options are currently lacking. Nevertheless, clinical validation of novel biomarkers and treatment strategies still represents an issue.
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Affiliation(s)
- Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA 90033 USA
- Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Madiha Naseem
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA 90033 USA
| | - Alberto Puccini
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA 90033 USA
- Oncologia Medica 1, Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA 90033 USA
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18
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Wang ZH, Shen L. Management of gastrointestinal adverse events induced by immune-checkpoint inhibitors. Chronic Dis Transl Med 2018; 4:1-7. [PMID: 29756118 PMCID: PMC5938241 DOI: 10.1016/j.cdtm.2017.12.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Indexed: 12/26/2022] Open
Affiliation(s)
- Zheng-Hang Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
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19
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Mizrak Kaya D, Harada K, Amlashi FG, Vasilakopoulou M, Ajani JA. Customization of therapy for gastroesophageal adenocarcinoma patients. Chronic Dis Transl Med 2018; 4:8-17. [PMID: 29756119 PMCID: PMC5938285 DOI: 10.1016/j.cdtm.2018.02.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Indexed: 12/18/2022] Open
Abstract
Gastroesophageal adenocarcinomas (GEACs) remain a global health problem. These are most often diagnosed at advanced stage and the estimated 5-year relative survival rate is about 5%. Although cure is not possible for patients with advanced GEAC, systemic therapy (chemotherapy or biochemotherapy) can palliate symptoms, improve survival and provide a better quality of life. One of the most promising options for some patients with advanced stage GEAC is immunotherapy, which can result in durable responses. Numerous phase III trials evaluating targeted therapies in different lines are ongoing and it is hoped that better biomarkers will emerge to identify patients who can benefit from targeted agents and immunotherapy in the future. Surgery remains as the corner stone for localized GEAC and adjunctive therapies can increase the survival rates by about 10%. The high toxicity and low completion rates of adjuvant therapy led to the strategies of preoperative treatment. With the results of ongoing pre-operative therapy trials we will be able to determine the optimal adjunctive approach for resectable GEAC.
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Affiliation(s)
| | | | | | | | - Jaffer A. Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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20
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Kelly RJ. Immunotherapy for Esophageal and Gastric Cancer. Am Soc Clin Oncol Educ Book 2017; 37:292-300. [PMID: 28561677 DOI: 10.1200/edbk_175231] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
PD-L1 upregulation occurs in approximately 40% of gastroesophageal cancers. However, unlike other solid tumors, there is minimal PD-L1 expressed on the cancer cells; rather, expression occurs predominantly on infiltrating myeloid cells. Preliminary clinical data involving single-agent PD-1/PD-L1 inhibitors in metastatic gastroesophageal cancer have reported response rates of 22%-27% for patients with PD-L1+ tumors and 10%-17% for unselected patients. The phase III ONO-4538-12 (ATTRACTION 2) trial has demonstrated an improved overall survival for nivolumab compared with placebo for patients with heavily pretreated gastric cancer. In the future, we will need better biomarkers to select those most likely to respond and/or identify patients who may need combination immunotherapeutics or alternate strategies. A number of subsets of gastric cancer with different immune signatures, most notably tumors positive for Epstein-Barr virus and microsatellite instability, have been identified, with approximately 50% and 94% PD-L1+ staining seen on tumor cells and immune cells in the EBV subtype and approximately 33% and 45% PD-L1+ staining seen on tumor cells and immune cells in MSI high tumors. Both subtypes demonstrate PD-L1+ immune cells with tumor-infiltrating patterns, unlike the more commonly seen PD-L1+ immune cells at the invasive margin. PD-L2 expression has been reported in 52% of esophageal adenocarcinomas but little is known about the expression of other immune checkpoints. Additional factors that suggest gastroesophageal cancers may respond to checkpoint inhibition include the high somatic mutation burden and the link with chronic inflammation. Here we provide a comprehensive review of the checkpoint inhibitor data published to date in advanced esophagogastric cancers and rationalize how the immune microenvironment in these diverse tumors can explain response or resistance to immunotherapeutics.
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Affiliation(s)
- Ronan J Kelly
- From The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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21
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Janmaat VT, Steyerberg EW, van der Gaast A, Mathijssen RHJ, Bruno MJ, Peppelenbosch MP, Kuipers EJ, Spaander MCW. Palliative chemotherapy and targeted therapies for esophageal and gastroesophageal junction cancer. Cochrane Database Syst Rev 2017; 11:CD004063. [PMID: 29182797 PMCID: PMC6486200 DOI: 10.1002/14651858.cd004063.pub4] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Almost half of people with esophageal or gastroesophageal junction cancer have metastatic disease at the time of diagnosis. Chemotherapy and targeted therapies are increasingly used with a palliative intent to control tumor growth, improve quality of life, and prolong survival. To date, and with the exception of ramucirumab, evidence for the efficacy of palliative treatments for esophageal and gastroesophageal cancer is lacking. OBJECTIVES To assess the effects of cytostatic or targeted therapy for treating esophageal or gastroesophageal junction cancer with palliative intent. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Web of Science, PubMed Publisher, Google Scholar, and trial registries up to 13 May 2015, and we handsearched the reference lists of studies. We did not restrict the search to publications in English. Additional searches were run in September 2017 prior to publication, and they are listed in the 'Studies awaiting assessment' section. SELECTION CRITERIA We included randomized controlled trials (RCTs) on palliative chemotherapy and/or targeted therapy versus best supportive care or control in people with esophageal or gastroesophageal junction cancer. DATA COLLECTION AND ANALYSIS Two authors independently extracted data. We assessed the quality and risk of bias of eligible studies according to the Cochrane Handbook for Systematic Reviews of Interventions. We calculated pooled estimates of effect using an inverse variance random-effects model for meta-analysis. MAIN RESULTS We identified 41 RCTs with 11,853 participants for inclusion in the review as well as 49 ongoing studies. For the main comparison of adding a cytostatic and/or targeted agent to a control arm, we included 11 studies with 1347 participants. This analysis demonstrated an increase in overall survival in favor of the arm with an additional cytostatic or targeted therapeutic agent with a hazard ratio (HR) of 0.75 (95% confidence interval (CI) 0.68 to 0.84, high-quality evidence). The median increased survival time was one month. Five studies in 750 participants contributed data to the comparison of palliative therapy versus best supportive care. We found a benefit in overall survival in favor of the group receiving palliative chemotherapy and/or targeted therapy compared to best supportive care (HR 0.81, 95% CI 0.71 to 0.92, high-quality evidence). Subcomparisons including only people receiving second-line therapies, chemotherapies, targeted therapies, adenocarcinomas, and squamous cell carcinomas all showed a similar benefit. The only individual agent that more than one study found to improve both overall survival and progression-free survival was ramucirumab. Palliative chemotherapy and/or targeted therapy increased the frequency of grade 3 or higher treatment-related toxicity. However, treatment-related deaths did not occur more frequently. Quality of life often improved in the arm with an additional agent. AUTHORS' CONCLUSIONS People who receive more chemotherapeutic or targeted therapeutic agents have an increased overall survival compared to people who receive less. These agents, administered as both first-line or second-line treatments, also led to better overall survival than best supportive care. With the exception of ramucirumab, it remains unclear which other individual agents cause the survival benefit. Although treatment-associated toxicities of grade 3 or more occurred more frequently in arms with an additional chemotherapy or targeted therapy agent, there is no evidence that palliative chemotherapy and/or targeted therapy decrease quality of life. Based on this meta-analysis, palliative chemotherapy and/or targeted therapy can be considered standard care for esophageal and gastroesophageal junction carcinoma.
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Affiliation(s)
- Vincent T Janmaat
- Erasmus University Medical CenterDepartment of Gastroenterology and HepatologyRotterdamNetherlands
| | - Ewout W Steyerberg
- Erasmus University Medical CenterDepartment of Public HealthPO Box 2040RotterdamNetherlands3000 CA
| | - Ate van der Gaast
- Erasmus MC Cancer Institute, Erasmus University Medical CenterDepartment of Medical OncologyDr. Molewaterplein 40RotterdamNetherlands3015 GD
| | - Ron HJ Mathijssen
- Erasmus MC Cancer Institute, Erasmus University Medical CenterDepartment of Medical OncologyDr. Molewaterplein 40RotterdamNetherlands3015 GD
| | - Marco J Bruno
- Erasmus University Medical CenterDepartment of Gastroenterology and HepatologyRotterdamNetherlands
| | - Maikel P Peppelenbosch
- Erasmus University Medical CenterDepartment of Gastroenterology and HepatologyRotterdamNetherlands
| | - Ernst J Kuipers
- Erasmus University Medical CenterDepartment of Gastroenterology and HepatologyRotterdamNetherlands
| | - Manon CW Spaander
- Erasmus University Medical CenterDepartment of Gastroenterology and HepatologyRotterdamNetherlands
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22
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Will molecular target agents enable the multidisciplinary treatment in stage IV gastric cancer? Eur J Surg Oncol 2017; 43:1835-1845. [PMID: 28888797 DOI: 10.1016/j.ejso.2017.08.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 08/02/2017] [Accepted: 08/10/2017] [Indexed: 02/06/2023] Open
Abstract
A detailed molecular characterization of gastric cancer has been revealed by global initiatives and a number of new molecular agents are under investigation. Currently only trastuzumab, a monoclonal antibody for human epidermal growth factor receptor 2 (HER2), is clinically used for HER2 positive advanced gastric cancer patients and ramucirumab, a monoclonal antibody directed against the extracellular ligand-binding domain of vascular endothelial growth factor receptor (VEGFR)2, can be used in second line. However, despite the progress in gastric cancer treatment, the prognosis of stage IV gastric cancer patients remains dismal. To achieve a remarkable improvement in the prognosis of patients, a multidisciplinary treatment approach with the help of effective molecular target agents should be considered. So far the role of multidisciplinary treatment for stage IV gastric cancer is still uncertain due to limited available data and absence of long-lasting tumor control with systemic therapy. Herein, an overview of the latest developments of molecular targeted agents for gastric cancer in advanced stages, in the perioperative setting and in oligometastatic disease is provided. The possibility of a multidisciplinary strategy using molecular target agents and surgery for stage IV gastric cancer is also assessed.
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23
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Abstract
Gastric cancers, with gastric adenocarcinoma (GAC) as the most common histological type, impose a considerable global health burden. Although the screening strategies for early detection have been shown to be successful in Japan and South Korea, they are either not implemented or not feasible in most of the world, leading to late diagnosis in most patients. Helicobacter pylori infection contributes to the development of many endemic GACs, and pre-emptive eradication or early treatment of this bacterial infection might provide effective primary prevention. GACs are phenotypically and genotypically heterogeneous. Localized (clinical stage I) GAC is best treated either endoscopically or with limited surgical resection, but clinical stage II or stage III tumours require multidisciplinary adjunctive approaches in addition to surgery. Although GAC is highly treatable in its early stages, advanced (clinical stage IV) GAC has a median survival of just ∼9-10 months. However, detailed molecular and immune profiling of GAC is yielding promise; early studies with immune checkpoint inhibitors suggest that GAC is amenable to immune modulation. Molecular studies have yielded a vast quantity of new information for potential exploitation. Nevertheless, advances against GACs have lagged compared with other tumours of similar incidence, and more research is necessary to overcome the obstacles to prolong survival.
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Affiliation(s)
- Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77030, USA
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Takeshi Sano
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Tokyo, Japan
| | - Yelena Y Janjigian
- Department of Solid Tumor Gastrointestinal Service (Medical Oncology), Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Daiming Fan
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77030, USA
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24
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Myint ZW, Goel G. Role of modern immunotherapy in gastrointestinal malignancies: a review of current clinical progress. J Hematol Oncol 2017; 10:86. [PMID: 28434400 PMCID: PMC5402172 DOI: 10.1186/s13045-017-0454-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 03/29/2017] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal (GI) cancers are a group of highly aggressive malignancies with a huge disease burden worldwide. There is clearly a significant unmet need for new drugs and therapies to further improve the treatment outcomes of GI malignancies. Immunotherapy is a novel treatment strategy that is emerging as an effective and promising treatment option against several types of cancers. CTLA-4 and PD-1 are critical immune checkpoint molecules that negatively regulate T cell activation via distinct mechanisms. Immune checkpoint blockade with antibodies directed against these pathways has already shown clinical efficacy that has led to their FDA approval in the treatment of several solid tumors including melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck cancer. This review will summarize the current clinical progress of modern immunotherapy in the field of GI tumors, with a special focus on immune checkpoint blockade.
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Affiliation(s)
- Zin W Myint
- Division of Medical Oncology, Department of Medicine, Markey Cancer Center, University of Kentucky, 800 Rose Street, CC449, Lexington, KY, 40503, USA
| | - Gaurav Goel
- Division of Medical Oncology, Department of Medicine, Markey Cancer Center, University of Kentucky, 800 Rose Street, CC449, Lexington, KY, 40503, USA.
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25
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Abstract
This review summarizes completed and ongoing studies evaluating the activity of immune checkpoint inhibitors in esophagogastric cancer.
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Affiliation(s)
- Geoffrey Y Ku
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, Room 1035, New York, NY 10065, USA.
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26
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Chemotherapy for advanced gastric cancer: future perspective in Japan. Gastric Cancer 2017; 20:102-110. [PMID: 27699493 DOI: 10.1007/s10120-016-0648-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Accepted: 09/23/2016] [Indexed: 02/07/2023]
Abstract
Differences in clinical outcomes between advanced gastric cancer (AGC) in Asia and that in other regions have been discussed for a long time, although no major significant differences in molecular profiles have been reported. The anti-human epidermal growth factor receptor 2 antibody trastuzumab and the anti-vascular endothelial growth factor receptor 2 monoclonal antibody ramucirumab were both approved as a treatment for AGC on the basis of global phase 3 trials including Japan. In recent years, others new agents for treatment of AGC have been investigated in global or Asian studies. Randomized phase 2 trials in Japan showed a higher response rate to S-1 plus leucovorin and oxaliplatin than to standard S-1 plus cisplatin, which is the rationale for an ongoing phase 3 trial in Asia (SOLAR trial). A recent global phase 1 trial of the anti-programmed cell death 1 monoclonal antibody pembrolizumab showed similar efficacy results in Asian patients and non-Asian patients, which led to large global phase 2 and phase 3 studies. Although the perspective of treatment of AGC in the near future depends on the results of ongoing large clinical trials, individualized choice of treatment based on more detailed molecular information will become important.
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Harada K, Mizrak Kaya D, Shimodaira Y, Ajani JA. Global chemotherapy development for gastric cancer. Gastric Cancer 2017; 20:92-101. [PMID: 27718136 DOI: 10.1007/s10120-016-0655-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 09/28/2016] [Indexed: 02/07/2023]
Abstract
To combat the dismal mortality rates from metastatic gastric adenocarcinoma (GAC), new drugs and treatment strategies are needed. Today, metastatic GAC is predominantly treated by empiric chemotherapy. Combination of two cytotoxic agents has become commonplace in North America, Europe, and Asia. Human epidermal growth factor 2 (HER2) overexpression (protein or gene copy numbers) has resulted in the addition of trastuzumab in the first-line chemotherapy combination in patients whose tumor is HER2 positive. The addition of trastuzumab in this select population has provided a modest survival advantage. In this review we trace the global development of systemic therapy in patients with metastatic GAC and ponder what lies in the future.
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Affiliation(s)
- Kazuto Harada
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd (FC10.3022), Houston, TX, 77030, USA
| | - Dilsa Mizrak Kaya
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd (FC10.3022), Houston, TX, 77030, USA
| | - Yusuke Shimodaira
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd (FC10.3022), Houston, TX, 77030, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd (FC10.3022), Houston, TX, 77030, USA.
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