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Luo D, Liu Y, Lu Z, Huang L. Targeted therapy and immunotherapy for gastric cancer: rational strategies, novel advancements, challenges, and future perspectives. Mol Med 2025; 31:52. [PMID: 39923010 PMCID: PMC11806620 DOI: 10.1186/s10020-025-01075-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 01/10/2025] [Indexed: 02/10/2025] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors worldwide, and its treatment has been a focus of medical research. Herein we systematically review the current status of and advancements in targeted therapy and immunotherapy for GC, which have emerged as important treatment strategies in recent years with great potential, and summarize the efficacy and safety of such treatments. Targeted therapies against key targets in GC, including epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR), have shown remarkable therapeutic efficacies by inhibiting tumor progression and/or blood supply. In particular, markable breakthroughs have been made in HER2-targeting drugs for HER2-positive GC patients. To address intrinsic and acquired resistances to HER2-targeting drugs, novel therapeutic agents including bispecific antibodies and antibody-drug conjugates (ADC) targeting HER2 have been developed. Immunotherapy enhances the recognition and elimination of cancer cells by activating body anticancer immune system. Programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) antibodies are the most commonly used immunotherapeutic agents and have been used with some success in GC treatment. Innovative immunotherapy modalities, including adoptive immune cell therapy, tumor vaccines, and non-specific immunomodulators therapy, and oncolytic viruses have shown promise in early-stage clinical trials for GC. Clinical trials have supported that targeted therapy and immunotherapy can significantly improve the survival and quality of life of GC patients. However, the effects of such therapies need to be further improved and more personalized, with advancement in researches on tumor immune microenvironment. Further studies remain needed to address the issues of drug resistance and adverse events pertaining to such therapies for GC. The combined application of such therapies and individualized treatment strategies should be further explored with novel drugs developed, to provide more effective treatments for GC patients.
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Affiliation(s)
- Dong Luo
- Department of Gastroenterology, National Clinical Research Center for Digestive Diseases, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
- Center of Structural Heart Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yunmei Liu
- School of Cultural Heritage and Information Management, Shanghai University, Shanghai, 200444, China.
| | - Zhengmao Lu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
| | - Lei Huang
- Department of Gastroenterology, National Clinical Research Center for Digestive Diseases, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China.
- National Key Laboratory of Immunity and Inflammation, Changhai Clinical Research Unit, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China.
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Zhang B, Li Y, Zhu X, Chen Z, Huang X, Gong T, Zheng W, Bi Z, Zhu C, Qian J, Li X, Jin C. OncoVee™-MiniPDX-guided anticancer treatment for HER2-negative intermediate-advanced gastric cancer patients: a single-arm, open-label phase I clinical study. Discov Oncol 2023; 14:46. [PMID: 37093368 PMCID: PMC10126180 DOI: 10.1007/s12672-023-00661-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 04/17/2023] [Indexed: 04/25/2023] Open
Abstract
BACKGROUND Chemotherapy is the main treatment strategy for patients with advanced HER2-negative gastric cancer (GC); yet, many patients do not respond well to treatment. This study evaluated the sensitivity of a mini patient-derived xenograft (MiniPDX) animal model in patients with HER2-negative intermediate-advanced GC. METHODS In this single-arm, open-label clinical study, we consecutively recruited patients with HER2-negative advanced or recurrent GC from September 2018 to July 2021. Tumor tissues were subjected to MiniPDX drug sensitivity tests for screening individualized anti-tumor drugs; appropriate drug types or combinations were selected based on drug screening results. The primary endpoints were progression-free survival (PFS) and safety, and the secondary endpoints were overall survival (OS) and objective response rate (ORR). RESULTS A total of 17 patients were screened, and 14 eligible patients were included.The median follow-up time was 9 (2-34) months. The median PFS time was 14.1 (2-34) months, the median OS time was 16.9 (2-34) months, ORR was 42.9% (6/14), and DCR was 92.9% (13/14). The most common treatment-related adverse events (TRAE) were fatigue (14 (100%)), anorexia (13 (93%)) and insomnia (12 (86%)), and the most common grade 3 or worse TRAE was fatigue (6 (43%)), and anorexia (6 (43%)). The occurrence rate of myelosuppression, nausea and vomiting, abnormal liver enzymes, and other grade 3-4 chemotherapy adverse reactions were relatively low, and no grade 5 treatment-related adverse events occurred. CONCLUSION Screening HER2-negative medium-advanced GC/GJC chemotherapy regimens and targeted drugs based on MiniPDX animal models showed good tumor activity and safety.
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Affiliation(s)
- Baonan Zhang
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, 8 West Zhongnan Road, Wuxi, 214071, China
| | - Yuzhen Li
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, 8 West Zhongnan Road, Wuxi, 214071, China
| | - Xiaodan Zhu
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, 8 West Zhongnan Road, Wuxi, 214071, China
| | - Zhe Chen
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, 8 West Zhongnan Road, Wuxi, 214071, China
| | - Xiaona Huang
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, 8 West Zhongnan Road, Wuxi, 214071, China
| | - Tingjie Gong
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, 8 West Zhongnan Road, Wuxi, 214071, China
| | - Weiwang Zheng
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, 8 West Zhongnan Road, Wuxi, 214071, China
| | - Zhenle Bi
- Department of Medical, Co. Ltd. Shanghai, Shanghai LIDE Biotech, China
| | - Chenyang Zhu
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, 8 West Zhongnan Road, Wuxi, 214071, China
| | - Jingyi Qian
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, 8 West Zhongnan Road, Wuxi, 214071, China
| | - Xiaoqiang Li
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, 8 West Zhongnan Road, Wuxi, 214071, China
| | - Chunhui Jin
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, 8 West Zhongnan Road, Wuxi, 214071, China.
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Ivey A, Pratt H, Boone BA. Molecular pathogenesis and emerging targets of gastric adenocarcinoma. J Surg Oncol 2022; 125:1079-1095. [PMID: 35481910 PMCID: PMC9069999 DOI: 10.1002/jso.26874] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/15/2022] [Accepted: 03/19/2022] [Indexed: 12/24/2022]
Abstract
Gastric adenocarcinoma (GC) is a devastating disease and is the third leading cause of cancer deaths worldwide. This heterogeneous disease has several different classification systems that consider histological appearance and genomic alterations. Understanding the etiology of GC, including infection, hereditary conditions, and environmental factors, is of particular importance and is discussed in this review. To improve survival in GC, we also must improve our therapeutic strategies. Here, we discuss new targets that warrant further exploration.
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Affiliation(s)
- Abby Ivey
- Department of Cancer Cell Biology, West Virginia University Cancer Institute, West Virginia University, Morgantown, West Virginia, USA
| | - Hillary Pratt
- Department of Cancer Cell Biology, West Virginia University Cancer Institute, West Virginia University, Morgantown, West Virginia, USA
| | - Brian A Boone
- Department of Cancer Cell Biology, West Virginia University Cancer Institute, West Virginia University, Morgantown, West Virginia, USA
- Department of Surgery, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, West Virginia, USA
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Ge Y, Zhang X, Liang W, Tang C, Gu D, Shi J, Wei X. OncoVee™-MiniPDX-Guided Anticancer Treatment for Gastric Cancer Patients With Synchronous Liver Metastases: A Retrospective Cohort Analysis. Front Oncol 2022; 11:757383. [PMID: 35047388 PMCID: PMC8761725 DOI: 10.3389/fonc.2021.757383] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 12/03/2021] [Indexed: 12/21/2022] Open
Abstract
Background It is estimated that 35% of gastric cancer patients appear with synchronous distant metastases—the vast majority of patients presenting with metastatic hepatic disease. How to choose the most appropriate drugs or regimens is crucial to improve the prognosis of patients. We conducted this retrospective cohort analysis to evaluate the efficacy of OncoVee™-MiniPDX-guided treatment for these patients. Methods Gastric cancer patients with liver metastases (GCLM) were enrolled. Patients were divided into MiniPDX and control group according to their wishes. In the observation group, the OncoVee™-MiniPDX model was conducted to screen the most sensitive drug or regimens to determine the clinical administration. Meanwhile, patients were treated with regular medications in the control group according to the guidelines without the MiniPDX model. The primary endpoint was overall survival (OS), and the secondary outcomes included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results A total of 68 patients with GCLM were included, with the observation and control groups of 21 and 47 patients, respectively. The baseline characteristics of patients were balanced between these two groups. MiniPDX drug sensitivity tests were associated with the increased use of targeted drugs when compared with the control group (33.3 vs. 0%, p=0.032). Median OS was estimated to be 9.4 (95% CI, 7.9–11.2) months and 7.9 (95% CI, 7.2–8.7) months in the observation and control group, respectively. Both univariate (control group vs. MiniPDX group: HR=2.586, 95% CI= 1.362–4.908, p=0.004) and multivariate regression analyses (Control group vs. MiniPDX group: adjusted HR (aHR)=4.288, 95% CI= 1.452–12.671, p=0.008) showed the superiority of the observation group on OS. Similarly, MiniPDX-based regiments significantly improve the PFS of these cases (median PFS 6.7 months vs. 4.2 months, aHR=2.773, 95% CI=1.532–3.983, p=0.029). ORR and DCR were also improved in MiniPDX group comparing with control group (ORR, 57.14 vs. 25.53%, p=0.029; DCR: 85.71 vs. 68.08%, p=0.035). Conclusion OncoVee™-MiniPDX model, which was used to select drugs to guide antitumor treatment, was promising to prolong survival and improve the response rate of patients with GCLM. Further well-designed studies are needed to confirm the clinical benefits of MiniPDX.
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Affiliation(s)
- Yutong Ge
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xin Zhang
- Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Wei Liang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Cuiju Tang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Dongying Gu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Junfeng Shi
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xiaowei Wei
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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Yin X, Fang T, Wang Y, Li C, Wang Y, Zhang D, Xue Y. Efficacy of Postoperative FOLFOX Versus XELOX Chemotherapy for Gastric Cancer and Prognostic Value of Platelet-Lymphocyte Ratio in Patients Receiving XELOX. Front Oncol 2020; 10:584772. [PMID: 33425738 PMCID: PMC7786002 DOI: 10.3389/fonc.2020.584772] [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: 07/18/2020] [Accepted: 11/16/2020] [Indexed: 12/23/2022] Open
Abstract
Background Surgery combined with postoperative chemotherapy is an effective method for treating patients with gastric cancer (GC) in Asia. The important roles of systemic inflammatory response in chemotherapy have been gradually verified. The purpose of this study was to assess the difference in clinical effectiveness of FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) and XELOX (oxaliplatin + capecitabine), and the prognostic value of postoperative platelet–lymphocyte ratio (PLR) in the XELOX group. Methods Patients who received radical gastrectomy combined with postoperative chemotherapy between 2004 and 2014 were consecutively selected into the FOLFOX and XELOX groups. Group bias was reduced through propensity score matching, which resulted in 278 patients in each group. Cut-off values of systemic immune inflammation (SII) score and PLR were obtained by receiver operating characteristic curve. Kaplan–Meier and Log-rank tests were used to analyze overall survival. The chi-square test was used to analyze the association between clinical characteristics and inflammatory indexes. Univariate and multivariate analyses based on Cox regression analysis showed independent risk factors for prognosis. The nomogram was made by R studio. Results Patients receiving XELOX postoperative chemotherapy had better survival than those receiving FOLFOX (P < 0.001), especially for stage III GC (P = 0.002). Preoperative SII was an independent risk factor for prognosis in the FOLFOX group, and PLR of the second postoperative chemotherapy regimen in the XELOX group, combined with tumor size and pTNM stage, could construct a nomogram for evaluating recurrence and prognosis. Conclusion XELOX is better than FOLFOX for treatment of GC in Chinese patients, and a nomogram constructed by PLR, tumor size and pTNM stage can predict recurrence and prognosis.
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Affiliation(s)
- Xin Yin
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
| | - Tianyi Fang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
| | - Yimin Wang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
| | - Chunfeng Li
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
| | - Yufei Wang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
| | - Daoxu Zhang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
| | - Yingwei Xue
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
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Reizine N, Peterson B, Moya S, Wang Y, Tan YHCYH, Eng OS, Bilimoria M, Lengyel E, Turaga K, Catenacci DVT. Complete Response in a Patient With Chemorefractory EGFR-Amplified, PD-L1-Positive Metastatic Gastric Cancer Treated By Dual Anti-EGFR and Anti-PD-1 Monoclonal Antibody Therapy. JCO Precis Oncol 2020; 4:2000239. [PMID: 33215053 DOI: 10.1200/po.20.00239] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/31/2020] [Indexed: 12/18/2022] Open
Affiliation(s)
| | | | | | - Yan Wang
- University of Chicago, Chicago, IL
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Maron SB, Alpert L, Kwak HA, Lomnicki S, Chase L, Xu D, O'Day E, Nagy RJ, Lanman RB, Cecchi F, Hembrough T, Schrock A, Hart J, Xiao SY, Setia N, Catenacci DVT. Targeted Therapies for Targeted Populations: Anti-EGFR Treatment for EGFR-Amplified Gastroesophageal Adenocarcinoma. Cancer Discov 2018; 8:696-713. [PMID: 29449271 PMCID: PMC5984701 DOI: 10.1158/2159-8290.cd-17-1260] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 01/11/2018] [Accepted: 02/09/2018] [Indexed: 02/07/2023]
Abstract
Previous anti-EGFR trials in unselected patients with gastroesophageal adenocarcinoma (GEA) were resoundingly negative. We identified EGFR amplification in 5% (19/363) of patients at the University of Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy. Seven patients received ≥1 dose of treatment: three first-line FOLFOX plus ABT-806, one second-line FOLFIRI plus cetuximab, and three third/fourth-line cetuximab alone. Treatment achieved objective response in 58% (4/7) and disease control in 100% (7/7) with a median progression-free survival of 10 months. Pretreatment and posttreatment tumor next-generation sequencing (NGS), serial plasma circulating tumor DNA (ctDNA) NGS, and tumor IHC/FISH for EGFR revealed preexisting and/or acquired genomic events, including EGFR-negative clones, PTEN deletion, KRAS amplification/mutation, NRAS, MYC, and HER2 amplification, and GNAS mutations serving as mechanisms of resistance. Two evaluable patients demonstrated interval increase of CD3+ infiltrate, including one who demonstrated increased NKp46+, and PD-L1 IHC expression from baseline, suggesting an immune therapeutic mechanism of action. EGFR amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged.Significance: This paper highlights the role of EGFR inhibitors in EGFR-amplified GEA-despite negative results in prior unselected phase III trials. Using serial ctDNA and tissue NGS, we identified mechanisms of primary and acquired resistance in all patients, as well as potential contribution of antibody-dependent cell-mediated cytotoxicity to their clinical benefit. Cancer Discov; 8(6); 696-713. ©2018 AACR.See related commentary by Strickler, p. 679This article is highlighted in the In This Issue feature, p. 663.
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Affiliation(s)
- Steven B Maron
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Lindsay Alpert
- Department of Pathology, University of Chicago, Chicago, Illinois
| | - Heewon A Kwak
- Department of Pathology, University of Chicago, Chicago, Illinois
| | | | - Leah Chase
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - David Xu
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Emily O'Day
- Department of Medicine, University of Chicago, Chicago, Illinois
| | | | | | | | | | | | - John Hart
- Department of Pathology, University of Chicago, Chicago, Illinois
| | - Shu-Yuan Xiao
- Department of Pathology, University of Chicago, Chicago, Illinois
| | - Namrata Setia
- Department of Pathology, University of Chicago, Chicago, Illinois
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Kim HJ, Oh SC. Novel Systemic Therapies for Advanced Gastric Cancer. J Gastric Cancer 2018; 18:1-19. [PMID: 29629216 PMCID: PMC5881006 DOI: 10.5230/jgc.2018.18.e3] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/14/2018] [Accepted: 02/26/2018] [Indexed: 12/27/2022] Open
Abstract
Gastric cancer (GC) is the second leading cause of cancer mortality and the fourth most commonly diagnosed malignant diseases. While continued efforts have been focused on GC treatment, the introduction of trastuzumab marked the beginning of a new era of target-specific treatments. Considering the diversity of mutations in GC, satisfactory results obtained from various target-specific therapies were expected, yet most of them were unsuccessful in controlled clinical trials. There are several possible reasons underlying the failures, including the absence of patient selection depending on validated predictive biomarkers, the inappropriate combination of drugs, and tumor heterogeneity. In contrast to targeted agents, immuno-oncologic agents are designed to regulate and boost immunity, are not target-specific, and may overcome tumor heterogeneity. With the successful establishment of predictive biomarkers, including Epstein-Barr virus pattern, microsatellite instability status, and programmed death-ligand 1 (PD-L1) expression, as well as ideal combination regimens, a new frontier in the immuno-oncology of GC treatment is on the horizon. Since the field of immuno-oncology has witnessed innovative, practice-changing successes in other cancer types, several trials on GC are ongoing. Among immuno-oncologic therapies, immune checkpoint inhibitors are the mainstay of clinical trials performed on GC. In this article, we review target-specific agents currently used in clinics or are undergoing clinical trials, and highlight the future clinical application of immuno-oncologic agents in inoperable GC.
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Affiliation(s)
- Hong Jun Kim
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Sang Cheul Oh
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
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Kim ST, Lee J, Lee SJ, Park SH, Jung SH, Park YS, Lim HY, Kang WK, Park JO. Prospective phase II trial of pazopanib plus CapeOX (capecitabine and oxaliplatin) in previously untreated patients with advanced gastric cancer. Oncotarget 2018; 7:24088-96. [PMID: 27003363 PMCID: PMC5029686 DOI: 10.18632/oncotarget.8175] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 02/25/2016] [Indexed: 02/06/2023] Open
Abstract
We designed a single-arm, open label phase II study to determine the efficacy and toxicity of the combination of pazopanib with CapeOx (capecitabine and oxaliplatin) in metastatic /recurrent advanced gastric cancer (AGC) patients. Previously untreated AGC patients received capecitabine (850 mg/m2 bid, day 1–14) plus oxaliplatin (130 mg/m2, day 1) in combination with pazopanib (800 mg, day 1–21) every three weeks. Treatment was continued until progression of the disease or intolerable toxicity was observed. In all, 66 patients were treated with pazopanib plus CapeOx. The median age of the patients was 51.5 years (range, 23.0–77), and the median ECOG performance status was 1 (0–1). Among all 66 patients, one complete response and 37 partial responses were observed (overall response rate, 62.4%; 95% confidence interval (CI), 45.7–73.5% accounting for the 2-stage design of this trial). Stable disease was observed in 23 patients (34.8%), revealing a 92.4% disease control rate. The median progression free survival and overall survival were 6.5 months (95% CI, 5.6–7.4) and 10.5 months (95% CI, 8.1–12.9), respectively. Thirty-four patients (51.5%) experienced a treatment-related toxicity of grade 3 or more. The most common toxicities of grade 3 or more were neutropenia (15.1%), anemia (10.6%), thrombocytopenia (10.6%), anorexia (7.6%), nausea (3.0%), and vomiting (3.0%). There were no treatment-related deaths. The combination of pazopanib and CapeOx showed moderate activity and an acceptable toxicity profile as a first-line treatment in metastatic / recurrent AGC patients (ClinicalTrials.gov NCT01130805).
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Affiliation(s)
- Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Su Jin Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sin-Ho Jung
- Center of Biostatistics and Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Wang X, Fu R, Hu Y, Du H, Li S, Li Z, Liu Y, Li Q, Zhang L, Ji J. EGFR gene status predicts response and survival benefit in a preclinical gastric cancer trial treating patient‑derived xenografts with cetuximab. Oncol Rep 2017; 38:2387-2393. [PMID: 28849161 DOI: 10.3892/or.2017.5907] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 06/21/2017] [Indexed: 11/05/2022] Open
Abstract
Cetuximab has been evaluated as a first-line treatment with conflicting results. The aim of the present study was to investigate the relationship between epidermal growth factor receptor (EGFR) status, and response and survival benefit following cetuximab treatment in gastric cancer (GC). Using 20 patient-derived GC xenograft (PDX) models, the mice (10 mice/model) were randomly assigned into two groups. The control group and treatment group were treated with PBS and cetuximab, respectively. The drug response was evaluated by monitoring tumor growth. Survival benefit was evaluated by comparing the survival curves corresponding to the time for the tumors to reach 600 mm3. Our results revealed that the PDX models treated with cetuximab had better survival than that noted for the non-treated group (P<0.05). The EGFR status was measured by FISH, qPCR, RNAish and immunohistochemistry, respectively. Four cases in the treated group were identified as responsive to cetuximab. EGFR mRNA and protein overexpression were associated with the response to cetuximab (P<0.05). EGFR amplification, mRNA and protein overexpression were associated with prolonged survival in the cetuximab-treated PDX models. Moreover, in the PDX models with EGFR amplification, mRNA or protein overexpression, cetuximab treatment was associated with a better survival compared with that noted in the untreated group in the PDX models (P<0.05), while the survival was not statistically different in the other cases (P>0.05). In conclusion, cetuximab provided survival benefit in the trial. The level of EGFR amplification and overexpression significantly predicted response and survival benefit, particularly the mRNA and protein expression level. A combination of mRNA and protein expression may predict efficacy of cetuximab more efficiently.
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Affiliation(s)
- Xiaohong Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Tissue Bank, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Runjia Fu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Ying Hu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Tissue Bank, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Hong Du
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Shuangxi Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Ziyu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Yiqiang Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Qixiang Li
- Crown Bioscience Inc., Light Muller Building, Changping Sector of Zhongguancun Science Park, Changping, Beijing 102200, P.R. China
| | - Lianhai Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Jiafu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
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11
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Liu X, Guo W, Zhang W, Yin J, Zhang J, Zhu X, Liu T, Chen Z, Wang B, Chang J, Lv F, Hong X, Wang H, Wang J, Zhao X, Wu X, Li J. A multi-center phase II study and biomarker analysis of combined cetuximab and modified FOLFIRI as second-line treatment in patients with metastatic gastric cancer. BMC Cancer 2017; 17:188. [PMID: 28288572 PMCID: PMC5348753 DOI: 10.1186/s12885-017-3174-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 03/04/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND To evaluate the efficacy of cetuximab combined with modified FOLFIRI (mFOLFIRI) as a second-line treatment in metastatic gastric cancer patients and to identify potential biomarkers of clinical outcomes. METHODS All 61 patients received an initial intravenous (IV) dose of cetuximab (400 mg/m2) and weekly doses (250 mg/m2) thereafter, starting on day 1. On day 2 of each 14-day period, patients received IV irinotecan (180 mg/m2), leucovorin (200 mg/m2), and an IV bolus dose of 5-FU (400 mg/m2) followed by a continuous infusion of 5-FU (2400 mg/m2) for 46 h. The primary endpoint was time-to-progression (TTP). RESULTS The response rate (RR) was 33.3% among 54 evaluable patients. In the intention-to-treat analysis, median TTP was 4.6 months (95% confidential interval [CI]: 3.6-5.6 months) and median overall survival (OS) was 8.6 months (95% CI: 7.3-9.9 months). In univariate analyses, plasma vascular endothelial growth factor (VEGF) levels were correlated with clinical outcome. In patients with low (≤12.6 pg/ml) and high (>12.6 pg/ml) baseline plasma VEGF levels, RR values were 55.0% and 5.3%, respectively (P = 0.001); median TTP values were 6.9 months and 2.8 months, respectively (P = 0.0005); and median OS values were 12 months and 5 months, respectively (P <0.0001). None of these patients exhibited KRAS, BRAF, or PIK3CA mutations. CONCLUSIONS Combination therapy comprising cetuximab and mFOLFIRI was well tolerated and active as a second-line treatment for patients with metastatic gastric cancer. Patients with low baseline plasma VEGF levels were associated with better clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov. NCT00699881 . Registered 17 June 2008 (retrospectively registered).
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Affiliation(s)
- Xin Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Weijian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Wen Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jiliang Yin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jun Zhang
- Department of Oncology, Ruijin Hospital of Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Xiaodong Zhu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China
| | - Zhiyu Chen
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Biyun Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jianhua Chang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Fangfang Lv
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Xiaonan Hong
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Huijie Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jialei Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Xinmin Zhao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Xianghua Wu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China
| | - Jin Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China.
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12
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Mizrak Kaya D, Harada K, Shimodaira Y, Amlashi FG, Lin Q, Ajani JA. Advanced gastric adenocarcinoma: optimizing therapy options. Expert Rev Clin Pharmacol 2017; 10:263-271. [PMID: 28094573 DOI: 10.1080/17512433.2017.1279969] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
INTRODUCTION Gastric adenocarcinoma (GAC) is the fifth most common cancer and third leading cause of cancer related mortality worldwide. When localized, cure is achievable with surgery and adjunctive therapies in some patients, however, once advanced, GAC is not a curable condition. Only two targeted agents (trastuzumab and ramucirumab) have been approved and apatinib was approved only in China. Because of the heterogeneous nature of GAC, it is not possible to assess a standard therapeutic approach. Areas covered: In this review, we aimed to describe the optimal systemic therapy regimens for advanced GAC. A literature search was performed to identify all phase II-III studies about advanced GAC from PubMed, clinicaltrials.gov, American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) websites. Expert commentary: A combination of a platinum compound and a fluoropyrimidine is ideal as first line therapy. Trastuzumab should be added if the tumor is HER2 positive. In the second line setting, paclitaxel/ramucirumab is preferred over ramucirumab alone. Recently, two similar molecular classifications for GAC have been proposed. A better understanding of molecular and immune biology of GAC could identify new therapeutic targets.
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Affiliation(s)
- Dilsa Mizrak Kaya
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Kazuto Harada
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Yusuke Shimodaira
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Fatemeh G Amlashi
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Quan Lin
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Jaffer A Ajani
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
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13
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Pasini F, Fraccon AP, Modena Y, Bencivenga M, Giacopuzzi S, La Russa F, Gusella M, de Manzoni G. Targeted therapies for advanced and metastatic adenocarcinoma of the gastroesophageal junction: is there something new? Gastric Cancer 2017; 20:31-42. [PMID: 27568322 DOI: 10.1007/s10120-016-0626-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Accepted: 08/02/2016] [Indexed: 02/07/2023]
Abstract
Despite improvements in systemic chemotherapy (CT), the prognosis of metastatic adenocarcinoma of the gastroesophageal junction remains poor. Over the years, new targeting agents have become available and were tested, with or without CT, in first or subsequent lines of therapy. The epidermal growth factor receptor family was targeted with monoclonal antibodies (MoAbs) (trastuzumab, cetuximab, panitumumab) and tyrosin kinase inhibitors (TKIs) (lapatinib, erlotinib, gefitinib). Only trastuzumab, in combination with cisplatin and fluoropyrimidines, significantly improved overall survival (OS) in first-line therapy (13.8 vs. 11.1 months). Angiogenesis also was targeted with MoAbs (bevacizumab and ramucirumab); ramucirumab, a vascular endothelial growth factor-receptor 2 antagonist, enhanced OS in two phase III studies in the first (9.6 vs. 7.4 months) and subsequent lines of treatment (5.2 vs. 3.8 months), while the bevacizumab study was negative. TKIs (sunitinib, sorafenib, regorafenib, apatinib) were tested in this setting in phase II studies in the second/third line, only showing modest antitumor activity. The hepatocyte growth factor receptor (MET) was targeted in untreated patients in a phase III trial with MoAb rilotumumab, with or without CT, but the study was stopped because of mortality excess in the rilotumumab arm. Mammalian target of rapamycin (MTOR) pathway inhibition with everolimus was tested in pretreated patients in a placebo-controlled phase III trial who failed to improve OS (5.4 vs. 4.3 months). In conclusion, considering the modest survival gain obtained overall, the high cost of these therapies and the quality of life issue must be primarily considered in treating these patients.
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Affiliation(s)
- Felice Pasini
- Department of Medical Oncology, Ospedale S. Maria della Misericordia, Viale Tre Martiri, 140-45100, Rovigo, Italy.
| | - Anna Paola Fraccon
- Medical Oncology Unit, Casa di Cura Pederzoli, Peschiera del Garda, Verona, Italy
| | - Yasmina Modena
- Department of Medical Oncology, Ospedale S. Maria della Misericordia, Viale Tre Martiri, 140-45100, Rovigo, Italy
| | - Maria Bencivenga
- General and Upper GI Surgery Division, University of Verona, Verona, Italy
| | - Simone Giacopuzzi
- General and Upper GI Surgery Division, University of Verona, Verona, Italy
| | - Francesca La Russa
- Department of Medical Oncology, Ospedale S. Maria della Misericordia, Viale Tre Martiri, 140-45100, Rovigo, Italy
| | - Milena Gusella
- Department of Medical Oncology, Ospedale S. Maria della Misericordia, Viale Tre Martiri, 140-45100, Rovigo, Italy
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14
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Lazăr DC, Tăban S, Cornianu M, Faur A, Goldiş A. New advances in targeted gastric cancer treatment. World J Gastroenterol 2016; 22:6776-6799. [PMID: 27570417 PMCID: PMC4974579 DOI: 10.3748/wjg.v22.i30.6776] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 06/13/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
Despite a decrease in incidence over past decades, gastric cancer remains a major global health problem. In the more recent period, survival has shown only minor improvement, despite significant advances in diagnostic techniques, surgical and chemotherapeutic approaches, the development of novel therapeutic agents and treatment by multidisciplinary teams. Because multiple genetic mutations, epigenetic alterations, and aberrant molecular signalling pathways are involved in the development of gastric cancers, recent research has attempted to determine the molecular heterogeneity responsible for the processes of carcinogenesis, spread and metastasis. Currently, some novel agents targeting a part of these dysfunctional molecular signalling pathways have already been integrated into the standard treatment of gastric cancer, whereas others remain in phases of investigation within clinical trials. It is essential to identify the unique molecular patterns of tumours and specific biomarkers to develop treatments targeted to the individual tumour behaviour. This review analyses the global impact of gastric cancer, as well as the role of Helicobacter pylori infection and the efficacy of bacterial eradication in preventing gastric cancer development. Furthermore, the paper discusses the currently available targeted treatments and future directions of research using promising novel classes of molecular agents for advanced tumours.
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15
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Riquelme I, Saavedra K, Espinoza JA, Weber H, García P, Nervi B, Garrido M, Corvalán AH, Roa JC, Bizama C. Molecular classification of gastric cancer: Towards a pathway-driven targeted therapy. Oncotarget 2016; 6:24750-79. [PMID: 26267324 PMCID: PMC4694793 DOI: 10.18632/oncotarget.4990] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 07/17/2015] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer mortality worldwide. Although surgical resection is a potentially curative approach for localized cases of GC, most cases of GC are diagnosed in an advanced, non-curable stage and the response to traditional chemotherapy is limited. Fortunately, recent advances in our understanding of the molecular mechanisms that mediate GC hold great promise for the development of more effective treatment strategies. In this review, an overview of the morphological classification, current treatment approaches, and molecular alterations that have been characterized for GC are provided. In particular, the most recent molecular classification of GC and alterations identified in relevant signaling pathways, including ErbB, VEGF, PI3K/AKT/mTOR, and HGF/MET signaling pathways, are described, as well as inhibitors of these pathways. An overview of the completed and active clinical trials related to these signaling pathways are also summarized. Finally, insights regarding emerging stem cell pathways are described, and may provide additional novel markers for the development of therapeutic agents against GC. The development of more effective agents and the identification of biomarkers that can be used for the diagnosis, prognosis, and individualized therapy for GC patients, have the potential to improve the efficacy, safety, and cost-effectiveness for GC treatments.
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Affiliation(s)
- Ismael Riquelme
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Kathleen Saavedra
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Jaime A Espinoza
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Helga Weber
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Patricia García
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Bruno Nervi
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marcelo Garrido
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alejandro H Corvalán
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
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16
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Park JS, Kim HS, Bae YS, Cheong JH, Rha SY, Noh SH, Kim H. Prognostic significance and frequency of EGFR expression and amplification in surgically resected advanced gastric cancer. Jpn J Clin Oncol 2016; 46:507-16. [PMID: 27008850 DOI: 10.1093/jjco/hyw030] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Accepted: 02/14/2016] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE The aim of this study is to find the frequency and the role of epidermal growth factor receptor expression as a prognostic biomarker in gastric cancer. METHODS We evaluated the prognostic value and frequency of epidermal growth factor receptor expression and amplification using immunohistochemistry and silver in situ hybridization in a large cohort of curatively resected gastric cancer. RESULTS Of the total of 935 cases, 294 (31.4%), 101 (10.8%) and 36 (3.9%) patients showed epidermal growth factor receptor 1+, 2+ and 3+ expression on immunohistochemistry, respectively. Epidermal growth factor receptor-positive (2+/3+) patients more frequently had intestinal type than epidermal growth factor receptor-negative (0/1+) patients (82.5 vs. 44.1%, P < 0.001). After adjusting for sex, age, stage and adjuvant chemotherapy, epidermal growth factor receptor-positive patients had a favorable overall survival outcome compared with epidermal growth factor receptor-negative patients (hazard ratio, 0.734; 95% confidence interval, 0.541-0.997; P = 0.047), especially in Stage III disease (hazard ratio, 0.676; 95% confidence interval, 0.472-0.968; P = 0.033). Among the 393 cases available for in situ hybridization, the correlation between immunohistochemistry and in situ hybridization was statistically significant (P = 0.001). Thirteen patients with gene amplification (3.3%) did not show different survival outcome with others (P = 0.359). CONCLUSION Epidermal growth factor receptor positivity was an independent favorable prognostic factor for gastric cancer, especially in Stage III disease.
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Affiliation(s)
- Ji Soo Park
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul Department of Internal Medicine, Yonsei University College of Medicine, Seoul
| | - Hyo Song Kim
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul Department of Internal Medicine, Yonsei University College of Medicine, Seoul
| | - Yoon Sung Bae
- Department of Pathology, Yonsei University College of Medicine, Seoul
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sun Young Rha
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul Department of Internal Medicine, Yonsei University College of Medicine, Seoul
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul
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17
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Aguiar PN, Muniz TP, Miranda RR, Tadokoro H, Forones NM, Monteiro IDP, Castelo-Branco P, Janjigian YY, De Mello RA. Current advances in targeted therapies for metastatic gastric cancer: improving patient care. Future Oncol 2016; 12:839-854. [PMID: 26838766 DOI: 10.2217/fon.15.348] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 12/07/2015] [Indexed: 02/07/2023] Open
Abstract
In this article, we review the literature on the current advances in targeted therapies for metastatic gastric cancer aimed at improving patient care. We conclude that the key to guiding targeted therapy is individual biomarkers, which are not completely elucidated. HER2 overexpression is the only predictive biomarker currently in use. Furthermore, it is necessary to understand that gastric tumors are heterogeneous; therefore, is impossible to evaluate a novel biological compound without evaluating personal biomarkers. The selection of patients who are able to receive each treatment is paramount for improving advanced gastric cancer survival and reducing unnecessary costs.
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Affiliation(s)
| | | | | | - Hakaru Tadokoro
- Division of Medical Oncology, Federal University of São Paulo, São Paulo, Brazil
| | | | | | - Pedro Castelo-Branco
- Department of Biomedical Sciences & Medicine, Division of Oncology, University of Algarve, Faro, Portugal
| | - Yelena Y Janjigian
- Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ramon Andrade De Mello
- Department of Medicine, Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Biomedical Sciences & Medicine, Division of Oncology, University of Algarve, Faro, Portugal
- Clinical Research Center & Department of Medical Oncology, Centro Oncológico São Mateus, Ceará Cancer Institute, Rua Papi Junior 1222, Rodolfo Teófilo, CEP 60430-235, Fortaleza-CE, Brazil
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18
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Yazici O, Sendur MAN, Ozdemir N, Aksoy S. Targeted therapies in gastric cancer and future perspectives. World J Gastroenterol 2016; 22:471-89. [PMID: 26811601 PMCID: PMC4716053 DOI: 10.3748/wjg.v22.i2.471] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Revised: 10/05/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023] Open
Abstract
Advanced gastric cancer (AGC) is associated with a high mortality rate and, despite multiple new chemotherapy options, the survival rates of patients with AGC remains poor. After the discovery of targeted therapies, research has focused on the new treatment options for AGC. In the last two decades, many targeted molecules were developed against AGC. Currently, two targeted therapy molecules have been approved for patients with AGC. In 2010, trastuzumab was the first molecule shown to improve survival in patients with HER2-positive AGC as part of a first-line combination regimen. In 2014, ramucirumab was the second targeted molecule to improve survival rates and was suggested as treatment for patients with AGC who had progressed after first-line platinum plus fluoropyrimidine with or without anthracycline chemotherapy. Ramucirumab was the first targeted therapy acting as a single agent in patients with advanced gastroesophageal cancers. Although these two molecules were introduced into clinical use, many other promising molecules have been tested in phase I-II trials. It is obvious that in the near future many different targeted therapies will be in use for treatment of AGC. In this review, the current status of targeted therapies in the treatment of AGC and gastroesophageal junction tumors, including HER (2-3) inhibitors, epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, antiangiogenic agents, c-MET inhibitors, mammalian target of rapamycin inhibitors, agents against other molecular pathways fibroblast growth factor, Claudins, insulin-like growth factor, heat shock proteins, and immunotherapy, will be discussed.
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Affiliation(s)
- Ozan Yazici
- Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara 06100, Turkey
| | - M Ali Nahit Sendur
- Department of Medical Oncology, Yildirim Beyazit University, Ankara 06100, Turkey
| | - Nuriye Ozdemir
- Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara 06100, Turkey
| | - Sercan Aksoy
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara 06100, Turkey
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19
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Xu W, Yang Z, Lu N. Molecular targeted therapy for the treatment of gastric cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:1. [PMID: 26728266 PMCID: PMC4700735 DOI: 10.1186/s13046-015-0276-9] [Citation(s) in RCA: 143] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 12/18/2015] [Indexed: 12/24/2022]
Abstract
Despite the global decline in the incidence and mortality of gastric cancer, it remains one of the most common malignant tumors of the digestive system. Although surgical resection is the preferred treatment for gastric cancer, chemotherapy is the preferred treatment for recurrent and advanced gastric cancer patients who are not candidates for reoperation. The short overall survival and lack of a standard chemotherapy regimen make it important to identify novel treatment modalities for gastric cancer. Within the field of tumor biology, molecular targeted therapy has attracted substantial attention to improve the specificity of anti-cancer efficacy and significantly reduce non-selective resistance and toxicity. Multiple clinical studies have confirmed that molecular targeted therapy acts on various mechanisms of gastric cancer, such as the regulation of epidermal growth factor, angiogenesis, immuno-checkpoint blockade, the cell cycle, cell apoptosis, key enzymes, c-Met, mTOR signaling and insulin-like growth factor receptors, to exert a stronger anti-tumor effect. An in-depth understanding of the mechanisms that underlie molecular targeted therapies will provide new insights into gastric cancer treatment.
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Affiliation(s)
- Wenting Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Zhen Yang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
| | - Nonghua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
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20
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Woo J, Cohen SA, Grim JE. Targeted therapy in gastroesophageal cancers: past, present and future. Gastroenterol Rep (Oxf) 2015; 3:316-29. [PMID: 26510453 PMCID: PMC4650980 DOI: 10.1093/gastro/gov052] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 09/09/2015] [Indexed: 12/12/2022] Open
Abstract
Gastroesophageal cancer is a significant global problem that frequently presents at an incurable stage and has very poor survival with standard chemotherapy approaches. This review will examine the epidemiology and molecular biology of gastroesophageal cancer and will focus on the key deregulated signaling pathways that have been targeted in the clinic. A comprehensive overview of clinical data highlighting successes and failures with targeted agents will be presented. Most notably, HER2-targeted therapy with the monoclonal antibody trastuzumab has proven beneficial in first-line therapy and has been incorporated into standard practice. Targeting the VEGF pathway has also proven beneficial, and the VEGFR-targeted monoclonal antibody ramucirumab is now approved for second-line therapy. In contrast to these positive results, agents targeting the EGFR and MET pathways have been evaluated extensively in gastroesophageal cancer but have repeatedly failed to show benefit. An increased understanding of the molecular predictors of response to targeted therapies is sorely needed. In the future, improved molecular pathology approaches should subdivide this heterogeneous disease entity to allow individualization of cancer therapy based on integrated and global identification of deregulated signaling pathways. Better patient selection, rational combinations of targeted therapies and incorporation of emerging immunotherapeutic approaches should further improve the treatment of this deadly disease.
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Affiliation(s)
- Janghee Woo
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Division of Medical Oncology, University of Washington, Seattle, WA, USA and
| | - Stacey A Cohen
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Division of Medical Oncology, University of Washington, Seattle, WA, USA and
| | - Jonathan E Grim
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Division of Medical Oncology, University of Washington, Seattle, WA, USA and Hospital and Specialty Medicine, VA Puget Sound Health Care System, Seattle, WA, USA
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21
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Sudo K, Yamada Y. Advancing pharmacological treatment options for advanced gastric cancer. Expert Opin Pharmacother 2015; 16:2293-305. [PMID: 26359224 DOI: 10.1517/14656566.2015.1080238] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
INTRODUCTION Gastric cancer is the third most common cause of cancer-related deaths worldwide. Improvement of conventional chemotherapy has been modest in the past decades. AREAS COVERED We review recent important studies of metastatic or recurrent gastric cancer. For human epidermal growth factor receptors 2 (HER2) negative cancer, standard treatments are combinations of fluoropyrimidine and platinum with or without epirubicin or docetaxel in first-line therapy. Controversy exists regarding the use of triplet chemotherapies due to their toxicity. For HER2 positive cancer, standard treatments are combinations of fluoropyrimidine and cisplatin with trastuzumab. As second- or third-line treatment, taxanes or irinotecan prolonged survival compared with best supportive care alone, but the extension of overall survival was only 1 - 2 months. A recent study demonstrated that ramucirumab plus paclitaxel improved survival as a second-line therapy. EXPERT OPINION Most trials have failed to demonstrate a benefit of targeted agents. It is important to identify predictive biomarkers to enrich an appropriate patient population for targeted agents such as HER2 status for trastuzumab.
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Affiliation(s)
- Kazuki Sudo
- a 1 National Cancer Center Hospital , 5-1-1 Tsukiji, Chuo-ku, 104-0045 Tokyo, Japan +81 3 3542 2511 ; +81 3 3542 3815 ; .,b 2 Juntendo University Graduate School of Medicine, Advanced Clinical Research of Cancer , Tokyo, Japan
| | - Yasuhide Yamada
- a 1 National Cancer Center Hospital , 5-1-1 Tsukiji, Chuo-ku, 104-0045 Tokyo, Japan +81 3 3542 2511 ; +81 3 3542 3815 ;
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Liu FT, Ou-Yang X, Zhang GP, Luo HL. Nanobodies for targeted treatment of gastric cancer. Shijie Huaren Xiaohua Zazhi 2015; 23:3714-3719. [DOI: 10.11569/wcjd.v23.i23.3714] [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] [Indexed: 02/06/2023] Open
Abstract
With the development and application of monoclonal antibody-based targeted therapy drugs in recent years, some achievements have been made in the treatment of gastric cancer; however, because their preparation is relatively complex and expensive, their application is limited. Nanobodies have some advantages over conventional molecular targeted drugs, such as small molecular weight and unique structural features, and provide a new treatment strategy for targeted therapy of gastric cancer. In this paper, we review the nanobodies that have the potential for targeted treatment of gastric cancer.
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23
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Koo DH, Ryu MH, Ryoo BY, Seo J, Lee MY, Chang HM, Lee JL, Lee SS, Kim TW, Kang YK. Improving trends in survival of patients who receive chemotherapy for metastatic or recurrent gastric cancer: 12 years of experience at a single institution. Gastric Cancer 2015; 18:346-53. [PMID: 24832201 DOI: 10.1007/s10120-014-0385-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 04/23/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND The aim of this retrospective study was to evaluate the changes in clinical features and treatment outcomes of the patients with metastatic or recurrent gastric cancer (MRGC) treated in the past 12 years. METHODS A total of 3888 patients who received chemotherapy for MRGC between January 2000 and December 2011 were analyzed via a prospectively collected registry. The analysis focused on the comparison among three periods: 2000-2003 (period 1), 2004-2007 (period 2) and 2008-2011 (period 3). RESULTS There were 880 patients (23%) in period 1, 1573 (40%) in period 2 and 1435 (37%) in period 3. The most commonly used first-line chemotherapy regimen was fluoropyrimidine with/without platinum (72%) for all periods. The use of second- and third-line chemotherapy was slightly but significantly more common in the two recent periods: 46 and 19 % in period 1, 54 and 26% in period 2, and 53 and 27% in period 3, respectively. Overall, 3494 patients (89.9%) died with a median overall survival (OS) of 10.6 months (95% CI 10.2-11.0). The OS was statistically significantly improved over the study period: 9.6 months (95% CI 9.0-10.2) in period 1, 10.3 months (95% CI 9.8-10.9) in period 2 and 11.7 months (95% CI 11.0-12.4) in period 3 (p for trend <0.001). Multivariate analysis including eight prognostic factors (performance, gastrectomy, peritoneal/bone/lung metastasis, abnormal alkaline phosphatase/albumin/total bilirubin) showed that the more recent treatment period was an independent favorable prognostic factor for OS (p < 0.001). CONCLUSION The OS of patients who receive chemotherapy for MRGC has been shown to improve over time.
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Affiliation(s)
- Dong Hoe Koo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea
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24
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Stahl P, Seeschaaf C, Lebok P, Kutup A, Bockhorn M, Izbicki JR, Bokemeyer C, Simon R, Sauter G, Marx AH. Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer. BMC Gastroenterol 2015; 15:7. [PMID: 25649416 PMCID: PMC4324419 DOI: 10.1186/s12876-015-0231-4] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 01/13/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Intra-tumor heterogeneity is a potential cause for failure of targeted therapy in gastric cancer, but the extent of heterogeneity of established (HER2) or potential (EGFR, CCND1) target genes and prognostic gene alterations (MYC) had not been systematically studied. METHODS To study heterogeneity of these genes in a large patient cohort, a heterogeneity tissue microarray was constructed containing 0.6 mm tissue cores from 9 different areas of the primary gastric cancers of 113 patients and matched lymph node metastases from 61 of these patients. Dual color fluorescence in-situ hybridization was performed to assess amplification of HER2, EGFR, CCND1 and MYC using established thresholds (ratio ≥ 2.0). Her2 immunohistochemistry (IHC) was performed in addition. RESULTS Amplification was found in 17.4% of 109 interpretable cases for HER2, 6.4% for EGFR, 17.4% for CCND1, and 24.8% for MYC. HER2 amplification was strongly linked to protein overexpression by IHC in a spot-by-spot analysis (p < 0.0001). Intra-tumor heterogeneity was found in the primary tumors of 9 of 19 (47.3%) cancers with HER2, 8 of 17 (47.0%) cancers with CCND1, 5 of 7 (71.4%) cancers with EGFR, and 23 of 27 (85.2%) cancers with MYC amplification. Amplification heterogeneity was particularly frequent in case of low-level amplification (<10 gene copies). While the amplification status was often different between metastases, unequivocal intra-tumor heterogeneity was not found in individual metastases. CONCLUSION The data of our study demonstrate that heterogeneity is common for biomarkers in gastric cancer. Given that both TMA tissue cores and clinical tumor biopsies analyze only a small fraction of the tumor bulk, it can be concluded that such heterogeneity may potentially limit treatment decisions based on the analysis of a single clinical cancer biopsy.
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Affiliation(s)
- Phillip Stahl
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Carsten Seeschaaf
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Asad Kutup
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Maximillian Bockhorn
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Jakob R Izbicki
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Carsten Bokemeyer
- II Med. Klinik, Oncology, Hematology with section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Andreas H Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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25
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Rolfo C, Bronte G, Sortino G, Papadimitriou K, Passiglia F, Fiorentino E, Marogy G, Russo A, Peeters M. The role of targeted therapy for gastrointestinal tumors. Expert Rev Gastroenterol Hepatol 2014; 8:875-85. [PMID: 24957206 DOI: 10.1586/17474124.2014.922870] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Many targeted drugs have been studied to target the molecular pathways involved in the development of gastrointestinal cancers. Anti-VEGF, anti-EGFR agents, and recently also multi-kinase inhibitor regorafenib, have already been available for the treatment of metastatic colorectal cancer patients. To date, Her-2 positive, gastric cancer patients, are also treated with trastuzumab, while the multi-targeted inhibitor, sorafenib, represents the standard treatment for hepatocellular carcinoma patients. Finally, sunitinib and everolimus, have been approved for the treatment of the neuroendocrine gastroenteropancreatic tumors. Actually a great number of further drugs are under preclinical and clinical development. The aim of this review is to provide a comprehensive overview of the state of art, focusing on the new emerging strategies in the personalized treatment of gastrointestinal tumors.
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Affiliation(s)
- Christian Rolfo
- Oncology Department, University Hospital Antwerp UZA, University of Antwerp, Wilrijkstraat 10, 2650, Antwerp, Belgium
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26
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Vita FD, Martino ND, Fabozzi A, Laterza MM, Ventriglia J, Savastano B, Petrillo A, Gambardella V, Sforza V, Marano L, Auricchio A, Galizia G, Ciardiello F, Orditura M. Clinical management of advanced gastric cancer: the role of new molecular drugs. World J Gastroenterol 2014; 20:14537-14558. [PMID: 25356019 PMCID: PMC4209522 DOI: 10.3748/wjg.v20.i40.14537] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/19/2014] [Accepted: 06/02/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the fourth most common malignant neoplasm and the second leading cause of death for cancer in Western countries with more than 20000 new cases yearly diagnosed in the United States. Surgery represents the main approach for this disease but, notwithstanding the advances in surgical techniques, we observed a minimal improvement in terms of overall survival with a significant increasing of relapsing disease rates. Despite the development of new drugs has significantly improved the effectiveness of chemotherapy, the prognosis of patients with unresectable or metastatic gastric adenocarcinoma remains poor. Recently, several molecular target agents have been investigated; in particular, trastuzumab represents the first target molecule showing improvements in overall survival in human epithelial growth factor 2-positive gastric cancer patients. New molecules targeting vascular epithelial growth factor, mammalian target of rapamycin, and anti hepatocyte growth factor-c-Met pathway are also under investigation, with interesting results. Anyway, it seems necessary to select more accurately the population to treat with new agents by the identification of new biomarkers in order to optimize the results. In this paper we review the actual "scenario" of targeted treatments, also focusing on the new agents in development for gastric cancer and gastro-esophageal carcinoma, discussing their efficacy and potential applications in clinical practice.
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27
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Aoyagi K, Kouhuji K, Kizaki J, Isobe T, Hashimoto K, Shirouzu K. Molecular targeting to treat gastric cancer. World J Gastroenterol 2014; 20:13741-55. [PMID: 25320512 PMCID: PMC4194558 DOI: 10.3748/wjg.v20.i38.13741] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 01/13/2014] [Accepted: 05/23/2014] [Indexed: 02/06/2023] Open
Abstract
Trastuzumab that targets human epidermal growth factor receptor 2 (HER2) protein is the only approved molecular targeting agent for treating gastric cancer in Japan and the outcomes have been favorable. However, trastuzumab is effective for only 10% to 20% of the population with gastric cancer that expresses HER2 protein. Molecular targeting therapy with bevacizumab against vascular endothelial growth factors (VEGF) and with cetuximab and panitumumab against the epidermal growth factors pathway that have been approved for treating colorectal cancer are not considered effective for treating gastric cancer according to several clinical trials. However, ramucirumab that targets VEGF receptor-2 prolonged overall survival in a large phase III clinical trial and it might be an effective molecular targeting therapy for gastric cancer. The significance of molecular targeting therapy for gastric cancer remains controversial. A large-scale randomized clinical trial of novel molecular targeting agents with which to treat gastric cancer is needed.
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28
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Zhang X, Xu J, Liu H, Yang L, Liang J, Xu N, Bai Y, Wang J, Shen L. Predictive biomarkers for the efficacy of cetuximab combined with cisplatin and capecitabine in advanced gastric or esophagogastric junction adenocarcinoma: a prospective multicenter phase 2 trial. Med Oncol 2014; 31:226. [PMID: 25234930 DOI: 10.1007/s12032-014-0226-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 09/02/2014] [Indexed: 12/17/2022]
Abstract
Cetuximab presents a potential therapy for gastric or esophagogastric junction adenocarcinoma. We aim to evaluate the predictive value of potential biomarkers of cetuximab efficacy. In this prospective phase 2 trial (NCT00477711), we enrolled untreated 47 patients with un-resectable or metastatic gastric or esophagogastric junction adenocarcinoma from seven sites in China. Patients with histologically confirmed adenocarcinoma were given cisplatin (80 mg/m2, triweekly), capecitabine (2,000 mg/m2, triweekly for 2 weeks), and cetuximab weekly (400 mg/m2 at first infusion and 250 mg/m2 subsequently). Sample size was calculated using Simon's two-stage design. The primary endpoint was the objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), toxicity, and predictive biomarkers. The ORR was 53.2%, median PFS 5.2 months, and OS 10.8 months. The most frequent toxicities included neutropenia (25.0%), nausea/vomiting (11.5%), and rash/desquamation (9.6%). Patients with grade 2-4 rash achieved a significantly better ORR, longer PFS, and OS than those with grade 0-1 rash. Seven patients (15.9%) with epidermal growth factor receptor (EGFR) strong expression (3+) showed great tumor shrinkage, longer PFS (7.1 months), and OS (16.6 months). EGFR gene amplification was detected in four patients (8.5%), all of whom responded well. Compared to patients with lower levels of transforming growth factor-alpha (TGF-α), those with high levels showed better response and longer PFS (6.0 vs 2.7 months, p=0.001) and OS (12.9 vs 7.0 months, p=0.001). C+XP was well tolerated and effective for advanced gastric or esophagogastric junction adenocarcinoma as first-line therapy. Severity of skin rash and TGF-α level correlated with efficacy, and EGFR overexpression might predict cetuximab efficacy.
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Affiliation(s)
- Xiaotian Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, 100142, China,
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Al-Batran SE, Werner D. Recent advances and future trends in the targeted therapy of metastatic gastric cancer. Expert Rev Gastroenterol Hepatol 2014; 8:555-69. [PMID: 24665840 DOI: 10.1586/17474124.2014.902304] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The better understanding of the molecular mechanisms behind gastric cancer has led to the development of new therapeutic strategies that are likely to improve patient outcomes in the near future. Recently, targeting the HER2 and the VEGF pathways with trastuzumab and ramucirumab, respectively, have been found to improve survival, while directed therapies against a number of other pathways are under clinical evaluation. These include the hepatocyte growth factor and its receptor c-MET, the insulin-like growth factor 1, the fibroblast growth factor, the mammalian target of rapamycin (mTOR), the epidermal growth factor receptor, and other pathways, as well as relevant immunotherapeutic strategies. This article reviews recent advances and future trends of these concepts for gastric cancer and adenocarcinoma of the gastroesophageal junction.
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Affiliation(s)
- Salah-Eddin Al-Batran
- Krankenhaus Nordwest, UCT-University Cancer Center Frankfurt, Frankfurt am Main, Germany
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30
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Garrido M, Fonseca PJ, Vieitez JM, Frunza M, Lacave AJ. Challenges in first line chemotherapy and targeted therapy in advanced gastric cancer. Expert Rev Anticancer Ther 2014; 14:887-900. [PMID: 24953238 DOI: 10.1586/14737140.2014.915194] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Chemotherapy prolongs survival in advanced gastric cancer (AGC). The challenges involved in this procedure are providing a framework to aid in determining the best single or combined chemotherapy protocols for targeted agents in front-line therapy for patients in a clinical setting. A review of Phase II-III studies published or referenced in major oncology congress publications from 1970 to 2013 was performed. Cisplatin and fluoropyrimidine remain the reference regimen. Fluoropyrimidine combined with oxaliplatin or irinotecan may also be employed in special situations. There are no comparative studies of the same regimens with or without anthacyclines; thus, the effectiveness of anthacyclines remains under debate. The introduction of trastuzumab in the front-line therapy of HER2-positive patients and ramucirumab in refractory patients ushered in an age of targeted therapy for this disease.
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Affiliation(s)
- Marcelo Garrido
- Hemato-Oncology Department, Pontifical Catholic University of Chile, Diagonal paraguay 319, Santiago de chile, Chile
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31
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Moorcraft SY, Chau I. Investigational therapies targeting the ErbB family in oesophagogastric cancer. Expert Opin Investig Drugs 2014; 23:1349-63. [PMID: 24949530 DOI: 10.1517/13543784.2014.930126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The prognosis for patients with oesophagogastric (OG) cancer remains poor, with a median survival of approximately 9 - 11 months for patients with metastatic disease. However, a more personalised approach to treatment, using drugs tailored to the molecular characteristics of patients' tumours, has the potential to improve patient outcomes. Drugs targeting the ErbB family of receptors have been developed, but these have had varying degrees of success in clinical practice. AREAS COVERED The authors provide an overview of the ErbB receptor family with regard to OG cancers. Furthermore, they evaluate the evidence from preclinical and clinical trials of therapeutics targeting this family, including monoclonal antibodies, tyrosine kinase inhibitors and novel agents. EXPERT OPINION Drugs targeting the ErbB family have been evaluated in OG cancer, with a notable success story in the case of trastuzumab, although there have been disappointing failures with anti-EGFR therapy. The response to targeted treatment remains variable and further biomarker research is essential to identify patients most likely to benefit from these therapies. The treatment of OG cancer remains challenging, but new anti-HER2 therapies and combination therapies hold promise for the future.
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Affiliation(s)
- Sing Yu Moorcraft
- The Royal Marsden NHS Foundation Trust, Gastrointestinal Unit, Department of Medicine , Sutton SM2 5PT , UK +44 020 8642 6011 ; +44 020 8643 9414 ;
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Morishita A, Gong J, Masaki T. Targeting receptor tyrosine kinases in gastric cancer. World J Gastroenterol 2014; 20:4536-4545. [PMID: 24782606 PMCID: PMC4000490 DOI: 10.3748/wjg.v20.i16.4536] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 12/19/2013] [Accepted: 03/19/2014] [Indexed: 02/07/2023] Open
Abstract
Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials. One group of representative targeted oncogenic kinases, the receptor tyrosine kinases (RTKs), has been associated with gastric cancer development. Trastuzumab, an inhibitor of ERBB2, has been approved for the treatment of gastric cancer, although other receptor tyrosine kinases, such as epidermal growth factor receptor, vascular endothelial growth factor, platelet-derived growth factor receptor, c-Met, IGF-1R and fibroblast growth factor receptor 2, are also activated in gastric cancer. The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients. On the other hand, the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients; however, a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial. Other clinical trials, especially phase III trials that have tested drugs targeting RTKs, such as cetuximab, panitumumab, gefitinib, erlotinib, figitumumab, sorafenib, sunitinib and lapatinib, have shown that these drugs have modest effects against gastric cancer. This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies.
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Kasper S, Schuler M. Targeted therapies in gastroesophageal cancer. Eur J Cancer 2014; 50:1247-58. [PMID: 24495747 DOI: 10.1016/j.ejca.2014.01.009] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 01/07/2014] [Accepted: 01/08/2014] [Indexed: 02/07/2023]
Abstract
Gastroesophageal cancers comprising gastric cancer (GC), and cancers of the distal oesophagus and gastroesophageal junction (GEJ) are a global health threat. In Western populations the incidence of GC is declining which has been attributed to effective strategies of eradicating Helicobacter pylori infection. To the contrary, GEJ cancers are on the rise, with obesity and reflux disease being viewed as major risk factors. During the past decade perioperative chemotherapy, pre- or postoperative radio-chemotherapy, and, in Asian populations, adjuvant chemotherapy have been shown to improve the outcome of patients with advanced GC and GEJ cancers suited for surgery. Less progress has been made in the treatment of metastatic disease. The introduction of trastuzumab in combination with platinum/fluoropyrimidine-based chemotherapy for patients with HER2-positive disease has marked a turning point. Recently, several novel agents targeting growth factor receptors, angiogenic pathways, adhesion molecules and mediators of intracellular signal transduction have been clinically explored. Here we summarise the current status and future developments of molecularly targeted therapies in GC and GEJ cancer.
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Affiliation(s)
- Stefan Kasper
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Martin Schuler
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
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Zhang L, Zhao G, Hou Y, Zhang J, Hu J, Zhang K. The experimental study on the treatment of cytokine-induced killer cells combined with EGFR monoclonal antibody against gastric cancer. Cancer Biother Radiopharm 2014; 29:99-107. [PMID: 24443838 DOI: 10.1089/cbr.2012.1381] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIMS To investigate the antitumor activity of cytokine-induced killer (CIK) cells combined with epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) against gastric cancer cell line SGC7901. MATERIALS AND METHODS Immunocytochemistry assay was performed to detect the expression of EGFR in SGC7901 cell lines. The cytotoxicity activity of CIK cells combined with EGFR mAb was analyzed by the (51)Cr release assay. Then, the comparison of the cytotoxicity activity between CIK cells combined with EGFR mAb and CIK cells combined with CD3 mAb and CIK cells was conducted. Antitumor activity of CIK cells combined with EGFR mAb in vivo was analyzed by tumor growth assay and tumor reduction assay. RESULTS The cell lysis rate of CIK cells combined with EGFR mAb was higher than those of CIK cells combined with CD3 mAb and CIK cells only (p<0.05). The lysis rates of the latter two groups were not different. The antitumor activity of CIK cells combined with EGFR mAb was higher than those of other groups in vivo (p<0.05). CONCLUSION It was suggested in the current study that EGFR mAb could enhance the antitumor ability of CIK cells to bind and kill the gastric cancer cells in vitro and in vivo.
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Affiliation(s)
- Lin Zhang
- 1 Department of Gastroenterology, The 309 Hospital of PLA , Beijing, P.R. China
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35
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Qiu MZ, Xu RH. The progress of targeted therapy in advanced gastric cancer. Biomark Res 2013; 1:32. [PMID: 24330856 PMCID: PMC3878836 DOI: 10.1186/2050-7771-1-32] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 12/02/2013] [Indexed: 12/13/2022] Open
Abstract
Although palliative chemotherapy has been shown to prolong survival and improve quality of life, the survival of advanced gastric cancer (AGC) patients remains poor. With the advent of targeted therapy, many molecular targeted agents have been evaluated in clinical studies. Trastuzumab, an anti-HER2 monoclonal antibody, has shown activity against HER2-positive AGC and becomes the first targeted agent approved in AGC. Drugs that target epidermal growth factor receptor, including monoclonal antibody and tyrosine kinase inhibitor, do not bring survival benefit to patients with AGC. Additionally, vascular endothelial growth factor inhibitors are also under investigation. Ramucirumab has shown promising result. Other targeted agents are in preclinical or early clinical development, such as mammalian target of rapamycinm inhibitors and c-MET inhibitors.
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Affiliation(s)
- Miao-zhen Qiu
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou 510060, China
| | - Rui-hua Xu
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou 510060, China
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Zhang L, Yang J, Cai J, Song X, Deng J, Huang X, Chen D, Yang M, Wery JP, Li S, Wu A, Li Z, Li Z, Liu Y, Chen Y, Li Q, Ji J. A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy. Sci Rep 2013; 3:2992. [PMID: 24141978 PMCID: PMC3801116 DOI: 10.1038/srep02992] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 09/27/2013] [Indexed: 12/18/2022] Open
Abstract
A preclinical trial identified 4 of 20 (20%) gastric cancer (GC) patient-derived xenografts responded to cetuximab. Genome-wide profiling and additional investigations revealed that high EGFR mRNA expression and immunohistochemistry score (3+) are associated with tumor growth inhibition. Furthermore, EGFR amplification were observed in 2/4 (50%) responders with average copy number 5.8 and >15 respectively. Our data suggest that a GC subtype with EGFR amplification and overexpression benefit from cetuximab treatment.
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Affiliation(s)
- Lianhai Zhang
- 1] Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Surgery [2]
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Chen C, Yang JM, Hu TT, Xu TJ, Yan G, Hu SL, Wei W, Xu WP. Prognostic role of human epidermal growth factor receptor in gastric cancer: a systematic review and meta-analysis. Arch Med Res 2013; 44:380-9. [PMID: 23871709 DOI: 10.1016/j.arcmed.2013.07.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Accepted: 06/27/2013] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Human epidermal growth factor receptor (EGFR) and HER2 (ErbB2) both belong to EGFR family, which are overexpressed in a significant proportion of cases of gastric cancer (GC). Various studies have evaluated the prognostic value of EGFR or HER level in GC. However, the overall test performance remains unclear. We undertook this study to perform a systematic review and meta-analysis of prognostic cohort studies evaluating the use of EGFR or HER2 as a predictor of survival time in patients with GC. METHODS Eligible studies were identified through multiple search strategies. Studies were assessed for quality using the Newcastle-Ottawa Tool. Data were collected comparing overall survival (OS) in patients with high and low EGFR or HER2 level. Studies were pooled and summary hazard ratios were calculated. RESULTS Studies were listed twice if they provided overall survival data for both EGFR and HER2. Eight studies (seven for EGFR and eight for HER2) were included. Two distinct groups were pooled for analysis and revealed that high EGFR, HER2 levels predicted poor overall (HR = 1.66, 95% CI: 1.35-2.02) and (HR = 1.43, 95% CI: 1.09-1.88) survival. No publication bias was found. CONCLUSIONS This meta-analysis result suggested that EGFR or HER2 should have significant predictive ability for estimating overall survival in GC patients and may be useful for defining prognosis of GC patients.
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Affiliation(s)
- Cheng Chen
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immunopharmacology of Education Ministry, Hefei, China
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38
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Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, Park JO, Sawaki A, Celik I, Götte H, Melezínková H, Moehler M. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol 2013; 14:490-9. [PMID: 23594786 DOI: 10.1016/s1470-2045(13)70102-5] [Citation(s) in RCA: 669] [Impact Index Per Article: 55.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Patients with advanced gastric cancer have a poor prognosis and few efficacious treatment options. We aimed to assess the addition of cetuximab to capecitabine-cisplatin chemotherapy in patients with advanced gastric or gastro-oesophageal junction cancer. METHODS In our open-label, randomised phase 3 trial (EXPAND), we enrolled adults aged 18 years or older with histologically confirmed locally advanced unresectable (M0) or metastatic (M1) adenocarcinoma of the stomach or gastro-oesophageal junction. We enrolled patients at 164 sites (teaching hospitals and clinics) in 25 countries, and randomly assigned eligible participants (1:1) to receive first-line chemotherapy with or without cetuximab. Randomisation was done with a permuted block randomisation procedure (variable block size), stratified by disease stage (M0 vs M1), previous oesophagectomy or gastrectomy (yes vs no), and previous (neo)adjuvant (radio)chemotherapy (yes vs no). Treatment consisted of 3-week cycles of twice-daily capecitabine 1000 mg/m(2) (on days 1-14) and intravenous cisplatin 80 mg/m(2) (on day 1), with or without weekly cetuximab (400 mg/m(2) initial infusion on day 1 followed by 250 mg/m(2) per week thereafter). The primary endpoint was progression-free survival (PFS), assessed by a masked independent review committee in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. This study is registered at EudraCT, number 2007-004219-75. FINDINGS Between June 30, 2008, and Dec 15, 2010, we enrolled 904 patients. Median PFS for 455 patients allocated capecitabine-cisplatin plus cetuximab was 4.4 months (95% CI 4.2-5.5) compared with 5.6 months (5.1-5.7) for 449 patients who were allocated to receive capecitabine-cisplatin alone (hazard ratio 1.09, 95% CI 0.92-1.29; p=0.32). 369 (83%) of 446 patients in the chemotherapy plus cetuximab group and 337 (77%) of 436 patients in the chemotherapy group had grade 3-4 adverse events, including grade 3-4 diarrhoea, hypokalaemia, hypomagnesaemia, rash, and hand-foot syndrome. Grade 3-4 neutropenia was more common in controls than in patients who received cetuximab. Incidence of grade 3-4 skin reactions and acne-like rash was substantially higher in the cetuximab-containing regimen than in the control regimen. 239 (54%) of 446 in the cetuximab group and 194 (44%) of 436 in the control group had any grade of serious adverse event. INTERPRETATION Addition of cetuximab to capecitabine-cisplatin provided no additional benefit to chemotherapy alone in the first-line treatment of advanced gastric cancer in our trial. FUNDING Merck KGaA.
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Affiliation(s)
- Florian Lordick
- University Cancer Center Leipzig, University of Leipzig, Leipzig, Germany.
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Kanat O, O'Neil BH. Metastatic gastric cancer treatment: a little slow but worthy progress. Med Oncol 2013; 30:464. [PMID: 23335104 DOI: 10.1007/s12032-013-0464-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2012] [Accepted: 01/09/2013] [Indexed: 02/07/2023]
Abstract
Metastatic gastric cancer is incurable and remains one of the leading causes of cancer-related deaths around the world. Despite the significant progress in its systemic treatment, metastatic gastric cancer is still a major therapeutic challenge for oncologists. Newer chemotherapy regimens and the addition of molecularly targeted agents to chemotherapy seem to provide better clinical outcomes for patients with metastatic gastric cancer. The objective of this article is to review the current treatment approach for this formidable disease.
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Affiliation(s)
- Ozkan Kanat
- Faculty of Medicine, Department of Medical Oncology, Uludag University, Bursa, Turkey.
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40
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Cidon EU, Ellis SG, Inam Y, Adeleke S, Zarif S, Geldart T. Molecular targeted agents for gastric cancer: a step forward towards personalized therapy. Cancers (Basel) 2013; 5:64-91. [PMID: 24216699 PMCID: PMC3730303 DOI: 10.3390/cancers5010064] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 01/01/2013] [Accepted: 01/14/2013] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer (GC) represents a major cancer burden worldwide, and remains the second leading cause of cancer-related death. Due to its insidious nature, presentation is usually late and often carries a poor prognosis. Despite having improved treatment modalities over the last decade, for most patients only modest improvements have been seen in overall survival. Recent progress in understanding the molecular biology of GC and its signaling pathways, offers the hope of clinically significant promising advances for selected groups of patients. Patients with Her-2 overexpression or amplification have experienced benefit from the integration of monoclonal antibodies such as trastuzumab to the standard chemotherapy. Additionally, drugs targeting angiogenesis (bevacizumab, sorafenib, sunitinib) are under investigation and other targeted agents such as mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors are in preclinical or early clinical development. Patient selection and the development of reliable biomarkers to accurately select patients most likely to benefit from these tailored therapies is now key. Future trials should focus on these advances to optimize the treatment for GC patients. This article will review recent progress and current status of targeted agents in GC.
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Affiliation(s)
- Esther Una Cidon
- Medical Oncology Department, The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Castle Lane East, BH7 7DW Bournemouth, Dorset, UK.
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41
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Wong H, Yau T. Molecular targeted therapies in advanced gastric cancer: does tumor histology matter? Therap Adv Gastroenterol 2013; 6:15-31. [PMID: 23320047 PMCID: PMC3539290 DOI: 10.1177/1756283x12453636] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
It is increasingly recognized that gastric cancer is a heterogeneous disease which may be divided into subgroups based on histological, anatomical, epidemiological and molecular classifications. Distinct molecular drivers and tumor biology, and thus different treatment targets and predictive biomarkers, may be implicated in each subtype. However, there is little evidence in the literature regarding the correlation among these different classifications, and particularly the molecular aberrations present in each subtype. In this review, we approach advanced gastric cancer (AGC) by presenting aberrant molecular pathways and their potential therapeutic targets in gastric cancer according to histological and anatomical classification, dividing gastric cancer into proximal nondiffuse, distal nondiffuse and diffuse disease. Several pathways are involved predominantly, although not exclusively, in different subtypes. This may help to explain the disappointing results of many published AGC trials in which study populations were heterogeneous regardless of clinicopathological characteristics of the primary tumor. Histological and anatomical classification may provide insights into tumor biology and facilitate selection of an enriched patient population for targeted agents in future studies and in the clinic. However, some molecular pathways implicated in gastric cancer have not been studied in correlation with histological or anatomical subtypes. Further studies are necessary to confirm the suggestion that such classification may predict tumor biology and facilitate selection of an enriched patient population for targeted agents in future studies and in the clinic.
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Affiliation(s)
- Hilda Wong
- Division of Hematology and Medical Oncology, Department of Medicine, Queen Mary Hospital, Hong Kong
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Cheung DY, Kim JK. Perspectives of the Stomach Cancer Treatment: The Introduction of Molecular Targeted Therapy and the Hope for Cure. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2013; 61:117-27. [DOI: 10.4166/kjg.2013.61.3.117] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Dae Young Cheung
- Department of Internal Medicine, The Catholic University of Korea, College of Medicine, Seoul, Korea
| | - Jae Kwang Kim
- Department of Internal Medicine, The Catholic University of Korea, College of Medicine, Seoul, Korea
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43
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Liu L, Wu N, Li J. Novel targeted agents for gastric cancer. J Hematol Oncol 2012; 5:31. [PMID: 22709792 PMCID: PMC3411478 DOI: 10.1186/1756-8722-5-31] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2012] [Accepted: 06/18/2012] [Indexed: 12/16/2022] Open
Abstract
Contemporary advancements have had little impact on the treatment of gastric cancer (GC), the world’s second highest cause of cancer death. Agents targeting human epidermal growth factor receptor mediated pathways have been a common topic of contemporary cancer research, including monoclonal antibodies (mAbs) and receptor tyrosine kinase inhibitors (TKIs). Trastuzumab is the first target agent evidencing improvements in overall survival in HER2-positive (human epidermal growth factor receptor 2) gastric cancer patients. Agents targeting vascular epithelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and other biological pathways are also undergoing clinical trials, with some marginally positive results. Effective targeted therapy requires patient selection based on predictive molecular biomarkers. Most phase III clinical trials are carried out without patient selection; therefore, it is hard to achieve personalized treatment and to monitor patient outcome individually. The trend for future clinical trials requires patient selection methods based on current understanding of GC biology with the application of biomarkers.
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Affiliation(s)
- Lian Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
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Kulig J, Kołodziejczyk P, Kulig P, Legutko J. Targeted therapy for gastric cancer--current status. J Oncol Pharm Pract 2012; 19:75-81. [PMID: 22711713 DOI: 10.1177/1078155212449030] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
In patients with metastatic gastric cancer, median overall survival remains under 1 year and standard chemotherapy regimens are not able to substantially improve the prognosis of the patients. Amplification and over-expression of HER2 is reported in approximately 20% of gastric tumours, challenging the use of targeted therapies. There are several targeted therapies in different stages of clinical development with trastuzumab being the first overcoming the regulatory hurdle and getting European Medicines Agency approval. In patients with advanced gastric or gastro-oesophageal junction cancer, addition of trastuzumab to chemotherapy significantly improved overall survival compared with chemotherapy alone. Addition of trastuzumab to chemotherapy did not increase the incidence of adverse events. Other agents targeting the HER2 pathway (lapatinib) or other domains of epidermal growth factor receptor family (cetuximab) are currently being investigated for the treatment of an advanced gastric cancer.
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Affiliation(s)
- Jan Kulig
- Department of General and Gastroenterological Surgery, Jagiellonian University Medical College, Krakow, Poland
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45
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Kneissl J, Keller S, Lorber T, Heindl S, Keller G, Drexler I, Hapfelmeier A, Höfler H, Luber B. Association of amphiregulin with the cetuximab sensitivity of gastric cancer cell lines. Int J Oncol 2012; 41:733-44. [PMID: 22614881 DOI: 10.3892/ijo.2012.1479] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2011] [Accepted: 03/02/2012] [Indexed: 01/22/2023] Open
Abstract
The therapeutic activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab in gastric cancer is currently being investigated in clinical studies. Reliable biomarkers for the identification of patients who are likely to benefit from this treatment are not available. In this study, we assessed the activity of cetuximab in five gastric cancer cell lines (AGS, AZ521, Hs746T, LMSU and MKN1). The viability of two of these cell lines, AZ521 and MKN1, was significantly reduced by cetuximab treatment. High expression and secretion levels of the EGFR-binding ligand, amphiregulin (AREG), were associated with cetuximab responsiveness. MET activation and mutations in Kirsten-Ras gene (KRAS) were associated with cetuximab resistance. By introducing a hierarchy between these markers, we established a model that facilitated the correct classification of all five gastric cancer cell lines as cetuximab responsive or non-responsive. The highest priority was allocated to activating KRAS mutations, followed by MET activation and finally by the levels of secreted AREG. In order to validate these results, we used three additional human gastric cancer cell lines (KATOIII, MKN28 and MKN45). In conclusion, we propose that our model allows the response of gastric cancer cell lines to cetuximab treatment to be predicted.
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Affiliation(s)
- Julia Kneissl
- Institute of Pathology, Technische Universität München, Klinikum rechts der Isar, Munich, Germany
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De Vita F, Giuliani F, Silvestris N, Rossetti S, Pizzolorusso A, Santabarbara G, Galizia G, Colucci G, Ciardiello F, Orditura M. Current status of targeted therapies in advanced gastric cancer. Expert Opin Ther Targets 2012; 16 Suppl 2:S29-34. [PMID: 22443228 DOI: 10.1517/14728222.2011.652616] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
INTRODUCTION In metastatic gastric cancer, chemotherapy is the standard treatment because it prolongs survival when compared to best supportive care alone. However, even after the use of more effective regimens, the overall survival remains disappointing, justifying the need for new treatment options. AREAS COVERED Areas covered in this review include the most common molecular pathways, which have provided novel targets in gastric cancer therapy. These therapeutic strategies include EGFR inhibitors, anti-angiogenic agents, cell cycle inhibitors and apoptosis promoters. EXPERT OPINION Several mAbs and kinase inhibitors, especially those targeting EGFR and VEGF/VEGFR, have already demonstrated promising activity in gastric cancer. The Phase III ToGA trial reported an increase in overall survival for patients with human EGF receptor (HER)2-positive gastric cancer treated with chemotherapy and trastuzumab compared to chemotherapy alone. This means that accurate HER2 testing in gastric cancer is necessary. Final data of ongoing trials with novel agents will be critical to further progress with this cancer.
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Affiliation(s)
- Ferdinando De Vita
- Oncologia Medica, Seconda Università di Napoli, Via S.Pansini 5, 80131, Napoli, Italia.
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Abstract
Gastric cancer remains a global public health problem with considerable heterogeneity in pathogenesis and clinical presentation across geographic regions. Improved understanding of the molecular biology of this disease has opened avenues for targeted intervention. An individualized treatment approach is required for optimal management of this cancer. Overcoming resistance to therapy requires combining targeted agents with the traditional options of chemotherapy/radiation therapy, and also targeting more than 1 pathway of carcinogenesis at a time. Encouraging molecular hypothesis and biomarker-driven trials will lead to improved patient outcomes and may eventually enable the therapeutic nihilism associated with gastric cancer to be overcome.
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Wong H, Yau T. Targeted therapy in the management of advanced gastric cancer: are we making progress in the era of personalized medicine? Oncologist 2012; 17:346-58. [PMID: 22334453 PMCID: PMC3316920 DOI: 10.1634/theoncologist.2011-0311] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2011] [Accepted: 12/19/2011] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Gastric cancer is one of the leading causes of cancer death. With greater understanding of the molecular basis of carcinogenesis, targeted agents have led to a modest improvement in the outcome of advanced gastric cancer (AGC) patients. METHODS AND RESULTS We conducted an overview of the published evidence regarding the use of targeted therapy in AGC patients. Thus far, the human epidermal growth factor receptor (HER) pathway, angiogenic pathway, and phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin pathway have emerged as potential avenues for targeted therapy in AGC patients. The promising efficacy results of the Trastuzumab for Gastric Cancer trial led to the approved use of trastuzumab-based therapy as first-line treatment for patients with HER-2+ AGC. On the other hand, the Avastin® in Gastric Cancer trial evaluating bevacizumab in combination with chemotherapy did not meet its primary endpoint of a longer overall survival duration despite a significantly higher response rate and longer progression-free survival time in patients in the bevacizumab arm. Phase III data are awaited for other targeted agents, including cetuximab, panitumumab, lapatinib, and everolimus. CONCLUSION Recent progress in targeted therapy development for AGC has been modest. Further improvement in the outcome of AGC patients will depend on the identification of biomarkers in different patient populations to facilitate the understanding of gastric carcinogenesis, combining different targeted agents with chemotherapy, and unraveling new molecular targets for therapeutic intervention.
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Affiliation(s)
- Hilda Wong
- Division of Hematology and Medical Oncology, Department of Medicine, and
| | - Thomas Yau
- Division of Hematology and Medical Oncology, Department of Medicine, and
- Department of Surgery, Queen Mary Hospital, Hong Kong
- Centre for Cancer Research, The University of Hong Kong, Hong Kong
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Abstract
Gastric cancer represents one of the most common cancers internationally. Unfortunately the majority of patients still present at an advanced stage, and despite advances in diagnostic and treatment strategies, outcomes still remain poor with high mortality rates despite a decline in incidence. Whilst the utility of classical chemotherapy agents has been explored thoroughly (and continues to be investigated, alone or in various combinations), advances have been slow and the efficacy of these agents has reached a plateau. As such, the focus of recent study has shifted toward developing a greater understanding of the molecular biology of carcinogenesis and the cancer cell phenotype, and, in turn, the development of rationally designed drugs that target molecular aberrancies in signal transduction pathways specific to gastric cancer. These targets include circulating growth and angiogenic factors, cell surface receptors, and other molecules that comprise downstream intracellular signalling pathways, including receptor tyrosine kinases. Therapeutic advances in this area significantly lag behind other solid organ malignancies such as breast and colorectal cancer. This article reviews the role of targeted therapies in gastric cancer, including rationale and mechanism of action, current and emerging data, as single-agent therapy or in combination regimens. A recently published randomized phaseIII trial supporting the use of trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2)/neu monoclonal antibody, in a selected population of patients is discussed. Therapies that have been evaluated in phase II trials are also reviewed, as well as promising new therapies currently being investigated in preclinical or phase I studies. There is optimism that targeted therapies, whether as single-agent therapy or in combination with traditional therapies, including chemotherapy, radiotherapy and surgery, may yet have an impact on improvement of the overall prognosis of gastric cancer.
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Affiliation(s)
- Jaclyn Yoong
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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