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Yu X, Cui R, Guo P. Evaluation of the efficacy and safety of toripalimab combination therapy for treatment of advanced gastric cancer: a meta-analysis. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2025; 18:96-109. [PMID: 40226111 PMCID: PMC11982770 DOI: 10.62347/gzow5960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 02/12/2025] [Indexed: 04/15/2025]
Abstract
BACKGROUND To systematically evaluate the efficacy and safety of combination therapy with toripalimab in the treatment of advanced gastric cancer (GC). METHODS We conducted a thorough search for relevant studies in PubMed, Embase, Cochrane Library, and Web of Science. Effect estimates were computed utilizing Stata software (version 14.0) and either random or fixed effects models, as applicable. A subgroup analysis was undertaken to assess the effect of various combination therapies on overall response rate (ORR). Begg and Egger's tests were employed to assess publication bias. RESULTS The study consisted of 8 trials, which included 277 participants with advanced gastric cancer. The overall ORR was 41.4% (95% CI, 32.4%-50.3%), with a disease control rate (DCR) of 83.6% (95% CI, 74.6%-92.7%), a median overall survival (mOS) of 11.0 months (95% CI, 9.6-12.4), and a median progression-free survival (mPFS) of 4.2 months (95% CI, 2.5-6.0) for the combination therapy with toripalimab. Subgroup analysis revealed that the combination of toripalimab and chemotherapy achieved a greater ORR compared to the non-chemotherapy group, with ORR rates of 49.8% (95% CI, 42.2%-57.4%) and 31.9% (95% CI, 26.7%-37.1%), respectively. The combination therapy with toripalimab led to adverse events (AEs) of any grade at 94.0% of cases (95% CI, 89.5%-98.5%) and grade 3 AEs at 32.4% (95% CI, 17.8%-47.1%). The sensitivity analysis indicated that no single study affected the overall results. CONCLUSIONS Combination therapy of toripalimab can improve clinical efficacy, although with increased but manageable toxicity. Additional clinical trials are required to assess comprehensively the efficacy and safety of alternative toripalimab regimens. The review agreement has been recorded with PROSPERO (CRD42024585696).
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Affiliation(s)
- Xinlin Yu
- Department of Oncology, Affiliated Hospital Chengdu UniversityChengdu, Sichuan, China
| | - Ran Cui
- Department of Emergency, The First People’s Hospital of NeijiangNeijiang, Sichuan, China
| | - Ping Guo
- Department of Cardiology, Affiliated Hospital Chengdu UniversityChengdu, Sichuan, China
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Li CF, Lian LL, Li QR, Jiao Y. Immunotherapy for metastatic gastric cancer. World J Gastrointest Surg 2024; 16:3408-3412. [PMID: 39649204 PMCID: PMC11622096 DOI: 10.4240/wjgs.v16.i11.3408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/20/2024] [Accepted: 08/26/2024] [Indexed: 10/30/2024] Open
Abstract
This editorial discusses the article written by Chen et al that was published in the latest edition of the World Journal of Gastrointestinal Surgery. The current study found that programmed cell death 1 ligand 1 (PD-L1) expression is considered as one of the pan-cancer biomarkers of immune checkpoint inhibitors (ICIs) treatment response. Four molecular subtypes are widely used to guide and evaluate the prognosis and diagnosis and treatment of gastric cancer (GC) patients. Clinical trials of ICI treatment including Nivolumab, Pembrolizumab, Avelumab have been conducted for metastatic GC (mGC). The effects of various single agent ICIs on mGC therapy varied. ICIs combined with chemotherapy can indeed bring survival benefits to patients with mGC. Combining ICIs with chemotherapy can give more patients the chance of surgery in the treatment of GC transformation. However, not all PD-L1 positive patients can benefit from it. It is urgent to find better biomarkers to predict the response of ICIs for more precise clinical treatment.
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Affiliation(s)
- Chang-Fei Li
- Department of Patient Service Center, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Li-Li Lian
- Department of Neurology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Qiu-Ru Li
- Department of Neurology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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Zhang P, Chen Z, Shi S, Li Z, Ye F, Song L, Zhang Y, Yin F, Zhang X, Xu J, Cheng Y, Su W, Shi M, Fan S, Tan P, Zhong C, Lu M, Shen L. Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer. Cancer Immunol Immunother 2024; 73:119. [PMID: 38713205 PMCID: PMC11076424 DOI: 10.1007/s00262-024-03677-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 03/15/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study. METHODS This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every three weeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1. RESULTS Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 28 (46.7%) patients. CONCLUSIONS Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors. CLINICALTRIALS gov NCT04169672.
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Affiliation(s)
- Panpan Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Centre, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Zhendong Chen
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, No.678 Furong Road, Economic and Technological Development Zone, Hefei, Anhui, China
| | - Si Shi
- Department of Pancreatic Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No.270 Dong'an Road, Xuhui District, Shanghai, China
| | - Zhiping Li
- Department of Abdominal Oncology, West China Hospital of Sichuan University, No.37 Guoxue Lane, Wuhou District, Chengdu, Sichuan, China
| | - Feng Ye
- Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, No.55 Zhenhai Road, Siming District, Xiamen, Fujian, China
| | - Lijie Song
- First Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, Henan, China
| | - Yanqiao Zhang
- Second Department of Gastroenterology, Harbin Medical University Cancer Hospital, No.150 Haping Road, Nangang District, Harbin, Heilongjiang, China
| | - Fei Yin
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, No.12 Jiankan Road, Shijiazhuang, Hebei, China
| | - Xing Zhang
- Biotherapy Center, Sun Yat-sen University Cancer Center, No.651 East Dongfeng Road, Yuexiu District, Guangzhou, Guangdong, China
| | - Jianming Xu
- Department of Gastrointestinal Oncology, The Fifth Medical Center of Chinese PLA General Hospital, No.8 East Avenue, Fengtai District, Beijing, China
| | - Ying Cheng
- Department of Thoracic Oncology, Jilin Cancer Hospital, No.1066 Jinghu Avenue, Gaoxin District, Changchun, Jilin, China
| | - Weiguo Su
- HUTCHMED Limited, Building 4, 720 Cailun Road, Pilot Free Trade Zone, Shanghai, China
| | - Michael Shi
- HUTCHMED Limited, Building 4, 720 Cailun Road, Pilot Free Trade Zone, Shanghai, China
| | - Songhua Fan
- HUTCHMED Limited, Building 4, 720 Cailun Road, Pilot Free Trade Zone, Shanghai, China
| | - Panfeng Tan
- HUTCHMED Limited, Building 4, 720 Cailun Road, Pilot Free Trade Zone, Shanghai, China
| | - Chen Zhong
- HUTCHMED Limited, Building 4, 720 Cailun Road, Pilot Free Trade Zone, Shanghai, China
| | - Ming Lu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China.
| | - Lin Shen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China.
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Galos D, Balacescu L, Vidra R, Sur D. Real-World Data on Second-Line Therapy with Ramucirumab for Metastatic Gastric Cancer: A Two-Center Study on Romanian Population. Life (Basel) 2023; 13:2300. [PMID: 38137901 PMCID: PMC10744814 DOI: 10.3390/life13122300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/24/2023] [Accepted: 12/01/2023] [Indexed: 12/24/2023] Open
Abstract
(1) Background: Following the results of RAINBOW and REGARD trials, ramucirumab was approved as the standard second-line treatment for patients with advanced or metastatic gastric or gastroesophageal junction (GEJ) cancer, alone or in combination with paclitaxel. The present study aimed to evaluate the efficacy and safety of ramucirumab in the Romanian population during every-day clinical practice. (2) Methods: A two-center, retrospective, observational study evaluated patients with metastatic gastric and GEJ cancer treated with ramucirumab monotherapy or associated with paclitaxel. The patients were treated between 2018 and 2022 in two Romanian centers as follows: 18 patients underwent treatment with ramucirumab monotherapy, while 51 received the combined treatment regimen. Study endpoints included median progression-free survival (PFS), median overall survival (OS), and the evaluation of treatment-induced adverse events (AEs). (3) Results: In the study cohort (n = 69), the most frequent treatment-induced AE in the ramucirumab plus paclitaxel arm was hematological toxicity; the most common AE for patients treated with ramucirumab monotherapy was fatigue and headache. Overall, the median PFS was 4.7 months (95% CI: 3.4-5.9 months) and median OS was 18.23 months (95% CI: 15.6-20.7 months). PFS was correlated with the number of treatment cycle administrations, Eastern Cooperative Oncology Group performance status at treatment initiation, and metastatic site (visceral vs. peritoneal). OS was correlated with the number of treatment cycles administered and human epidermal growth factor receptor-2 status. (4) Conclusions: The results support the previously described toxicity profile for ramucirumab monotherapy or associated with paclitaxel and demonstrated a relatively superior median PFS.
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Affiliation(s)
- Diana Galos
- Department of Medical Oncology, The Oncology Institute Prof. Dr. Ion Chiricuţă, 400015 Cluj-Napoca, Romania;
| | - Loredana Balacescu
- Department of Genetics, Genomics and Experimental Pathology, The Oncology Institute Prof. Dr. Ion Chiricuţă, 400015 Cluj-Napoca, Romania;
| | - Radu Vidra
- Postgraduate Program for Bio-Behavioral Integrative Medicine, Babes-Bolyai University, 400084 Cluj-Napoca, Romania
- Department of Medical Oncology, Regional Institute of Gastroenterology and Hepatology Prof. Dr. Octavian Fodor, 400162 Cluj-Napoca, Romania
| | - Daniel Sur
- Department of Medical Oncology, The Oncology Institute Prof. Dr. Ion Chiricuţă, 400015 Cluj-Napoca, Romania;
- Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hațieganu”, 400012 Cluj-Napoca, Romania
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Riccò B, Martinelli G, Bardasi C, Dominici M, Spallanzani A, Salati M. Optimizing the Continuum of Care in Gastric Cancer. Onco Targets Ther 2023; 16:995-1012. [PMID: 38021446 PMCID: PMC10680466 DOI: 10.2147/ott.s365505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 11/15/2023] [Indexed: 12/01/2023] Open
Abstract
Gastric cancer (GC) still ranks as the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide. Despite the recent progress in the therapeutic algorithm of the advanced disease with the advent of immune checkpoint inhibitors (ICIs) and next-generation HER2-directed therapies, survival rates remain poor, with a median survival hardly exceeding 12 months. Furthermore, only 40% of patients remain eligible for second- and later-line treatments due to the aggressiveness of the disease and the rapid deterioration of performance status (PS). Thus, current research is focusing either on the identification of novel treatment options or the development of personalized strategies to optimize the continuum of care and ultimately improve patients' outcome. In this article, we provide an overview of the current treatment landscape for advanced GC with a particular emphasis on later-line treatments and outline novel perspectives on the horizon.
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Affiliation(s)
- Beatrice Riccò
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Giulio Martinelli
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Camilla Bardasi
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Massimo Dominici
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Andrea Spallanzani
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Massimiliano Salati
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
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Roviello G, Martina C, Winchler C, De Gennaro Aquino I, Papa F, Buttitta E, Rossi G, Antonuzzo L. Correlation Between Tumor Response and Survival Outcomes in Patients with Advanced Gastric Cancer Receiving Ramucirumab and Paclitaxel as Second-Line Therapy. J Gastrointest Cancer 2023; 54:802-808. [PMID: 36109437 PMCID: PMC10613139 DOI: 10.1007/s12029-022-00865-5] [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] [Accepted: 09/11/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. The first-line treatment for GC is a combination of platinum and fluoropyrimidine-based therapy. Based on the positive results of RAINBOW and REGARD trials, ramucirumab either alone or in combination with paclitaxel has proved to be a safe and active option for second-line treatment in GC patients. MATERIAL AND METHODS Advanced GC patients who received a 28-day cycles of ramucirumab and paclitaxel until disease progression or unacceptable toxicity were evaluated. Eligible patients had ECOG PS ≤ 1 and adequate organ function. Baseline characteristics were assessed for progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method and Cox proportional-hazards regression models were used for survival analyses. RESULTS In our single institution experience, we included a total of 67 patients. A median OS of 8 months and a median PFS of 4 months, were recorded. In patients experiencing an initial partial response (PR), we observed a significant association between tumor response and survival outcomes (OS and PFS). The OS and PFS were 15 and 11 months in patients who experienced PR compared to 8 and 4 months in patients without PR (p = 0.02; p = 0.04). CONCLUSION Treatment with ramucirumab plus paclitaxel yielded the highest overall response rate reported to date for patients with previously treated advanced GC. In our experience, the initial tumor response is associated with a greater survival benefit which could be further improved by the identification of biomarkers predicting response.
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Affiliation(s)
- Giandomenico Roviello
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy.
| | - Catalano Martina
- School of Human Health Sciences, University of Florence, Largo Brambilla 3, 50134, Florence, Italy
| | - Costanza Winchler
- School of Human Health Sciences, University of Florence, Largo Brambilla 3, 50134, Florence, Italy
| | - Irene De Gennaro Aquino
- School of Human Health Sciences, University of Florence, Largo Brambilla 3, 50134, Florence, Italy
| | - Francesca Papa
- School of Human Health Sciences, University of Florence, Largo Brambilla 3, 50134, Florence, Italy
| | - Eleonora Buttitta
- School of Human Health Sciences, University of Florence, Largo Brambilla 3, 50134, Florence, Italy
| | - Gemma Rossi
- School of Human Health Sciences, University of Florence, Largo Brambilla 3, 50134, Florence, Italy
| | - Lorenzo Antonuzzo
- Department of Experimental and Clinical Medicine, University of Florence, 50134, Florence, Italy
- Medical Oncology Unit, Careggi University Hospital, 50134, Florence, Italy
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Zhao Z, Mak TK, Shi Y, Li K, Huo M, Zhang C. Integrative analysis of cancer-associated fibroblast signature in gastric cancer. Heliyon 2023; 9:e19217. [PMID: 37809716 PMCID: PMC10558323 DOI: 10.1016/j.heliyon.2023.e19217] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 08/11/2023] [Accepted: 08/16/2023] [Indexed: 10/10/2023] Open
Abstract
Background CAFs regulate the signaling of GC cells by promoting their migration, invasion, and proliferation and the function of immune cells as well as their location and migration in the TME by remodeling the extracellular matrix (ECM). This study explored the understanding of the heterogeneity of CAFs in TME and laid the groundwork for GC biomarker and precision treatment development. Methods The scRNA-seq and bulk RNA-seq datasets were obtained from GEO and TCGA. The prognostic significance of various CAFs subtypes was investigated using ssGSEA combined with Kaplan-Meier analysis. POSTN expression in GC tissues and CAFs was detected using immunohistochemistry, immunofluorescence, and Western blotting. Differential expression analysis identified the differentially expressed genes (DEGs) between normal and tumor samples in TCGA-STAD. Pearson correlation analysis identified DEGs associated with adverse prognosis CAF subtype, and univariate Cox regression analysis determined prognostic genes associated with CAFs. LASSO regression analysis and Multivariate Cox regression were used to build a prognosis model for CAFs. Results We identified five CAFs subtypes in GC, with the CAF_0 subtype associated with poor prognosis. The abundance of CAF_0 correlated with T stage, clinical stage, histological type, and immune cell infiltration levels. Periostin (POSTN) exhibited increased expression in both GC tissues and CAFs and was linked to poor prognosis in GC patients. Through LASSO and multivariate Cox regression analysis, three genes (CXCR4, MATN3, and KIF24) were selected to create the CAFs-score. We developed a nomogram to facilitate the clinical application of the CAFs-score. Notably, the CAFs signature showed significant correlations with immune cells, stromal components, and immunological scores, suggesting its pivotal role in the tumor microenvironment (TME). Furthermore, CAFs-score demonstrated prognostic value in assessing immunotherapy outcomes, highlighting its potential as a valuable biomarker to guide therapeutic decisions. Conclusion CAF_0 subtype in TME is the cause of poor prognosis in GC patients. Furthermore, CAFs-score constructed from the CAF_0 subtype can be used to determine the clinical prognosis, immune infiltration, clinicopathological characteristics, and assessment of personalized treatment of GC patients.
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Affiliation(s)
- Zidan Zhao
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Tsz Kin Mak
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yuntao Shi
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Kuan Li
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Mingyu Huo
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Changhua Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
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Li M, Zhao Z, Mak TK, Wang X, Chen J, Ren H, Yu Z, Zhang C. Neutrophil extracellular traps-related signature predicts the prognosis and immune infiltration in gastric cancer. Front Med (Lausanne) 2023; 10:1174764. [PMID: 37636564 PMCID: PMC10447905 DOI: 10.3389/fmed.2023.1174764] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 07/27/2023] [Indexed: 08/29/2023] Open
Abstract
Introduction Gastric cancer (GC) is the fifth most prevalent cancer globally, with the third highest case fatality rate. Neutrophil extracellular traps (NETs) are a reticulated structure of DNA, histones, and antimicrobial peptides produced by active neutrophils that trap pathogens. Even though NETs are associated with poorer recurrence-free survival (RFS) and overall survival (OS), the specifics of this interaction between NETs and cancer cells are yet unknown. Methods The keywords "neutrophil extracellular traps and gastric cancer" were used in the GEO database for retrieval, and the GSE188741 dataset was selected to obtain the NETs-related gene. 27 NETs-related genes were screened by univariate Cox regression analysis (p < 0.05). 27 NETs-related genes were employed to identify and categorize NETs-subgroups of GC patients under the Consensus clustering analysis. 808 GC patients in TCGA-STAD combined with GES84437 were randomly divided into a training group (n = 403) and a test group (n = 403) at a ratio of 1:1 to validate the NETs-related signature. Results Based on Multivariate Cox regression and LASSO regression analysis to develop a NETs-related prognosis model. We developed a very specific nomogram to improve the NETs-clinical score's usefulness. Similarly, we also performed a great result in pan-cancer study with NETs-score. Low NETs scores were linked to higher MSI-H (microsatellite instability-high), mutation load, and immune activity. The cancer stem cell (CSC) index and chemotherapeutic treatment sensitivity were also connected to the NET score. Our comprehensive analysis of NETs in GC suggests that NETs have a role in the tumor microenvironment, clinicopathological features, and prognosis. Discussion The NETs-score risk model provides a basis for better prognosis and therapy outcomes in GC patients.
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Affiliation(s)
- Mingzhe Li
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Zidan Zhao
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Tsz Kin Mak
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Xiaoqun Wang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Jingyao Chen
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Hui Ren
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Zhiwei Yu
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Changhua Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
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Lordick F, Thuss-Patience P, Bitzer M, Maurus D, Sahin U, Türeci Ö. Immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer. J Cancer Res Clin Oncol 2023:10.1007/s00432-022-04459-3. [PMID: 36607429 PMCID: PMC10356865 DOI: 10.1007/s00432-022-04459-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/01/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE Zolbetuximab (IMAB362) is engineered to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity. We evaluated ADCC activity and the impact of the immune-modulating drugs zoledronic acid (ZA) and interleukin-2 (IL-2) as co-treatment with zolbetuximab on relevant immune cell populations and ADCC lysis activity. METHODS This phase 1, multicenter, open-label study investigated the immunological effects and activity, safety, tolerability, and antitumor activity of multiple doses of zolbetuximab alone (n = 5) or in combination with ZA (n = 7) or with ZA plus two different dose levels of IL-2 (low dose: 1 million international units [mIU] [n = 9]; intermediate dose: 3 mIU [n = 7]) in pretreated patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. RESULTS Twenty-eight patients with previously treated advanced G/GEJ adenocarcinoma that was CLDN18.2-expressing were enrolled into four treatment arms. Treatment with zolbetuximab + ZA + IL-2 induced short-lived expansion and activation of ADCC-mediating cell populations, namely γ9δ2 T cells and natural killer cells, within 2 days after administration; this effect was more pronounced with intermediate-dose IL-2. Expansion and activation of regulatory T cells treated with either IL2 dose was moderate and short-lived. Strong ADCC activity was observed with zolbetuximab alone. Short-lived ADCC activity was observed in several patients treated with ZA + intermediate-dose IL-2, but not lower-dose IL-2. In the clinical efficacy population, the best confirmed response was stable disease (n = 11/19; 58%). CONCLUSIONS Zolbetuximab mediates proficient ADCC in patients with pretreated advanced G/GEJ cancers. Co-treatment with ZA + IL-2 did not further improve this effect. TRIAL REGISTRATION NCT01671774.
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Affiliation(s)
- Florian Lordick
- Department of Oncology, Gastroenterology, Hepatology, and Pulmonology, Comprehensive Cancer Center Central Germany (CCCG), University of Leipzig Medical Center, Liebigstraße 22, 04103, Leipzig, Germany.
| | - Peter Thuss-Patience
- Department of Hematology, Oncology and Tumor Immunology, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Michael Bitzer
- Department of Internal Medicine I, University Hospital, Eberhard Karls University Tuebingen, Otfried-Müller-Straße 10, 72076, Tübingen, Germany
| | - Daniel Maurus
- Ganymed Pharmaceuticals GmbH (Formerly Ganymed Pharmaceuticals AG), Mainz, Germany.,Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, 55131, Mainz, Germany.,Ci3-Cluster of Individualized Immune Intervention, Mainz, Germany
| | - Ugur Sahin
- Translational Oncology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.,University Medical Center, Johannes Gutenberg University Mainz, Freiligrathstraße 12, 55131, Mainz, Germany.,Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, 55131, Mainz, Germany
| | - Özlem Türeci
- Ganymed Pharmaceuticals GmbH (Formerly Ganymed Pharmaceuticals AG), Mainz, Germany.,Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, 55131, Mainz, Germany.,Ci3-Cluster of Individualized Immune Intervention, Mainz, Germany
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KN026 (anti-HER2 bispecific antibody) in patients with previously treated, advanced HER2-expressing gastric or gastroesophageal junction cancer. Eur J Cancer 2023; 178:1-12. [PMID: 36370604 DOI: 10.1016/j.ejca.2022.10.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 10/06/2022] [Accepted: 10/09/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND KN026 is a novel human epidermal growth factor receptor 2 (HER2)-targeted bispecific antibody that binds two distinct domains of HER2. We report the safety and efficacy results of the phase 2 trial in patients with advanced HER2-expressing gastric or gastroesophageal junction cancer who failed from at least one prior line of standard treatment. MATERIAL AND METHODS In this open-label, multicentre, phase 2 trial, eligible patients were enrolled in the high-level HER2 cohort or low-level HER2 cohort and assigned to receive KN026 10 mg/kg (once a week), 20 mg/kg (once every two weeks) or 30 mg/kg (once every three weeks) intravenously. The primary end-points were the objective response rate (ORR) and duration of response assessed according to Response Evaluation Criteria in Solid Tumours (version 1.1). RESULTS Between 17th June 2019 and 23rd August 2021, 45 patients were enrolled and received at least one dose of KN026, including 27 patients in the high-level HER2 cohort, 14 patients in the low-level HER2 cohort and four patients who had no HER2 expression. The ORR in the high-level HER2 cohort was 56% (95% confidence interval [CI] 35%-76%), with a durable response duration of 9.7 months (95% CI 4.2-not evaluable); while for the patients with low-level HER2, the ORR was 14% (95% CI 2%-43%). The most frequent ≥ grade 3 treatment-emergent adverse events were gastrointestinal disorders (five patients, 11%). No drug-related deaths were reported. CONCLUSIONS KN026 showed a favourable safety profile and promising anti-tumour activity. Our results support further studies evaluating KN026 and the combination treatment with other active drugs in patients with advanced gastric or gastroesophageal junction cancer having high-level HER2 expression.
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11
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Deng P, Hu C, Chen C, Cao L, Gu Q, An J, Qin L, Li M, He B, Jiang J, Yang H. Anlotinib plus platinum‐etoposide as a first‐line treatment for extensive‐stage small cell lung cancer: A single‐arm trial. Cancer Med 2022; 11:3563-3571. [PMID: 35526266 PMCID: PMC9554443 DOI: 10.1002/cam4.4736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/08/2022] [Accepted: 03/11/2022] [Indexed: 01/22/2023] Open
Abstract
Background Anlotinib as a third‐line or beyond therapy for extensive‐stage small‐cell lung cancer (ES‐SCLC) was studied. This single‐arm phase II trial was to investigate the value of anlotinib plus platinum‐etoposide as first‐line treatment in ES SCLC. Methods The primary endpoint was progression‐free survival (PFS) and objective response rate (ORR). The secondary endpoints included overall survival (OS), disease control rate (DCR), time to progression (TTP), duration of remission (DoR), and safety. The subgroups of preset liver metastasis and brain metastasis were analyzed. Results In 35 ES‐SCLC patients, the median PFS, ORR, DCR, and OS were 8.02 months [95% confidence interval (CI): 6.90–9.66], 85.71% (95% CI: 69.74–95.19), 94.29% (95% CI: 80.84–99.30), and 15.87 months (95% CI: 10.38–18.89), respectively. The median PFS in the liver metastasis and brain metastasis subgroups was 7.33 months (95% CI: 4.76–9.69) and 7.34 months (95% CI: 5.68–9.20), respectively. The most common AEs with grade 3–4 were hand–foot syndrome (17%), granulocytosis (17%), stomatitis (14%), hypertriglyceridemia (11%), hypercholesterolemia (11%), as well as nausea and vomiting (11%), and no grade 5 AEs were recorded. Conclusions Anlotinib combined with platinum‐etoposide provided an effective and safe therapy for patients with ES‐SCLC.
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Affiliation(s)
- Pengbo Deng
- Department of Respiratory Medicine National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University Changsha China
- Xiangya Lung Cancer Center Xiangya Hospital, Central South University Changsha China
- Center of Respiratory Medicine Xiangya Hospital, Central South University Changsha China
- Clinical Research Center for Respiratory Diseases in Hunan Province Changsha China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease Changsha China
| | - Chengping Hu
- Department of Respiratory Medicine National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University Changsha China
- Xiangya Lung Cancer Center Xiangya Hospital, Central South University Changsha China
- Center of Respiratory Medicine Xiangya Hospital, Central South University Changsha China
- Clinical Research Center for Respiratory Diseases in Hunan Province Changsha China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease Changsha China
| | - Cen Chen
- Department of Respiratory Medicine the First People's Hospital of Changde City Changde China
| | - Liming Cao
- Department of Respiratory Medicine National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University Changsha China
- Xiangya Lung Cancer Center Xiangya Hospital, Central South University Changsha China
- Center of Respiratory Medicine Xiangya Hospital, Central South University Changsha China
- Clinical Research Center for Respiratory Diseases in Hunan Province Changsha China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease Changsha China
| | - Qihua Gu
- Department of Respiratory Medicine National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University Changsha China
- Xiangya Lung Cancer Center Xiangya Hospital, Central South University Changsha China
- Center of Respiratory Medicine Xiangya Hospital, Central South University Changsha China
- Clinical Research Center for Respiratory Diseases in Hunan Province Changsha China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease Changsha China
| | - Jian An
- Department of Respiratory Medicine National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University Changsha China
- Xiangya Lung Cancer Center Xiangya Hospital, Central South University Changsha China
- Center of Respiratory Medicine Xiangya Hospital, Central South University Changsha China
- Clinical Research Center for Respiratory Diseases in Hunan Province Changsha China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease Changsha China
| | - Ling Qin
- Department of Respiratory Medicine National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University Changsha China
- Xiangya Lung Cancer Center Xiangya Hospital, Central South University Changsha China
- Center of Respiratory Medicine Xiangya Hospital, Central South University Changsha China
- Clinical Research Center for Respiratory Diseases in Hunan Province Changsha China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease Changsha China
| | - Min Li
- Department of Respiratory Medicine National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University Changsha China
- Xiangya Lung Cancer Center Xiangya Hospital, Central South University Changsha China
- Center of Respiratory Medicine Xiangya Hospital, Central South University Changsha China
- Clinical Research Center for Respiratory Diseases in Hunan Province Changsha China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease Changsha China
| | - Baimei He
- Xiangya Lung Cancer Center Xiangya Hospital, Central South University Changsha China
- National Clinical Research Center for Geriatric Disorders Xiangya Hospital, Central South University Changsha China
- Department of Geriatric Medicine Xiangya Hospital, Central South University Changsha China
| | - Juan Jiang
- Department of Respiratory Medicine National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University Changsha China
- Xiangya Lung Cancer Center Xiangya Hospital, Central South University Changsha China
- Center of Respiratory Medicine Xiangya Hospital, Central South University Changsha China
- Clinical Research Center for Respiratory Diseases in Hunan Province Changsha China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease Changsha China
| | - Huaping Yang
- Department of Respiratory Medicine National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University Changsha China
- Xiangya Lung Cancer Center Xiangya Hospital, Central South University Changsha China
- Center of Respiratory Medicine Xiangya Hospital, Central South University Changsha China
- Clinical Research Center for Respiratory Diseases in Hunan Province Changsha China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease Changsha China
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12
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Sundar R, Barr Kumarakulasinghe N, Huak Chan Y, Yoshida K, Yoshikawa T, Miyagi Y, Rino Y, Masuda M, Guan J, Sakamoto J, Tanaka S, Tan ALK, Hoppe MM, Jeyasekharan AD, Ng CCY, De Simone M, Grabsch HI, Lee J, Oshima T, Tsuburaya A, Tan P. Machine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial. Gut 2022; 71:676-685. [PMID: 33980610 PMCID: PMC8921574 DOI: 10.1136/gutjnl-2021-324060] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 04/26/2021] [Accepted: 04/29/2021] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery. DESIGN The primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort. RESULTS From the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction p<0.001. In the external Pac-Ram validation cohort, the signature predicted benefit for Pac-Sensitive (median PFS 147 days vs 112 days, HR 0.48, p=0.022). CONCLUSION Using machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit. TRIAL REGISTRATION NUMBER UMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial).
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Affiliation(s)
- Raghav Sundar
- Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Hospital, Singapore,Yong Loo Lin School of Medicine, National University of Singapore, Singapore,Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore,The N.1 Institute for Health, National University of Singapore, Singapore
| | | | - Yiong Huak Chan
- Biostatistics Unit, Yong Loo Lin School of Medicine, National University Singapore, Singapore
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takaki Yoshikawa
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Yohei Miyagi
- Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Yasushi Rino
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Munetaka Masuda
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Jia Guan
- Department of Clinical Biostatistics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Shiro Tanaka
- Department of Clinical Biostatistics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Angie Lay-Keng Tan
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore
| | - Michal Marek Hoppe
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Anand D. Jeyasekharan
- Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Hospital, Singapore,Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Cedric Chuan Young Ng
- Laboratory of Cancer Epigenome, Department of Medical Sciences, National Cancer Centre Singapore, Singapore
| | | | - Heike I. Grabsch
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands,Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Jeeyun Lee
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Gangnam-gu, Republic of Korea
| | - Takashi Oshima
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | | | - Patrick Tan
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore .,Cancer Science Institute of Singapore, National University of Singapore, Singapore.,Genome Institute of Singapore, Singapore.,SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Janjua KA, Shahzad R, Shehzad A. Development of Novel Cancer Biomarkers for Diagnosis and Prognosis. CANCER BIOMARKERS IN DIAGNOSIS AND THERAPEUTICS 2022:277-343. [DOI: 10.1007/978-981-16-5759-7_11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Said Helal N, Omran Z, Aboushousha T, Youssef M, Badawy A, Aboul-Ezz MA, Moussa M. Prognostic Significance of p27 and Survivin in H. pylori Gastritis and Gastric Cancer. Asian Pac J Cancer Prev 2021; 22:3553-3559. [PMID: 34837912 PMCID: PMC9068175 DOI: 10.31557/apjcp.2021.22.11.3553] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 11/14/2021] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE to assess expression of p27 and survivin in chronic gastritis with/without H. pylori ± intestinal metaplasia (IM) and in intestinal-type gastric cancer (IGC). MATERIALS AND METHODS Immunohistochemical staining for p27 and survivin on paraffin-embedded sections of 20 chronic gastritis, 20 H. pylori gastritis, 15 H. pylori gastritis with IM, 50 IGC, and 10 controls. Positivity (number of positive cases) and expression (mean percentage of positive gastric cells) for both proteins were evaluated. RESULTS P27 positivity and expression decreased from control to chronic gastritis to H. pylori gastritis to H. pylori gastritis with IM. In IGC, p27 positivity and expression were lower than controls and chronic gastritis but higher than H. pylori gastritis ±IM. High grade and advanced stage IGCs have insignificantly lower p27 positivity and expression than low grade and early stage IGCs. By contrast, survivin positivity and expression increased from chronic gastritis to H. pylori gastritis to H. pylori gastritis with IM to IGCs. High grade and advanced stage IGCs have significantly higher survivin positivity and expression than low grade and early stage IGCs. Males have higher positivity and expression for p27 and survivin than females. CONCLUSION Inverse relation between p27 and survivin in H. pylori gastritis, H. pylori gastritis with IM and IGCs lesions, suggesting that both proteins could be used as potential prognostic and/or diagnostic biomarkers in H. pylori and IM associated- gastritis as well as in IGC.
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Affiliation(s)
- Noha Said Helal
- Department of Pathology, Theodor Bilharz Research Institute, Giza, Egypt.
| | - Zeinab Omran
- Department of Pathology, Theodor Bilharz Research Institute, Giza, Egypt.
| | - Tarek Aboushousha
- Department of Pathology, Theodor Bilharz Research Institute, Giza, Egypt.
| | - Magdy Youssef
- Department of Hepatology and Gastroenterology, Theodor Bilharz Research Institute, Giza, Egypt.
| | - Afkar Badawy
- Department of Pathology, Theodor Bilharz Research Institute, Giza, Egypt.
| | - Mohammed A Aboul-Ezz
- Department of Hepatology and Gastroenterology, Theodor Bilharz Research Institute, Giza, Egypt.
| | - Mona Moussa
- Department of Pathology, Theodor Bilharz Research Institute, Giza, Egypt.
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Baxter MA, Middleton F, Cagney HP, Petty RD. Resistance to immune checkpoint inhibitors in advanced gastro-oesophageal cancers. Br J Cancer 2021; 125:1068-1079. [PMID: 34230609 PMCID: PMC8505606 DOI: 10.1038/s41416-021-01425-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 03/17/2021] [Accepted: 04/22/2021] [Indexed: 12/13/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have altered the treatment paradigm across a range of tumour types, including gastro-oesophageal cancers. For patients with any cancer type who respond, ICIs can confer long-term disease control and significantly improve survival and quality of life, but for patients with gastro-oesophageal cancer, ICIs can be transformative, as durable responses in advanced disease have hitherto been rare, especially in those patients who are resistant to first-line cytotoxic therapies. Results from trials in patients with advanced-stage gastro-oesophageal cancer have raised hopes that ICIs will be successful as adjuvant and neoadjuvant treatments in early-stage disease, when the majority of patients relapse after potential curative treatments, and several trials are ongoing. Unfortunately, however, ICI-responding patients appear to constitute a minority subgroup within gastro-oesophageal cancer, and resistance to ICI therapy (whether primary or acquired) is common. Understanding the biological mechanisms of ICI resistance is a current major research challenge and involves investigation of both tumour and patient-specific factors. In this review, we discuss the mechanisms underlying ICI resistance and their potential specific applications of this knowledge towards precision medicine strategies in the management of gastro-oesophageal cancers in clinical practice.
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Affiliation(s)
- Mark A Baxter
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
- Tayside Cancer Centre, Ninewells Hospital and Medical School, NHS Tayside, Dundee, UK.
| | - Fearghas Middleton
- Tayside Cancer Centre, Ninewells Hospital and Medical School, NHS Tayside, Dundee, UK
| | - Hannah P Cagney
- School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
| | - Russell D Petty
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
- Tayside Cancer Centre, Ninewells Hospital and Medical School, NHS Tayside, Dundee, UK.
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Longo F, Jorge M, Yaya R, Montes AF, Lago NM, Brozos E, Aparicio J, Quintero G, Ceballos E, Buxó E, Lopez AM, Pellón ML, Molina R, Diaz-Paniagua L, Cerdà P, Leiva PL, Carnicero AM, Cousillas A, Paris L, García-Paredes B, Romero C, Ortega M, Molero A, la Torre SD, Jen MH, Díaz-Cerezo S. Real-life use of ramucirumab in gastric cancer in Spain: the RAMIS study. Future Oncol 2021; 17:1777-1791. [PMID: 33590772 DOI: 10.2217/fon-2020-1216] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Aims: To obtain real-world data on ramucirumab use and effectiveness for the treatment of advanced gastric cancer (AGC) or gastroesophageal junction adenocarcinoma (GEJ). Methods: Observational, retrospective study carried out in 20 Spanish hospitals, in patients who started ramucirumab treatment between December 2015 and December 2018. Descriptive analysis was conducted for patient characteristics, treatment patterns and effectiveness outcomes. Results: Three hundred seventeen patients were included (93.7% treated with ramucirumab-paclitaxel and 6.3% with ramucirumab); age 62.5 (11.3) years; 66.9% male. Median progression-free survival and overall survival were 3.9 months (95% CI: 3.4-4.3) and 7.4 (95% CI: 6.4-8.9) in combination regimen and 2.0 (1.1-2.8) and 4.3 (95% CI: 1.9-7.3) in monotherapy, respectively. Conclusion: The study findings were consistent with available real-world studies and randomized clinical trials.
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Affiliation(s)
- Federico Longo
- Hospital Universitario Ramón y Cajal, IRYCIS, CIBERONC, Madrid, 28034, Spain
| | - Mónica Jorge
- Hospital Álvaro Cunqueiro, Vigo (Pontevedra), 36213, Spain
| | - Ricardo Yaya
- Instituto Valenciano de Oncología (IVO), Valencia, 46009, Spain
| | | | | | - Elena Brozos
- Complejo Hospitalario Universitario de Santiago, Santiago de Compostela (La Coruña), 15706, Spain
| | - Jorge Aparicio
- Hospital Universitario y Politécnico La Fe, Valencia, 46026, Spain
| | | | | | - Elvira Buxó
- Hospital Quirón Salud, Barcelona, 08023, Spain
| | | | - Maria Luz Pellón
- Complexo Universitario Hospitalario de El Ferrol (La Coruña), 15405, Spain
| | - Raquel Molina
- Hospital Universitario Príncipe de Asturias, Alcalá de Henares (Madrid), 28805, Spain
| | | | - Paula Cerdà
- Centro Médico Teknon, Barcelona, 08022, Spain
| | | | | | - Antía Cousillas
- Complexo Universitario Hospitalario de Pontevedra, 36071, Spain
| | - Lorena Paris
- Centro Oncológico de Galicia, La Coruña, 15009, Spain
| | | | | | - María Ortega
- Department of Medical, Lilly, Madrid, 28108, Spain
| | | | | | - Min-Hua Jen
- European Statistics Group, Lilly, Surrey, GU206PH, UK
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Yang MJ, Choi YJ, Kim HJ, Kim DY, Seol YM. Treatment with Ramucirumab-paclitaxel in a metastatic gastric cancer patient undergoing hemodialysis: A case report. Medicine (Baltimore) 2021; 100:e24795. [PMID: 33607838 PMCID: PMC7899881 DOI: 10.1097/md.0000000000024795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/20/2021] [Accepted: 01/29/2021] [Indexed: 01/05/2023] Open
Abstract
RATIONALE Ramucirumab, a human Ig 1 monoclonal antibody against vascular endothelial growth factor receptor-2, in combination with paclitaxel is a second-line chemotherapy for patients with metastatic gastric cancer. Several reports have suggested that dose adjustments of cetuximab, an anti- epidermal growth factor receptor antibody, are not required in patients with renal impairment. However, the combination chemotherapy of ramucirumab and cytotoxic drug for hemodialysis (HD) patients has not been reported. PATIENT CONCERNS A 65-year-old man on HD was diagnosed with gastric cancer and underwent a subtotal gastrectomy with D2 lymphadenectomy. Abdominal computed tomography (CT) was examined after completion of 8 cycles of adjuvant chemotherapy with capecitabine combination oxaliplatin. DIAGNOSIS The patient was diagnosed with advanced gastric cancer at stage IIIb (pT3N2M0) 11 months ago. Unfortunately, 9 months after the start of adjuvant chemotherapy, multiple liver metastases from gastric cancer were found by abdominal CT. INTERVENTIONS He began receiving weekly paclitaxel(80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week. OUTCOMES He was treated with ramucirumab without dose adjustment. The metastatic liver mass had a partial response, after 2 and 4 cycles of chemotherapy and had a stable disease up to 12 cycles of chemotherapy. No obvious adverse effect was observed during treatment. However, after 14 cycles chemotherapy, follow-up abdominal CT revealed progression disease of multiple liver metastasis and lymph nodes invasion. LESSONS The paclitaxel chemotherapy with ramucirumab is effective and safe in HD patients with metastatic gastric cancer. As seen in patients with normal kidney function, ramucirumab can be safely administered without a dose reduction.
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Tomita Y, Moldovan M, Chang Lee R, Hsieh AH, Townsend A, Price T. Salvage systemic therapy for advanced gastric and oesophago-gastric junction adenocarcinoma. Cochrane Database Syst Rev 2020; 11:CD012078. [PMID: 33210731 PMCID: PMC8094513 DOI: 10.1002/14651858.cd012078.pub2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Salvage systemic therapy has become the new standard of care in patients with advanced gastric and oesophago-gastric junction (OGJ) adenocarcinoma, following disease progression on first-line fluoropyrimidine and platinum-containing chemotherapy. Pharmacological agents proven to be effective in this setting include both chemotherapy and biological therapy, however, the consensus on the best salvage systemic therapy has not been reached. OBJECTIVES To assess the effects of systemic chemotherapy and biological therapy, either alone or in combination, on overall survival (OS) and progression-free survival (PFS) in patients with advanced gastric and OGJ adenocarcinoma, whose disease has progressed on, or relapsed after first-line fluoropyrimidine and platinum-containing chemotherapy. Adverse events (AEs), tumour response rate (TRR) and quality of life (QoL) associated with systemic chemotherapy and/or biological therapy were additionally assessed. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, trial registries and proceedings of the major oncology conferences up to October 2020. We additionally handsearched the reference lists of studies. No language restriction was applied. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing salvage systemic therapy (chemotherapy and/or biological therapy) and either another type of salvage systemic therapy, placebo, best supportive care (BSC) or no treatment in patients with gastric and OGJ adenocarcinoma refractory to first-line fluoropyrimidine and platinum-containing chemotherapy. DATA COLLECTION AND ANALYSIS Two review authors independently performed selection of eligible studies and the primary author extracted study characteristics and outcome data from included studies. We assessed the quality and risk of bias of eligible studies according to the Cochrane Handbook for Systematic Reviews of Interventions. We expressed pooled estimates of effect using hazard ratio (HR) calculated using an inverse variance random-effects model for time-to-event data, and risk ratio (RR) calculated using Mantel-Haenszel random-effects model for binary data. The certainty of evidence was graded using GRADEpro. MAIN RESULTS We identified 17 RCTs with 5110 participants for inclusion in this review. Tweenty-nine studies are ongoing and twenty studies are awaiting classification. No studies examined the following comparisons: chemotherapy combined with biological therapy versus placebo, BSC or no treatment, chemotherapy combined with biological therapy versus biological therapy, biological therapy versus biological therapy and chemotherapy combined with biological therapy versus chemotherapy combined with biological therapy. Chemotherapy versus placebo, best supportive care or no treatment Chemotherapy probably improves OS (HR = 0.66, 95% CI 0.52 to 0.83, moderate-certainty evidence) based on two studies involving 547 participants and improves PFS (HR = 0.57, 95% CI 0.47 to 0.69, high-certainty evidence) based on one study involving 507 participants over placebo and BSC. Chemotherapy probably increases serious AEs (SAEs) (RR = 1.38, 95% CI 1.20 to 1.59, moderate-certainty evidence) based on one study involving 503 participants. Biological therapy versus placebo, best supportive care or no treatment Biological therapy improves OS (HR = 0.55, 95% CI 0.41 to 0.73, high-certainty evidence) and probably improves PFS (HR = 0.33, 95% CI 0.19 to 0.57, moderate-certainty evidence) over placebo based on three studies involving 781 participants. There is currently insufficient evidence for increased SAEs from biological therapy (RR = 1.14, 95% CI 0.95 to 1.37, low-certainty evidence) based on two studies involving 638 participants. Chemotherapy versus biological therapy This comparison only considered immunotherapy. There is probably no evidence of a difference for OS (HR = 0.82, 95% CI 0.66 to 1.02, moderate-certainty evidence) between chemotherapy and immunotherapy, and immunotherapy probably reduces PFS (HR = 1.27, 95% CI 1.03 to 1.57, moderate-certainty evidence) based on one study involving 395 participants. SAEs may be less frequent with immunotherapy compared to chemotherapy (RR = 0.41, 95% CI 0.30 to 0.57, low-certainty evidence). Chemotherapy combined with biological therapy versus chemotherapy Addition of biological therapy to chemotherapy probably does not improve OS (HR = 0.93, 95% CI 0.83 to 1.04, moderate-certainty evidence) and we are uncertain whether it improves PFS (HR = 0.87, 95% CI 0.74 to 1.02, very low-certainty evidence) based on seven studies involving 2743 participants. We are similarly uncertain whether combined chemotherapy and biological therapy increases SAEs (RR = 1.17, 95% CI 0.95 to 1.44, very low-certainty evidence) based on four studies involving 1618 participants. Chemotherapy versus chemotherapy There is no evidence of a difference for OS and PFS between irinotecan and paclitaxel (HR = 1.13, 95% CI 0.86 to 1.48, low-certainty evidence for OS; HR = 1.14, 95% CI 0.88 to 1.48, low-certainty evidence for PFS) based on one study involving 219 participants. Similarly, there is no evidence to indicate improved OS and PFS from addition of another chemotherapy to docetaxel (HR = 1.05, 95% CI 0.72 to 1.54, low-certainty evidence for OS; HR = 0.75, 95% CI 0.52 to 1.09, low-certainty evidence for PFS) based on two studies involving 121 participants. Grade ≥ 3 neutropenia occurred commonly with both mono- and poly-chemotherapy except for docetaxel-S1 and EOX chemotherapy. AUTHORS' CONCLUSIONS Survival outcome of patients with advanced gastric and OGJ adenocarcinoma whose disease progressed on first-line fluoropyrimidine and platinum-containing chemotherapy can be improved by chemotherapy and biological therapy. Biological therapy, in particular, achieves this without clear increase in SAEs or QoL impairment. Whether biological therapy is preferred over chemotherapy is still unclear and there is no evidence of a difference for OS outcome, although immunotherapy may be associated with less SAEs. Addition of biological therapy to chemotherapy and poly-chemotherapy are associated with frequent treatment-related toxicity without clear survival benefit.
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Affiliation(s)
- Yoko Tomita
- Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Woodville, Adelaide, Australia
| | - Max Moldovan
- South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Rachael Chang Lee
- Department of Medical Oncology, Adelaide Cancer Centre, Windsor Gardens, Australia
| | - Amy Hc Hsieh
- Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Woodville, Adelaide, Australia
| | - Amanda Townsend
- Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Woodville, Adelaide, Australia
| | - Timothy Price
- Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Woodville, Adelaide, Australia
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Van Cutsem E, Muro K, Cunningham D, Bodoky G, Sobrero A, Cascinu S, Ajani J, Oh SC, Al-Batran SE, Wainberg ZA, Wijayawardana SR, Melemed S, Ferry D, Hozak RR, Ohtsu A. Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study. Eur J Cancer 2020; 127:150-157. [PMID: 32014812 DOI: 10.1016/j.ejca.2019.10.026] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 10/21/2019] [Accepted: 10/27/2019] [Indexed: 01/11/2023]
Abstract
BACKGROUND The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. PATIENTS AND METHODS Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. RESULTS The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. CONCLUSIONS Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.
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Affiliation(s)
- E Van Cutsem
- Digestive Oncology, University Hospitals Gasthuisberg, Leuven and KULeuven, Leuven, Belgium.
| | - K Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | | | - G Bodoky
- Department of Oncology, St. László Hospital, Budapest, Hungary
| | - A Sobrero
- Medical Oncology, IRCCS Ospedale San Martino IST, Genova, Italy
| | - S Cascinu
- Department of Medical Oncology, Università Politecnica Delle Marche, Ancona, Italy
| | - J Ajani
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - S C Oh
- Korea University Guro Hospital, Seoul, South Korea
| | - S E Al-Batran
- Institute of Clinical Cancer Research (IKF), UCT- University Cancer Center, Frankfurt, Germany
| | - Z A Wainberg
- Medical Hematology and Oncology, University of California Los Angeles, Los Angeles, CA, USA
| | | | - S Melemed
- Eli Lilly and Company, Indianapolis, IN, USA
| | - D Ferry
- Eli Lilly and Company, Bridgewater, NJ, USA
| | - R R Hozak
- Eli Lilly and Company, Indianapolis, IN, USA
| | - A Ohtsu
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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Herbst RS, Arkenau HT, Santana-Davila R, Calvo E, Paz-Ares L, Cassier PA, Bendell J, Penel N, Krebs MG, Martin-Liberal J, Isambert N, Soriano A, Wermke M, Cultrera J, Gao L, Widau RC, Mi G, Jin J, Ferry D, Fuchs CS, Petrylak DP, Chau I. Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. Lancet Oncol 2019; 20:1109-1123. [PMID: 31301962 DOI: 10.1016/s1470-2045(19)30458-9] [Citation(s) in RCA: 207] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/07/2019] [Accepted: 05/08/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Pre-clinical and clinical evidence suggests that simultaneous blockade of VEGF receptor-2 (VEGFR-2) and PD-1 or PD-L1 enhances antigen-specific T-cell migration, antitumour activity, and has favourable toxicity. In this study, we aimed to assess the safety and preliminary antitumour activity of ramucirumab (an IgG1 VEGFR-2 antagonist) combined with pembrolizumab (an IgG4 PD-1 antagonist) in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, or urothelial carcinoma. METHODS We did a multicohort, non-randomised, open-label, phase 1a/b trial at 16 academic medical centres, hospitals, and clinics in the USA, France, Germany, Spain, and the UK. We enrolled adult patients aged 18 years or older with histologically confirmed gastric or gastro-oesophageal junction adenocarcinoma (cohorts A and B), non-small-cell lung cancer (cohort C), or urothelial carcinoma (cohort D), whose disease had progressed on one or two lines of previous therapy (for those with gastric or gastro-oesophageal junction adenocarcinoma) or one to three lines of previous therapy (for those with non-small-cell lung cancer and urothelial carcinoma) that included platinum (for all tumour types) or fluoropyrimidine or both (for gastric or gastro-oesophageal junction adenocarcinoma). Eligibility criteria included presence of measurable disease and an Eastern Cooperative Oncology Group performance status of 0-1. Patients with previously untreated gastric or gastro-oesophageal junction adenocarcinoma and non-small-cell lung cancer were also enrolled (in two additional separate cohorts); the results for these cohorts will be reported separately. The first 21-day treatment cycle was a dose-limiting toxicity observation period (phase 1a; safety run-in), followed by a phase 1b cohort expansion stage. Pembrolizumab 200 mg was administered intravenously on day 1, and intravenous ramucirumab was administered at 8 mg/kg on days 1 and 8 for cohort A or at 10 mg/kg on day 1 for cohorts B, C, and D, every 3 weeks, until disease progression or other discontinuation criteria were met. The primary endpoint was the safety and tolerability of ramucirumab in combination with pembrolizumab assessed by the incidence of adverse events in both phase 1a and 1b and as dose-limiting toxicities during phase 1a. The safety and activity analysis set included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02443324, and is no longer enrolling patients. FINDINGS Between July 30, 2015 and June 24, 2016, we enrolled and treated 92 patients (41 with gastric or gastro-oesophageal junction adenocarcinoma, 27 with non-small-cell lung cancer, and 24 with urothelial carcinoma). Median follow-up was 32·8 months (IQR 28·1-33·6). During the first cycle of treatment (phase 1a safety run-in; n=11), one patient with gastro-oesophageal junction adenocarcinoma who received the 8 mg/kg dose of ramucirumab had grade 3 abdominal pain, colitis, hepatitis, interstitial lung disease, and jaundice, and grade 4 cholestasis, and died on treatment on day 40; the death was deemed related to progressive disease. No additional dose-limiting toxicities occurred and the decision was made to maintain the full planned doses of ramucirumab and pembrolizumab in phase 1b (n=81). Treatment-related adverse events occurred in 75 (82%) of 92 patients, the most common of which was fatigue (in 33 patients [36%]), predominantly of grade 1 or 2 severity. 22 patients (24%) had one or more treatment-related adverse events of grade 3 or worse, most commonly hypertension (six patients; 7%) and colitis (five patients; 5%). Serious adverse events occurred in 53 (58%) of 92 patients, and were deemed related to treatment in 22 (24%) patients. The most common treatment-related serious adverse events were abdominal pain in patients with gastric or gastro-oesophageal junction adenocarcinoma (in three [7%] of 41 patients); asthenia and myocardial infarction in patients with non-small-cell lung cancer (two [7%] of 27 patients), and colitis in patients with urothelial carcinoma (two [8%] of 24 patients). Six (7%) of 92 patients discontinued treatment because of treatment-related adverse events, and one death (from pulmonary sepsis in a patient with gastric or gastro-oesophageal junction adenocarcinoma) was deemed related to treatment. The number of patients achieving an objective response was three (7%; 95% CI 1·5-19·9) of 41 in the gastric or gastro-oesophageal junction adenocarcinoma cohort, eight (30%; 13·8-50·2) of 27 in the non-small-cell lung cancer cohort, and three (13%, 2·7-32·4) in the urothelial carcinoma cohort. INTERPRETATION Ramucirumab in combination with pembrolizumab showed a manageable safety profile with favourable antitumour activity in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, and urothelial carcinoma. Our results contribute to the growing evidence that supports dual inhibition of the VEGF-VEGFR2 and PD-1-PD-L1 pathways. This combination could be further explored with or without chemotherapy, especially for patients with tumours for which single-agent checkpoint inhibitors have shown no additional benefit over chemotherapy. FUNDING Eli Lilly and Company, and Merck and Co.
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Affiliation(s)
- Roy S Herbst
- Yale University School of Medicine, Yale Cancer Center, New Haven, CT, USA.
| | - Hendrik-Tobias Arkenau
- Drug Development Unit, Sarah Cannon Research Institute UK, London, UK; Cancer Institute, University College London, London, UK
| | | | - Emiliano Calvo
- Early Clinical Drug Development Program, START Madrid-HM Centro Integral Oncológico Clara Campal, Madrid, Spain
| | - Luis Paz-Ares
- Virgen del Rocio University Hospital, Seville, Spain
| | | | - Johanna Bendell
- Sarah Cannon Research Institute, Nashville, TN, USA; Tennessee Oncology, Nashville, TN, USA
| | - Nicolas Penel
- Centre Oscar Lambret, Lille, France; Department of Medical Oncology, Lille University, Lille, France
| | - Matthew G Krebs
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, NIHR Manchester Biomedical Research Centre and NIHR Manchester Clinical Research Facility, The Christie NHS Foundation Trust, Manchester, UK
| | - Juan Martin-Liberal
- Vall d'Hebron Institute of Oncology, Barcelona, Spain; Catalan Institute of Oncology, Hospitalet, Barcelona, Spain
| | | | | | - Martin Wermke
- University Hospital Carl Gustav Carus, NCT/UCC Early Clinical Trial Unit, Dresden, Germany
| | | | - Ling Gao
- Eli Lilly and Company, New York, NY, USA
| | | | - Gu Mi
- Eli Lilly and Company, Indianapolis, IN, USA
| | - Jin Jin
- Eli Lilly and Company, New York, NY, USA
| | | | - Charles S Fuchs
- Yale University School of Medicine, Yale Cancer Center, New Haven, CT, USA
| | - Daniel P Petrylak
- Yale University School of Medicine, Yale Cancer Center, New Haven, CT, USA
| | - Ian Chau
- Royal Marsden Hospital, Sutton, Surrey, UK
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Muro K, Jen MH, Cheng R. Is ramucirumab and paclitaxel therapy beneficial for second-line treatment of metastatic gastric or junctional adenocarcinoma for patients with ascites? Analysis of RAINBOW phase 3 trial data. Cancer Manag Res 2019; 11:2261-2267. [PMID: 30962715 PMCID: PMC6433106 DOI: 10.2147/cmar.s193739] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Purpose Second-line treatment with ramucirumab-paclitaxel has demonstrated statistically significant and clinically meaningful survival outcomes compared to paclitaxel-alone in patients with advanced gastric cancer (HR=0.807, 95% CI 0.678–0.962; P=0.017). Post hoc, exploratory analyses of RAINBOW patient data were performed to examine whether ascites impacted the efficacy and safety of ramucirumab-paclitaxel. Patients and methods Patients were placed in with- or without-ascites subgroups based on baseline information collected on case report forms. The Kaplan–Meier method was used to estimate median progression-free survival (PFS) and overall survival (OS) of the ascites subgroups. HR and 95% CI were calculated using the Cox proportional hazards model. Survival distributions within the two arms in each ascites subgroup were compared using the log-rank test. Results There were 36% of RAINBOW trial patients (237/665) that had ascites at baseline (with-ascites subgroup); 64% of patients (428/665) had no baseline ascites (without-ascites subgroup). Most baseline characteristics were balanced. The with-ascites subgroup had a higher percentage of patients with peritoneal metastases (91% vs 23%) as expected. Overall survival for the with-ascites subgroup was worse than for the without-ascites subgroup (median OS for placebo-treated patients: 5.2 vs 8.5 months, respectively). However, OS treatment effects did not seem to differ significantly among patients with ascites (OS stratified HR=0.864, 95% CI=0.644–1.161; P=0.3362) vs those without ascites (OS stratified HR=0.745, 95% CI=0.593–0.936; P=0.0115). Similar results were observed for PFS. Ramucirumab treatment was associated with a greater incidence of all-grade vomiting for the with-ascites subgroup vs the without-ascites subgroup (ramucirumab arm: 39.2% vs 18.8%; placebo arm: 23.3% vs 19.5%, respectively). The incidence of adverse events of special interest was not elevated among the ramucirumab-treated ascites subgroup over the without-ascites subgroup. Conclusion The benefit/risk profile of ramucirumab-paclitaxel remains favorable in patients with ascites and is consistent with the findings of the RAINBOW trial.
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Affiliation(s)
- Kei Muro
- Department of Clinical Oncology, Outpatient Treatment Center, Aichi Cancer Center Hospital, Nagoya, Japan,
| | - Min-Hua Jen
- Eli Lilly and Company Ltd, Windlesham, Surrey, UK
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Rogers JE, Xiao L, Amlashi FG, Elimova E, Blum Murphy MA, Sanders E, Shanbhag N, Thomas I, Ajani JA. Ramucirumab and Paclitaxel Administered Every 2 Weeks (mRAINBOW Regimen) in Advanced Gastroesophageal Adenocarcinoma. Oncology 2019; 96:252-258. [PMID: 30893708 DOI: 10.1159/000496978] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 01/07/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND The RAINBOW trial established ramucirumab combined with paclitaxel as a second-line option in metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma. Ramucirumab was given on days 1 and 15 with paclitaxel on days 1, 8, and 15 of a 28-day cycle. The median overall survival (OS) was significantly longer with ramuciru-mab plus paclitaxel (p = 0.017), and it led to 41% grade 3 or higher neutropenia. We review our experience with both ramucirumab plus paclitaxel given biweekly (mRAINBOW) to assess efficacy and safety. OBJECTIVES The primary objective was to assess OS. Secondary end points were progression-free survival (PFS), overall response, and safety. METHODS We identified 129 patients retrospectively from our database between November 2014 and May 2017. Patients were included if they were followed up at our institution. RESULTS Median doses given were ramucirumab 8 mg/kg i.v. plus paclitaxel 110 mg/m2 i.v. given once every 2 weeks. The median performance status was 1, and ∼60% had poorly differentiated histology; 55.8% had progression in < 6 months on first-line therapy, and the majority had measurable cancer. Median overall OS and PFS for the entire cohort was 9.4 months (95% CI: 8.05-10.74) and 3.68 months (95% CI: 2.73-4.5), respectively. Median OS was 9.46 months (95% CI: 8.05-14.95) and median PFS was 4.14 months (95% CI: 2.96-5.29) in those patients that received ramucirumab plus paclitaxel in the second-line setting. CONCLUSION Biweekly administration of ramucirumab plus paclitaxel did not compromise efficacy. Delays, adjustments, or doses held were similar to the RAINBOW trial, with 31% requiring a dose or schedule modification.
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Affiliation(s)
- Jane E Rogers
- Pharmacy Clinical Programs, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA
| | - Lianchun Xiao
- Department of Biostatistics, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA
| | - Fatemeh G Amlashi
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA
| | - Elena Elimova
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA
| | - Mariela A Blum Murphy
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA
| | - Elizabeth Sanders
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA
| | - Namita Shanbhag
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA
| | - Irene Thomas
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA,
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Paulson AS, Hess LM, Liepa AM, Cui ZL, Aguilar KM, Clark J, Schelman W. Ramucirumab for the treatment of patients with gastric or gastroesophageal junction cancer in community oncology practices. Gastric Cancer 2018; 21:831-844. [PMID: 29397460 DOI: 10.1007/s10120-018-0796-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 01/14/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Limited real-world research has investigated ramucirumab for the treatment of patients with gastric or gastroesophageal junction (GEJ) cancer. This study was designed to describe ramucirumab monotherapy or combination therapy use in a community oncology practice setting. METHODS This was a retrospective observational cohort study to describe the treatment of adult patients with gastric or GEJ cancer who initiated ramucirumab treatment between 4/21/14 and 6/30/16 within the US Oncology Network. Kaplan-Meier method and Cox proportional hazards regression analyses were used to assess clinical outcomes. Multivariable logistic regression models were used to assess patient-level predictors of ramucirumab monotherapy or combination therapy. RESULTS A total of 505 patients (mean age 64.4 years; 75.1% male) were included in the analysis; subgroups included: monotherapy (22.8%; n = 115), combination therapy (77.2%; n = 390). Monotherapy patients were significantly older (67.7 vs. 63.4 years; P = 0.0006), received ramucirumab approximately 3 months later after diagnosis (16.9 vs. 14.1 months; P = 0.0318) and more frequently initiated ramucirumab in the third or later lines of treatment (38.3 vs. 8.2%; P<0.0001) than patients receiving combination therapy. Median overall survival (OS) for monotherapy and combination therapy from the start of second-line therapy was 5.5 months (confidence interval [CI] 4.3, 7.8) and 7.4 months (CI 6.6, 8.8), respectively. CONCLUSIONS The results showed that patients who received ramucirumab monotherapy started ramucirumab therapy later after diagnosis and were older than those who received ramucirumab in combination. Additionally, survival data suggest that outcomes observed in community oncology practices are similar to data from phase 3 clinical trials.
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Affiliation(s)
- A Scott Paulson
- Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA
| | - Lisa M Hess
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | | | - Kathleen M Aguilar
- McKesson Specialty Health, 10101 Woodloch Forest Drive, The Woodlands, TX, 77380, USA.
| | - Jamyia Clark
- McKesson Specialty Health, 10101 Woodloch Forest Drive, The Woodlands, TX, 77380, USA
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Chuang YC, Wu HY, Lin YL, Tzou SC, Chuang CH, Jian TY, Chen PR, Chang YC, Lin CH, Huang TH, Wang CC, Chan YL, Liao KW. Blockade of ITGA2 Induces Apoptosis and Inhibits Cell Migration in Gastric Cancer. Biol Proced Online 2018; 20:10. [PMID: 29743821 PMCID: PMC5928594 DOI: 10.1186/s12575-018-0073-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 02/28/2018] [Indexed: 12/19/2022] Open
Abstract
Background Gastric cancer is currently the fourth leading cause of cancer-related death worldwide. Gastric cancer is often diagnosed at advanced stages and the outcome of the treatment is often poor. Therefore, identifying new therapeutic targets for this cancer is urgently needed. Integrin alpha 2 (ITGA2) subunit and the beta 1 subunit form a heterodimer for a transmembrane receptor for extracellular matrix, is an important molecule involved in tumor cell proliferation, survival and migration. Integrin α2β1 is over-expressed on a variety of cancer cells, but is low or absent in most normal organs and resting endothelial cells. Results In this report, we assessed the ITGA2 as the potential therapeutic target with the bioinformatics tools from the TCGA dataset in which composed of 375 gastric cancer tissues and 32 gastric normal tissues. According to the information from the Cancer Cell Line Encyclopedia (CCLE) database, the AGS cell line with ITGA2 high expression and the SUN-1 cell line with low expression were chosen for the further investigation. Interestingly, the anti-ITGA2 antibody (at 3 μg/ml) inhibited approximately 50% survival of the AGS cells (over-expressed ITGA2), but had no effect in SNU-1 cells (ITGA2 negative). The extents of antibody-mediated cancer inhibition positively correlated with the expression levels of the ITGA2. We further showed that the anti-ITGA2 antibody induced apoptosis by up-regulating the RhoA-p38 MAPK signaling to promote the expressions of Bim, Apaf-1 and Caspase-9, whereas the expressions of Ras and Bax/Bcl-2 were not affected. Moreover, blocking ITGA2 by the specific antibody at lower doses also inhibited cell migration of gastric cancer cells. Blockade of ITGA2 by a specific antibody down-regulated the expression of N-WASP, PAK and LIMK to impede actin organization and cell migration of gastric cancer cells. Conclusions Here, we showed that the mRNA expression levels of ITGA2 comparing to normal tissues significantly increased. In addition, the results revealed that targeting integrin alpha 2 subunit by antibodies did not only inhibit cell migration, but also induce apoptosis effect on gastric cancer cells. Interestingly, higher expression level of ITGA2 led to significant effects on apoptosis progression during anti-ITGA2 antibody treatment, which indicated that ITGA2 expression levels directly correlate with their functionality. Our findings suggest that ITGA2 is a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Yu-Chang Chuang
- 1Departmet of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Hsin-Yi Wu
- 2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Yu-Ling Lin
- 1Departmet of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China.,3Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, Taiwan, Republic of China
| | - Shey-Cherng Tzou
- 1Departmet of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China.,2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Cheng-Hsun Chuang
- 2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Ting-Yan Jian
- 2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Pin-Rong Chen
- 2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Yuan-Ching Chang
- 4Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China
| | - Chi-Hsin Lin
- 5Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan, Republic of China
| | - Tse-Hung Huang
- 6Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China.,7School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China.,8School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan, Republic of China
| | - Chao-Ching Wang
- 6Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China
| | - Yi-Lin Chan
- 9Department of Life Science, Chinese Culture University, 55, Hwa-Kang Rd., Yang-Ming-Shan, Taipei, 11114 Taiwan, Republic of China
| | - Kuang-Wen Liao
- 1Departmet of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China.,2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China.,10College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, Republic of China.,11Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China.,12Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan, Republic of China
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Bang YJ, Takano T, Lin CC, Fasanmade A, Yang H, Danaee H, Asato T, Kalebic T, Wang H, Doi T. TAK-264 (MLN0264) in Previously Treated Asian Patients with Advanced Gastrointestinal Carcinoma Expressing Guanylyl Cyclase C: Results from an Open-Label, Non-randomized Phase 1 Study. Cancer Res Treat 2018; 50:398-404. [PMID: 28494535 PMCID: PMC5912138 DOI: 10.4143/crt.2017.074] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 05/01/2017] [Indexed: 01/11/2023] Open
Abstract
PURPOSE This phase 1 dose-escalation portion of the study evaluated the safety, pharmacokinetics (PK), and antitumor activity of TAK-264 in Asian patients with advanced gastrointestinal (GI) carcinoma or metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma expressing guanylyl cyclase C (GCC). MATERIALS AND METHODS Adult patients with advanced GI malignancies expressing GCC (H-score ≥ 10) received TAK-264 on day 1 of 3-week cycles as 30-minute intravenous infusions for up to 1 year or until disease progression or unacceptable toxicity. The primary objectives were to evaluate the safety profile including dose-limiting toxicities (DLTs) during cycle 1, determine the maximum tolerated dose (MTD), and characterize the PK profile of TAK-264. RESULTS Twelve patients were enrolled and treated with 1.2 mg/kg (n=3), 1.5 mg/kg (n=3), or 1.8 mg/kg TAK-264 (n=6). Median number of treatment cycles received was two (range, 1 to 10). None of the patients experienced a DLT and the MTD was not determined. Ten patients (83%) experienced adverse events (AEs). The most common were neutropenia, anorexia, and nausea (each reported by four patients). Five patients (42%) experienced grade ≥ 3 AEs consisting of tumor hemorrhage and hypertension, ascites, adrenal insufficiency, neutropenia and asthenia. Serum exposure to TAK-264 increased proportionally with the dose and the median half-life was approximately 5.5-6.6 days. No patients experienced an objective response. CONCLUSION TAK-264 demonstrated a manageable safety profile with limited antitumor activity consistent with studies conducted in Western patients with advanced GI malignancies. TAK-264 exposure increased proportionally with the dose.
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Affiliation(s)
- Yung-Jue Bang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Toshimi Takano
- Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan
| | - Chia-Chi Lin
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Adedigbo Fasanmade
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
| | - Huyuan Yang
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
| | - Hadi Danaee
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
| | - Takayuki Asato
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
| | - Thea Kalebic
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
| | - Hui Wang
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
| | - Toshihiko Doi
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Chiba, Japan
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Jia S, Qu T, Wang X, Feng M, Yang Y, Feng X, Ma R, Li W, Hu Y, Feng Y, Ji K, Li Z, Jiang W, Ji J. KIAA1199 promotes migration and invasion by Wnt/β-catenin pathway and MMPs mediated EMT progression and serves as a poor prognosis marker in gastric cancer. PLoS One 2017; 12:e0175058. [PMID: 28422983 PMCID: PMC5397282 DOI: 10.1371/journal.pone.0175058] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 03/20/2017] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND KIAA1199 was upregulated in diverse cancers, but the association of KIAA1199 with gastric cancer (GC), the biological role of KIAA1199 in GC cells and the related molecular mechanisms remain to be elucidated. METHODS KIAA1199 expression was analysed by reverse transcription-polymerase chain reaction assay (RT-PCR) and immunohistochemistry (IHC) in GC patient tissue. The small hairpin RNA (shRNA) was applied for the knockdown of endogenous KIAA1199 in NCI-N87 and AGS cells. MTT, colony formation, scratch wounding migration, transwell chamber migration and invasion assays were employed respectively to investigate the role of KIAA1199 in GC cells. The potential signaling pathway of KIAA1199 induced migration and invasion was detected. RESULTS KIAA1199 was upregulated in GC tissue and was an essential independent marker for poor prognosis. Knockdown KIAA1199 suppressed the proliferation, migration and invasion in GC cells. KIAA1199 stimulated the Wnt/β-catenin signaling pathway and the enzymatic activity of matrix metalloproteinase (MMP) family members and thus accelerated the epithelial-to-mesenchymal transition (EMT) progression in GC cells. CONCLUSION These findings demonstrated that KIAA1199 was upregulated in GC tissue and associated with worse clinical outcomes in GC, and KIAA1199 acted as an oncogene by promoting migration and invasion through the enhancement of Wnt/β-catenin signaling pathway and MMPs mediated EMT progression in GC cells.
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Affiliation(s)
- Shuqin Jia
- Laboratory of Surgery, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
- Center for Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Tingting Qu
- Center for Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaohong Wang
- Tissue Bank, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Mengmeng Feng
- Laboratory of Surgery, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Yang Yang
- Laboratory of Surgery, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Xuemin Feng
- Laboratory of Surgery, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Ruiting Ma
- Laboratory of Surgery, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Wenmei Li
- Center for Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ying Hu
- Tissue Bank, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yi Feng
- Center for Molecular Diagnosis, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ke Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ziyu Li
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Wenguo Jiang
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Jiafu Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
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Katsha A, Wang L, Arras J, Omar OM, Ecsedy J, Belkhiri A, El-Rifai W. Activation of EIF4E by Aurora Kinase A Depicts a Novel Druggable Axis in Everolimus-Resistant Cancer Cells. Clin Cancer Res 2017; 23:3756-3768. [PMID: 28073841 DOI: 10.1158/1078-0432.ccr-16-2141] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 12/29/2016] [Accepted: 12/29/2016] [Indexed: 01/11/2023]
Abstract
Purpose: Aurora kinase A (AURKA) is overexpressed in several cancer types, making it an attractive druggable target in clinical trials. In this study, we investigated the role of AURKA in regulating EIF4E, cap-dependent translation, and resistance to mTOR inhibitor, RAD001 (everolimus).Experimental Design: Tumor xenografts and in vitro cell models of upper gastrointestinal adenocarcinomas (UGC) were used to determine the role of AURKA in the activation of EIF4E and cap-dependent translation. Overexpression, knockdown, and pharmacologic inhibition of AURKA were used in vitro and in vivoResults: Using in vitro cell models, we found that high protein levels of AURKA mediate phosphorylation of EIF4E and upregulation of c-MYC. Notably, we detected overexpression of endogenous AURKA in everolimus-resistant UGC cell models. AURKA mediated phosphorylation of EIF4E, activation of cap-dependent translation, and an increase in c-MYC protein levels. Targeting AURKA using genetic knockdown or a small-molecule inhibitor, alisertib, reversed these molecular events, leading to a decrease in cancer cell survival in acquired and intrinsic resistant cell models. Mechanistic studies demonstrated that AURKA binds to and inactivates protein phosphatase 2A, a negative regulator of EIF4E, leading to phosphorylation and activation of EIF4E in an AKT-, ERK1/2-, and mTOR-independent manner. Data from tumor xenograft mouse models confirmed that everolimus-resistant cancer cells are sensitive to alisertib.Conclusions: Our results indicate that AURKA plays an important role in the activation of EIF4E and cap-dependent translation. Targeting the AURKA-EIF4E-c-MYC axis using alisertib is a novel therapeutic strategy that can be applicable for everolimus-resistant tumors and/or subgroups of cancers that show overexpression of AURKA and activation of EIF4E and c-MYC. Clin Cancer Res; 23(14); 3756-68. ©2017 AACR.
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Affiliation(s)
- Ahmed Katsha
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Science and Engineering, Raritan Valley Community College, Branchburg, New Jersey
| | - Lihong Wang
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Janet Arras
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Omar M Omar
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jeffrey Ecsedy
- Translational Medicine, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Abbes Belkhiri
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Wael El-Rifai
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. .,Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee
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Jia S, Lu J, Qu T, Feng Y, Wang X, Liu C, Ji J. MAGI1 inhibits migration and invasion via blocking MAPK/ERK signaling pathway in gastric cancer. Chin J Cancer Res 2017; 29:25-35. [PMID: 28373751 PMCID: PMC5348473 DOI: 10.21147/j.issn.1000-9604.2017.01.04] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE To explore the association of membrane-associated guanylate kinase inverted 1 (MAGI1) with gastric cancer (GC) and the related molecular mechanisms. METHODS The reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) were utilized to measure the MAGI1 expression level in GC tissues. Quantitative real-time PCR and Western blotting were used to ensure the MAGI1 expression in GC cell lines. Small hairpin RNA (shRNA) was applied for knockdown of endogenous MAGI1 in GC cells. MTT assay and colony formation assay, scratch wounding migration assay and transwell chamber migration assay, as well as transwell chamber invasion assay were employed respectively to investigate the GC cell proliferation, migration and invasion in MAGI1-knockdown and control GC cells. The potential molecular mechanism mediated by MAGI1 was studied using Western blotting and RT- PCR. RESULTS RT-PCR and IHC verified MAGI1 was frequently expressed in matched adjacent noncancerous mucosa compared with GC tissues and the expression of MAGI1 was related to clinical pathological parameters. Functional assays indicated that MAGI1 knockdown significantly promoted GC cell migration and invasion. Further mechanism investigation demonstrated that one pathway of MAGI1 inhibiting migration and invasion was mainly by altering the expression of matrix metalloproteinases (MMPs) and epithelial-mesenchymal transition (EMT)-related molecules via inhibiting MAPK/ERK signaling pathway. CONCLUSIONS MAGI1 was associated with GC clinical pathological parameters and acted as a tumor suppressor via inhibiting of MAPK/ERK signaling pathway in GC.
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Affiliation(s)
- Shuqin Jia
- Laboratory of Surgery, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular Diagnosis, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Jiajia Lu
- Department of Medical Oncology, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
| | - Tingting Qu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular Diagnosis, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yi Feng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular Diagnosis, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xiaohong Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Tissue Bank, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Caixia Liu
- Department of Medical Oncology, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
| | - Jiafu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China
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Wang Y, Zeng J, Pan J, Geng X, Liu Y, Wu J, Song P, Wang Y, Jia J, Wang L. MicroRNA-200c is involved in proliferation of gastric cancer by directly repressing p27 Kip1. Biochem Biophys Rep 2016; 8:227-233. [PMID: 28955960 PMCID: PMC5613965 DOI: 10.1016/j.bbrep.2016.09.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 08/10/2016] [Accepted: 09/06/2016] [Indexed: 12/21/2022] Open
Abstract
P27Kip1, also known as Cyclin-dependent kinase inhibitor 1B, is an important check-point protein in the cell cycle. It has been identified that although as a tumor suppressor, P27Kip1 is expressed in different cancer cell types, which shows the therapeutic potential in tumor genesis. In this study, we examined the upstream regulatory mechanism of P27Kip1 at the microRNA (miRNA) level in gastric carcinogenesis. We used bioinformatics to predict that microRNA-200c (miR-200c) might be a direct upstream regulator of P27Kip1. It was also verified in gastric epithelial-derived cell lines that overexpression of miR-200c significantly inhibited the expression levels of P27Kip1, whereas knockdown of miR-200c promoted P27Kip1 expression in AGS and BGC-823 cells. Furthermore, we identified the direct binding of miR-200c on the P27Kip1 3′ -UTR sequence by luciferase assay. MiR-200c could enhance the colony formation of cells by repressing P27Kip1 expression. In addition, the negative correlation between P27Kip1 and miR-200c in human gastric cancer tissues and matched normal tissues further supported the tumor-promoting action of miR-200c in vivo. Our finding suggested that miR-200c directly regulates the expression of P27Kip1 and promotes cell growth in gastric cancer as an oncogene, which may provide new clues to treatment.
miR-200c is involved in the proliferation of gastric cancer cell lines. P27Kip1 is a direct downstream target of miR-200c. miR-200c is determined an oncogene in human gastric cancer tissue species.
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Affiliation(s)
- Yangyang Wang
- Department of Pharmocology, Shandong University School of Medicine, Jinan 250012, PR China
| | - Jiping Zeng
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, PR China
| | - Jianyong Pan
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Xue Geng
- Department of Pharmocology, Shandong University School of Medicine, Jinan 250012, PR China
| | - Yansong Liu
- Shandong Tumor's Hospital and Institute, Jinan 250117, PR China
| | - Jing Wu
- Department of Pharmocology, Shandong University School of Medicine, Jinan 250012, PR China
| | - Ping Song
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, PR China
| | - Ying Wang
- Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, PR China
| | - Jihui Jia
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, Jinan 250012, PR China
| | - Lixiang Wang
- Department of Pharmocology, Shandong University School of Medicine, Jinan 250012, PR China
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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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Shah BK, Khanal A, Hewett Y. Second Primary Malignancies in Adults with Gastric Cancer - A US Population-Based Study. Front Oncol 2016; 6:82. [PMID: 27148474 PMCID: PMC4826867 DOI: 10.3389/fonc.2016.00082] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 03/23/2016] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Multiple studies have examined the incidence of secondary primary malignancies (SPMs) in gastric cancer patients in Europe and Asia. This retrospective review was conducted to analyze risk of SPM in patients with gastric cancer diagnosed in the United States. METHODS We included adult patients diagnosed with gastric cancer from the surveillance, epidemiology, and end result (SEER) 13 database. We calculated the risk of SPMs in these patients using the multiple primary standardized incidence ratio session of SEER*stat software and performed subset analyses of SPM with regard to age, sex, radiotherapy used, and latency period. RESULTS Among 33,720 patients, 1838 (5.45%) developed 2019 SPMs with an observed/expected (O/E) ratio of 1.11 [95% confidence interval (CI) = 1.06-1.16, p < 0.001] and an absolute excess risk of 18.16 per 10,000 population. The median time to first SPM from the time of diagnosis of gastric cancer was 46.9 months (range 6-239 months). Significant excess risk was observed for gastrointestinal malignancies [O/E ratio 1.71 (CI = 1.59-1.84, p < 0.001)], thyroid [O/E ratio 2.00 (CI = 1.37-2.8, p < 0.001)], and pancreatic cancer [O/E ratio 1.60 (CI = 1.29-21.96, p < 0.001)]. Risk of secondary melanoma, breast cancer, and prostate cancer was lower than in the general population. CONCLUSION The risk for SPMs is significantly increased in adults with gastric cancer compared to the general population.
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Affiliation(s)
| | - Amit Khanal
- Section of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago , Chicago, IL , USA
| | - Yvonne Hewett
- PeaceHealth United General Medical Center , Lewiston, ID , USA
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