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Kang X, Li R, Li X, Xu X. EGFR mutations and abnormal trafficking in cancers. Mol Biol Rep 2024; 51:924. [PMID: 39167290 DOI: 10.1007/s11033-024-09865-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 08/14/2024] [Indexed: 08/23/2024]
Abstract
Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor and a member of the ErbB receptor family. As a significant cancer driver, EGFR undergoes mutations such as gene amplification or overexpression in a wide range of malignant tumors and is closely associated with tumorigenesis. This review examines the aberrant expression of EGFR in several common cancers and summarizes the current therapeutic strategies developed for this receptor. Additionally, this review compares the differences in EGFR activation, internalization, endocytosis, and sorting in normal and cancer cells, and highlights some regulatory factors that influence its trafficking process.Kindly check and confirm the edit made in the title.Yes, correctAs per journal instructions structured abstract is mandatory kindly provideThe abstract format does not apply to Review articles.
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Affiliation(s)
- Xiang Kang
- The First Clinical Medical College, Nanchang University, Nanchang, 30006, China
- The Department of Respiratory and Critical Care Medicine, Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Rendong Li
- The First Clinical Medical College, Nanchang University, Nanchang, 30006, China
- The Department of Respiratory and Critical Care Medicine, Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Xiaolei Li
- The Department of Respiratory and Critical Care Medicine, Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
- Jiangxi Hospital of China-Japan Friendship Hospital, Nanchang, 330052, China
| | - Xinping Xu
- The Department of Respiratory and Critical Care Medicine, Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
- Jiangxi Hospital of China-Japan Friendship Hospital, Nanchang, 330052, China.
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Du HJ, Chen FF, Liu Y, Zhou Y. Bone metastatic carcinoma with EGFR amplification and mutation: A case report and literature review. Medicine (Baltimore) 2023; 102:e32615. [PMID: 36701708 PMCID: PMC9857377 DOI: 10.1097/md.0000000000032615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
RATIONALE Mutations in the epidermal growth factor receptor (EGFR) gene are highly prevalent in non-small cell lung cancer, while rare in other cancers. Primarily it's hardly present in bone metastases from cancer of unknown primary (BMCUP). Currently, no specific treatment options for bone metastases from unknown primary cancers exist. PATIENT CONCERNS The right shoulder and back pain of a 72-years-old man had been persistent for 2 weeks and had developed worse on 1 particular day. The right upper arm was compromised, which also hindered the arm's ability to raise and flex, and nighttime sleep was impacted. After applying the analgesic patch externally, the symptoms did not improve. No coughing or sputum production, chest tightness, shortness of breath, acid reflux, belching, abdominal pain, distension, diarrhea, backache, hematuria, black or bloody feces, or other discomforts appeared over the course of the illness. DIAGNOSES The patient had a particular type of bone metastases from primary cancers with genetic test results indicating EGFR amplification and mutation. INTERVENTIONS A third-generation tyrosine kinase inhibitors drug, oral Osimertinib 80 mg once a day with bisphosphonates anti-bone destruction treatment was performed on schedule. OUTCOMES Following treatment, the patient's tumor-related symptoms were significantly improved by controlling the disease for up to 11 months and providing great pain relief. LESSON EGFR-based genetic testing has emerged as a key measure for targeted therapy in non-small cell lung cancer. However, there are fewer relevant studies for other tumor types like BMCUP. Combined with literature reviews and our report, we provide evidence that targeting EGFR mutations according to the "basket theory" for the treatment of BMCUP is effective.
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Affiliation(s)
- Hong-Juan Du
- Department of Oncology, Chongqing General Hospital, Chongqing, China
| | - Fang-Fang Chen
- Department of Oncology, Chongqing General Hospital, Chongqing, China
| | - Yu Liu
- Department of Oncology, Chongqing General Hospital, Chongqing, China
| | - Yu Zhou
- Department of Respiration, Fuling People’s Hospital, Chongqing, China
- * Correspondence: Yu Zhou, Department of Respiration, Fuling People’s Hospital, No. 6 Mingkang Lane, Fuling District, Chongqing 408000, China (e-mail: )
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Identification of Molecular Subtypes and Potential Small-Molecule Drugs for Esophagus Cancer Treatment Based on m 6A Regulators. JOURNAL OF ONCOLOGY 2022; 2022:5490461. [PMID: 35069736 PMCID: PMC8776445 DOI: 10.1155/2022/5490461] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/07/2021] [Accepted: 12/13/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Esophagus cancer (ESCA) is the sixth most frequent cancer in males, with 5-year overall survival of 15%-25%. RNA modifications function critically in cancer progression, and m6A regulators are associated with ESCA prognosis. This study further revealed correlations between m6A and ESCA development. METHODS Univariate Cox regression analysis and consensus clustering were applied to determine molecular subtypes. Functional pathways and gene ontology terms were enriched by gene set enrichment analysis. Protein-protein interaction (PPI) analysis on differentially expressed genes (DEGs) was conducted for hub gene screening. Public drug databases were employed to study the interactions between hub genes and small molecules. RESULTS Three molecular subtypes related to ESCA prognosis were determined. Based on multiple analyses among molecular subtypes, 146 DEGs were screened, and a PPT network of 15 hub genes was visualized. Finally, 8 potential small-molecule drugs (BMS-754807, gefitinib, neratinib, zuclopenthixol, puromycin, sulfasalazine, and imatinib) were identified for treating ESCA. CONCLUSIONS This study applied a new approach to analyzing the relation between m6A and ESCA prognosis, providing a reference for exploring potential targets and drugs for ESCA treatment.
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Hong MH, Heo SG, Lee YG, Kim HS, Park KU, Kim HG, Ko YH, Chung IJ, Min YJ, Kim MK, Kim KR, Yoo J, Kim TM, Kim HR, Cho BC. Phase 2 study of afatinib among patients with recurrent and/or metastatic esophageal squamous cell carcinoma. Cancer 2020; 126:4521-4531. [PMID: 32749686 DOI: 10.1002/cncr.33123] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 06/26/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND The objective of the current study was to investigate the clinical activity of, safety of, and predictive biomarkers for afatinib, an irreversible pan-ErbB kinase inhibitor, in patients with recurrent and/or metastatic esophageal squamous cell carcinoma (R/M-ESCC). METHODS Patients with R/M-ESCC that was refractory to platinum-based chemotherapy were enrolled in the current multicenter, single-arm, phase 2 study and received afatinib at a dose of 40 mg/day. The primary endpoint was the objective response rate. Secondary endpoints included progression-free survival, overall survival, the disease control rate, and the safety profile. To identify predictive biomarkers, single-nucleotide variations, short insertions/deletions, and somatic copy number alterations were assessed using whole-exome sequencing and their associations with clinical outcomes were analyzed. RESULTS Among 49 enrolled patients, the objective response rate and disease control rate were 14.3% and 73.3%, respectively. With a median follow-up of 6.6 months, the median progression-free survival and overall survival were 3.4 months and 6.3 months, respectively. Treatment-related adverse events were noted to have occurred in 33 patients (67.3%), with the majority being of grade 1 to 2 (adverse events were graded and recorded based on the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). Whole-exome sequencing demonstrated that the ESCC genomes of patients who demonstrated a response to afatinib were enriched with genomic alterations of TP53 and epidermal growth factor receptor (EGFR). As a predictive marker, a score derived from TP53 disruptive mutations and EGFR amplifications and/or missense mutations demonstrated a significant association with the response to afatinib. The score based on the mutational status of EGFR and TP53 achieved a performance of an area under the curve of 0.86 in predicting the sensitivity of afatinib. CONCLUSIONS The results of the current study demonstrated that afatinib can confer modest clinical benefits with manageable toxicity in patients with platinum-resistant R/M-ESCC. Identification of TP53 alterations and EGFR amplifications may serve as predictive markers with which to identify patients with R/M-ESCC who may benefit from afatinib. LAY SUMMARY Esophageal squamous cell carcinoma (ESCC) is a type of cancer with a dismal prognosis and very limited treatment options. The clinical efficacy of afatinib was evaluated in patients with recurrent and/or metastatic ESCC, with adverse events demonstrating the modest efficacy with manageable toxicity of this irreversible, pan-ErbB kinase inhibitor. Whole-exome sequencing analysis of 41 cases of ESCC further revealed that the patients harboring epidermal growth factor receptor (EGFR) amplifications and disruptive TP53 mutations are more likely to benefit from treatment with afatinib. The results of the current study have highlighted the clinical value of EGFR and TP53 as predictive biomarkers of platinum-resistant recurrent and/or metastatic ESCC for afatinib sensitivity.
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Affiliation(s)
- Min Hee Hong
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Seong Gu Heo
- JE-UK Institute for Cancer Research, JEUK Company Ltd, Gumi-City, Kyungbuk, Korea
| | - Yun-Gyoo Lee
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyo Song Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Keon Uk Park
- Division of Hematology/Oncology, Department of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, Korea
| | - Hoon-Gu Kim
- Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Yoon Ho Ko
- Division of Oncology, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ik-Joo Chung
- Department of Hemato-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Young Joo Min
- Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Min Kyoung Kim
- Department of Internal Medicine, Yeungnam University Medical Center, Daegu, Korea
| | - Kyu Ryung Kim
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jinseon Yoo
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Tae-Min Kim
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hye Ryun Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Byoung Chul Cho
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.,JE-UK Institute for Cancer Research, JEUK Company Ltd, Gumi-City, Kyungbuk, Korea
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Hsu A, Chudasama R, Almhanna K, Raufi A. Targeted therapies for gastroesophageal cancers. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1104. [PMID: 33145323 PMCID: PMC7576008 DOI: 10.21037/atm-20-3265] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/30/2020] [Indexed: 12/18/2022]
Abstract
Gastroesophageal cancers are some of the most common malignancies worldwide. A significant portion of patients are diagnosed with advanced or metastatic disease given the insidious nature of gastroesophageal cancers. In the instance where surgical resection for cure is no longer an option, the prognosis is poor and generally less than a year. Traditionally, standard front-line chemotherapy included two- to three-drug regimens with modest improvements in overall survival. Over the past two decades, with increased understanding of the biology of cancer, targeted therapies have been developed to stop the actions of molecules that are key in the growth and spread of cancer cells and have been successful in a number of cancers. In gastroesophageal cancer, these gains have been more modest with limited approval-trastuzumab being incorporated into front-line use in HER2-positive disease, and ramucirumab alone or in combination with paclitaxel becoming the preferred second-line regimen in progressive disease. However, with increased understanding of the biology of cancer, new and promising targeted therapies have emerged along with novel strategies in combining targeted therapies with traditional chemotherapy and immunotherapy. In this article, we will review the use of targeted therapies in the treatment of gastroesophageal cancer and touch upon future treatment strategies and therapeutics currently under investigation.
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Affiliation(s)
- Andrew Hsu
- Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Rhode Island Hospital, Providence, RI, USA
| | - Rani Chudasama
- Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Rhode Island Hospital, Providence, RI, USA
| | - Khaldoun Almhanna
- Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Rhode Island Hospital, Providence, RI, USA
| | - Alexander Raufi
- Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Rhode Island Hospital, Providence, RI, USA
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Wang Q, Zhang P, Li Z, Feng X, Lv C, Zhang H, Xiao H, Ding J, Chen X. Evaluation of Polymer Nanoformulations in Hepatoma Therapy by Established Rodent Models. Theranostics 2019; 9:1426-1452. [PMID: 30867842 PMCID: PMC6401493 DOI: 10.7150/thno.31683] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 01/08/2019] [Indexed: 01/10/2023] Open
Abstract
Hepatoma is one of the most severe malignancies usually with poor prognosis, and many patients are insensitive to the existing therapeutic agents, including the drugs for chemotherapy and molecular targeted therapy. Currently, researchers are committed to developing the advanced formulations with controlled drug delivery to improve the efficacy of hepatoma therapy. Numerous inoculated, induced, and genetically engineered hepatoma rodent models are now available for formulation screening. However, animal models of hepatoma cannot accurately represent human hepatoma in terms of histological characteristics, metastatic pathways, and post-treatment responses. Therefore, advanced animal hepatoma models with comparable pathogenesis and pathological features are in urgent need in the further studies. Moreover, the development of nanomedicines has renewed hope for chemotherapy and molecular targeted therapy of advanced hepatoma. As one kind of advanced formulations, the polymer-based nanoformulated drugs have many advantages over the traditional ones, such as improved tumor selectivity and treatment efficacy, and reduced systemic side effects. In this article, the construction of rodent hepatoma model and much information about the current development of polymer nanomedicines were reviewed in order to provide a basis for the development of advanced formulations with clinical therapeutic potential for hepatoma.
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Affiliation(s)
- Qilong Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, P. R. China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Ping Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, P. R. China
| | - Zhongmin Li
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Xiangru Feng
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
| | - Chengyue Lv
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
| | - Huaiyu Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Haihua Xiao
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, P. R. China
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Lei Y, Guo W, Chen B, Chen L, Gong J, Li W. Tumor‑released lncRNA H19 promotes gefitinib resistance via packaging into exosomes in non‑small cell lung cancer. Oncol Rep 2018; 40:3438-3446. [PMID: 30542738 PMCID: PMC6196604 DOI: 10.3892/or.2018.6762] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 09/19/2018] [Indexed: 02/05/2023] Open
Abstract
Currently, resistance to tyrosine kinase inhibitors, such as gefitinib, has become one major obstacle for improving the clinical outcome of patients with metastatic and advanced-stage non-small cell lung cancer (NSCLC). While cell behavior can be modulated by long non-coding RNAs (lncRNAs), the contributions of lncRNAs within extracellular vesicles (exosomes) are largely unknown. To this end, the involvement and regulatory functions of lncRNA H19 wrapped by exosomes during formation of gefitinib resistance in human NSCLC were investigated. Gefitinib-resistant cell lines were built by continuously grafting HCC827 and HCC4006 cells into gefitinib-contained culture medium. RT-qPCR assays indicated that H19 was increased in gefitinib-resistant cells when compared to sensitive parent cells. Functional experiments revealed that silencing of H19 potently promoted gefitinib-induced cell cytotoxicity. H19 was secreted by packaging into exosomes and this packaging process was specifically mediated by hnRNPA2B1. H19 wrapped in exosomes could be transferred to non-resistant cells, thus inducing gefitinib resistance. Moreover, treatment-sensitive cells with exosomes highly-expressing H19 induced gefitinib resistance, while knockdown of H19 abrogated this effect. In conclusion, H19 promoted gefitinib resistance of NSCLC cells by packaging into exosomes. Therefore, exosomal H19 may be a promising therapeutic target for EGFR+ NSCLC patients.
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Affiliation(s)
- Yi Lei
- International Medical Center/Department of General Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Wang Guo
- International Medical Center/Department of General Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Bowang Chen
- International Medical Center/Department of General Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lu Chen
- International Medical Center/Department of General Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jiaxin Gong
- International Medical Center/Department of General Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Weimin Li
- Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Kentepozidis N, Economopoulou P, Liontos M, Kotsakis A, Boukovinas I, Vardakis N, Kontopodis E, Prinarakis E, Skaltsi T, Souglakos J, Georgoulias V. Panitumumab in combination with modified docetaxel/cisplatin/5-fluorouracil as first-line treatment in gastric and gastroesophageal junction adenocarcinomas: a multicenter phase II study by the Hellenic Oncology Research Group. Ann Gastroenterol 2018; 31:698-704. [PMID: 30386120 PMCID: PMC6191861 DOI: 10.20524/aog.2018.0311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 06/29/2018] [Indexed: 12/21/2022] Open
Abstract
Background A phase I/II study to define the maximum tolerated dose (MTD) of biweekly docetaxel/cisplatin/5-fluorouracil (DCF) plus panitumumab (P), its efficacy, and tolerability as first-line treatment in advanced gastroesophageal cancer. Methods In phase I part, patients with unresectable locally advanced or metastatic adenocarcinomas of the stomach or the gastroesophageal junction received cisplatin (40 mg/m2 on day 1), leucovorin (400 mg/m2 on day 1), 5-fluorouracil (400 mg/m2 bolus on day 1), 5-fluorouracil (1000 mg/m2/daycontinuous infusion on days 1-2), and escalated doses of docetaxel (on day 1) plus P (6 mg/kg on day 1) every 2 weeks. In phase II part, patients were treated with DCF/P at the MTD and the primary endpoint was response rate. The expected response rate was set at >40%. Results The MTD for docetaxel in the mDCF/P was defined at 40 mg/m2 and a total of 40 evaluable patients were enrolled in phase II study. One (2.5%) complete and 13 (32.5%) partial responses (overall response rate: 35%), as well as 16 (40%) disease stabilizations were documented. The median progression-free survival was 6.9 months (95% confidence interval [CI] 3.5-10.3) and the median overall survival was 11.3 months (95%CI 7.7-14.8). Grade 3-4 neutropenia occurred in 10 patients (25%) and febrile neutropenia in 2 (5%). Allergic reactions (grade 1-4) occurred in 9 patients (22.5%). There was 1 treatment-related death. Conclusions mDCF/P combination was feasible, though associated with a poor toxicity profile. However, the study failed to meet its primary endpoint and was terminated prematurely due to futility.
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Zhu H, Wang C, Wang J, Chen D, Deng J, Deng J, Fan J, Badakhshi H, Huang X, Zhang L, Cai J, Guo S, Qian W, Nie Y, Li Q, Zhao K. A subset of esophageal squamous cell carcinoma patient-derived xenografts respond to cetuximab, which is predicted by high EGFR expression and amplification. J Thorac Dis 2018; 10:5328-5338. [PMID: 30416780 DOI: 10.21037/jtd.2018.09.18] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal tumors, but most targeted therapies showed no efficacy in non-selected patients. This study aims at investigating the adaptive cetuximab subset in a cohort of esophageal squamous cell carcinoma (ESCC) patient-derived xenografts (PDXs). Methods A large panel of ESCC PDXs has been established. The copy number, mRNA expression and immunohistochemistry (IHC) of key EGFR pathways have been examined along with cetuximab response. A preclinical trial on a randomly selected cohort of 16 ESCC PDXs was conducted, and the genomic annotations of these models were compared against the efficacy readout of the mouse trial. Results The trial identified that 7 of 16 (43.8%) responded to cetuximab (ΔT/ΔC <0 as responders). The gene amplification and expression analysis indicated that EGFR copy number ≥5 (P=0.035), high EGFR mRNA expression (P=0.001) and IHC score of 2-3 (P=0.034) are associated with tumor growth inhibition by cetuximab, suggesting EGFR may function as a single predictive biomarker for cetuximab response in ESCC. Conclusions Overall, our results suggest that an ESCC subtype with EGFR amplification and overexpression benefits from cetuximab treatment, which warrants further clinical confirmation.
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Affiliation(s)
- Hanting Zhu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Chunyu Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | | | - Dawei Chen
- Crown Bioscience, Inc., San Diego, CA, USA
| | - Jiaying Deng
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | | | - Jianhong Fan
- Department of Gynaecology, Renhe Hospital, Shanghai 200431, China
| | - Harun Badakhshi
- Department of Radiation Oncology, Charité School of Medicine and Centre for Cancer Medicine, Berlin, Germany
| | | | | | - Jie Cai
- Crown Bioscience, Inc., San Diego, CA, USA
| | - Sheng Guo
- Crown Bioscience, Inc., San Diego, CA, USA
| | - Wubin Qian
- Crown Bioscience, Inc., San Diego, CA, USA
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digest Diseases, Fourth Military Medical University, Xi'an 710032, China
| | - Qixiang Li
- Crown Bioscience, Inc., San Diego, CA, USA.,State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
| | - Kuaile Zhao
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Kang M, Ren M, Li Y, Fu Y, Deng M, Li C. Exosome-mediated transfer of lncRNA PART1 induces gefitinib resistance in esophageal squamous cell carcinoma via functioning as a competing endogenous RNA. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:171. [PMID: 30049286 PMCID: PMC6063009 DOI: 10.1186/s13046-018-0845-9] [Citation(s) in RCA: 155] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 04/28/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Currently, resistance to tyrosine kinase inhibitors, such as gefitinib, has become a major obstacle in improving the clinical outcome of patients with metastatic and advanced-stage esophageal squamous cell carcinoma (ESCC). While cell behavior can be modulated by long non-coding RNAs (lncRNAs), the roles of lncRNAs within extracellular vesicles (exosomes) are largely unknown. Therefore, we investigated the involvement and regulatory functions of potential lncRNAs enclosed in exosomes during formation of chemoresistance in human ESCC. METHODS Gefitinib-resistant cell lines were established by continuously grafting TE1 and KYSE-450 cells into gefitinib-containing culture medium. LncRNA microarray assay followed by RT-qPCR were used to verify the differential expression of lncRNA Prostate Androgen-Regulated Transcript 1 (PART1) between gefitinib resistant and parental cell lines. RNA fluorescence in situ hybridization (FISH) was used to investigate whether extracellular PART1 could be incorporated into exosomes and transmitted to recipient cells. Subsequently, a series of in vitro assays and a xenograft tumor model were used to observe the functions of lncRNA PART1 in ESCC cells. A signal transduction reporter array, bioinformatics analysis, western blotting, and immunofluorescence were carried out to verify the regulation of PART1 and its downstream Bcl-2 signaling pathway. RESULTS lncRNA PART1 was upregulated in gefitinib-resistant cells when compared to parental ESCC cells. It was found that STAT1 can bind to the promoter region of lncRNA PART1, resulting in its activation. Knockdown of lncRNA PART1 potently promoted the gefitinib-induced cell death, while elevated PART1 promoted gefitinib resistance by competitively binding to miR-129 to facilitate Bcl-2 expression in ESCC cells. In addition, extracellular PART1 could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating gefitinib resistance. Clinically, high levels of serum lncRNA PART1 in exosome were associated with poor response to gefitinib treatment in ESCC patients. CONCLUSIONS LncRNA PART1 promotes gefitinib resistance by regulating miR-129/Bcl-2 pathway, and may serve as a therapeutic target for ESCC patients.
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Affiliation(s)
- Min Kang
- Department of Digestive Diseases, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
| | - Meiping Ren
- Drug Discivery Research Center, Southwest Medical University, Luzhou, Sichuan, China
| | - Yan Li
- Molecular Medicine Experimental Center, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yuqiong Fu
- Department of Respiratory Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Minmin Deng
- Department of Digestive Diseases, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Changping Li
- Department of Digestive Diseases, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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11
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Gkolfinopoulos S, Papamichael D, Papadimitriou K, Papanastasopoulos P, Vassiliou V, Kountourakis P. Advances in molecular, genetic and immune signatures of gastric cancer: Are we ready to apply them in our patients' decision making? World J Gastrointest Oncol 2018; 10:172-183. [PMID: 30079143 PMCID: PMC6068857 DOI: 10.4251/wjgo.v10.i7.172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/16/2018] [Accepted: 06/13/2018] [Indexed: 02/05/2023] Open
Abstract
In the last few years we have witnessed a vast expansion of our knowledge regarding the molecular and genetic profile of gastric cancer. The molecular subtypes described have shed light on the pathogenesis of the disease, thus prompting the development of new therapeutic strategies and favoring a more individualized approach for treatment. Most of the clinical trials for so called targeted therapies could be considered, at best, partially successful. In addition, checkpoint inhibitors have recently been added to our armamentarium in later stages of the disease, and combinations with chemotherapy and targeted agents are currently under development. In view of the rapid advances of molecular oncology, a new challenge for the clinical oncologist arises: The appropriate patient selection for each new therapy, which can be made possible only through the implementation of predictive biomarkers in our therapy decision making.
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12
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Wang L, Zhang H, Zheng J, Wei X, Du J, Lu H, Sun Q, Zhou W, Zhang R, Han Y. Dual silencing of EGFR and HER2 enhances the sensitivity of gastric cancer cells to gefitinib. Mol Carcinog 2018; 57:1008-1016. [PMID: 29637613 DOI: 10.1002/mc.22821] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 03/16/2018] [Accepted: 04/04/2018] [Indexed: 01/06/2023]
Affiliation(s)
- Liying Wang
- Department of Oncology; Chaoyang Central Hospital; Chaoyang Liaoning Province China
| | - Hongfeng Zhang
- Department of Gastric Surgery; Harbin Medical University Cancer Hospital; Harbin Heilongjiang Province China
| | - Jiaxin Zheng
- Department of Nephrology; Heilongjiang Academy of Traditional Chinese Medicine; Harbin Heilongjiang Province China
| | - Xiaoli Wei
- Department of Gastrointestinal Oncology; Harbin Medical University Cancer Hospital; Harbin Heilongjiang Province China
| | - Jingwen Du
- Department of Gastrointestinal Oncology; Harbin Medical University Cancer Hospital; Harbin Heilongjiang Province China
| | - Haibo Lu
- Department of Gastrointestinal Oncology; Harbin Medical University Cancer Hospital; Harbin Heilongjiang Province China
| | - Qiuying Sun
- Department of Gastrointestinal Oncology; Harbin Medical University Cancer Hospital; Harbin Heilongjiang Province China
| | - Weiyu Zhou
- Department of Gastrointestinal Oncology; Harbin Medical University Cancer Hospital; Harbin Heilongjiang Province China
| | - Rui Zhang
- Department of Colorectal Surgery; Cancer Hospital of China Medical University; Liaoning Cancer Hospital and Institute; Shenyang Liaoning Province China
| | - Yu Han
- Department of Gastrointestinal Oncology; Harbin Medical University Cancer Hospital; Harbin Heilongjiang Province China
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13
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Abstract
Gastroesophageal cancer (GEC) remains a major cause of cancer-related mortality worldwide. Although the incidence of distal gastric adenocarcinoma (GC) is declining in the United States, proximal esophagogastric junction adenocarcinoma (EGJ) is increasing in incidence. GEC, including GC and EGJ, is treated uniformly in the metastatic setting. Overall survival in the metastatic setting remains poor. Molecular characterization of GEC has identified mutations and copy number variations, along with other oncogenes, biomarkers, and immuno-oncologic checkpoints that may serve as actionable therapeutic targets. This article reviews these key aberrations, their impact on protein expression, therapeutic implications, and clinical directions within each pathway.
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Affiliation(s)
- Steven B Maron
- Section of Hematology/Oncology, University of Chicago Comprehensive Cancer Center, 900 E 57th St, Suite 7128, Chicago, IL 60637, USA
| | - Daniel V T Catenacci
- Section of Hematology/Oncology, University of Chicago Comprehensive Cancer Center, 900 E 57th St, Suite 7128, Chicago, IL 60637, USA.
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14
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Pinto MP, Owen GI, Retamal I, Garrido M. Angiogenesis inhibitors in early development for gastric cancer. Expert Opin Investig Drugs 2017; 26:1007-1017. [PMID: 28770623 DOI: 10.1080/13543784.2017.1361926] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Angiogenesis, or the generation of new blood vessels from pre-existent ones is a critical process for tumor growth and progression. Hence, the development of angiogenesis inhibitors with therapeutic potential has been a central focus for researchers. Most angiogenesis inhibitors target the Vascular Endothelial Growth Factor (VEGF) pathway, however a number of tyrosine kinase inhibitors (TKIs), immunomodulatory drugs (IMiDs) and inhibitors of the mammalian Target-Of-Rapamycin (mTOR) pathway also display antiangiogenic activity. Areas covered: Here we review the effectiveness of a variety of compounds with antiangiogenic properties in preclinical and clinical settings in gastric cancer (GC). Expert opinion: In coming years angiogenesis will remain as a therapeutic target in GC. To date, ramucirumab a monoclonal antibody that targets VEGFR2 is the most successful antiangiogenic tested in clinical studies, and it is now well established as a second-line therapy in GC. The arrival of precision medicine and the success of immune checkpoint inhibitors will increase the number of clinical trials using targeted agents like ramucirumab in combination with immune checkpoint inhibitors. A hypothetical working model that combines ramucirumab with immunotherapy is presented. Also, the impact of nanotechnology and a molecular subtype classification of GC are discussed.
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Affiliation(s)
- Mauricio P Pinto
- a School of Biological Sciences, Department of Physiology , Pontificia Universidad Católica de Chile , Santiago , Chile
- b Center UC for Investigation in Oncology (CITO) , Pontificia Universidad Católica de Chile , Santiago , Chile
- c School of Chemistry and Biology, Laboratory on the Immunology of Reproduction , Universidad de Santiago de Chile, Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Gareth I Owen
- a School of Biological Sciences, Department of Physiology , Pontificia Universidad Católica de Chile , Santiago , Chile
- b Center UC for Investigation in Oncology (CITO) , Pontificia Universidad Católica de Chile , Santiago , Chile
- d School of Medicine, Department of Hematology and Oncology , Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Ignacio Retamal
- b Center UC for Investigation in Oncology (CITO) , Pontificia Universidad Católica de Chile , Santiago , Chile
- d School of Medicine, Department of Hematology and Oncology , Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Marcelo Garrido
- b Center UC for Investigation in Oncology (CITO) , Pontificia Universidad Católica de Chile , Santiago , Chile
- d School of Medicine, Department of Hematology and Oncology , Pontificia Universidad Católica de Chile , Santiago , Chile
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15
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Abstract
Gastroesophageal cancer (GEC) remains a major cause of cancer-related mortality worldwide. Although the incidence of distal gastric adenocarcinoma (GC) is declining in the United States, proximal esophagogastric junction adenocarcinoma (EGJ) incidence is rising. GC and EGJ, together, are treated uniformly in the metastatic setting as GEC. Overall survival in the metastatic setting remains poor, with few molecular targeted approaches having been successfully incorporated into routine care to date-only first-line anti-HER2 therapy for ERBB2 amplification and second-line anti-VEGFR2 therapy. This article reviews aberrations in epidermal growth factor receptor, MET, and ERBB2, their therapeutic implications, and future directions in targeting these pathways.
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Affiliation(s)
- Steven B Maron
- Section of Hematology/Oncology, University of Chicago Comprehensive Cancer Center, 5841 South Maryland Avenue, Chicago, IL 60637, USA
| | - Daniel V T Catenacci
- The University of Chicago Medical Center & Biological Sciences, 900 East 57th Street, KCBD Building, Office 7128, Chicago, IL 60637, USA.
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16
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Pasini F, Fraccon AP, Modena Y, Bencivenga M, Giacopuzzi S, La Russa F, Gusella M, de Manzoni G. Targeted therapies for advanced and metastatic adenocarcinoma of the gastroesophageal junction: is there something new? Gastric Cancer 2017; 20:31-42. [PMID: 27568322 DOI: 10.1007/s10120-016-0626-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Accepted: 08/02/2016] [Indexed: 02/07/2023]
Abstract
Despite improvements in systemic chemotherapy (CT), the prognosis of metastatic adenocarcinoma of the gastroesophageal junction remains poor. Over the years, new targeting agents have become available and were tested, with or without CT, in first or subsequent lines of therapy. The epidermal growth factor receptor family was targeted with monoclonal antibodies (MoAbs) (trastuzumab, cetuximab, panitumumab) and tyrosin kinase inhibitors (TKIs) (lapatinib, erlotinib, gefitinib). Only trastuzumab, in combination with cisplatin and fluoropyrimidines, significantly improved overall survival (OS) in first-line therapy (13.8 vs. 11.1 months). Angiogenesis also was targeted with MoAbs (bevacizumab and ramucirumab); ramucirumab, a vascular endothelial growth factor-receptor 2 antagonist, enhanced OS in two phase III studies in the first (9.6 vs. 7.4 months) and subsequent lines of treatment (5.2 vs. 3.8 months), while the bevacizumab study was negative. TKIs (sunitinib, sorafenib, regorafenib, apatinib) were tested in this setting in phase II studies in the second/third line, only showing modest antitumor activity. The hepatocyte growth factor receptor (MET) was targeted in untreated patients in a phase III trial with MoAb rilotumumab, with or without CT, but the study was stopped because of mortality excess in the rilotumumab arm. Mammalian target of rapamycin (MTOR) pathway inhibition with everolimus was tested in pretreated patients in a placebo-controlled phase III trial who failed to improve OS (5.4 vs. 4.3 months). In conclusion, considering the modest survival gain obtained overall, the high cost of these therapies and the quality of life issue must be primarily considered in treating these patients.
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Affiliation(s)
- Felice Pasini
- Department of Medical Oncology, Ospedale S. Maria della Misericordia, Viale Tre Martiri, 140-45100, Rovigo, Italy.
| | - Anna Paola Fraccon
- Medical Oncology Unit, Casa di Cura Pederzoli, Peschiera del Garda, Verona, Italy
| | - Yasmina Modena
- Department of Medical Oncology, Ospedale S. Maria della Misericordia, Viale Tre Martiri, 140-45100, Rovigo, Italy
| | - Maria Bencivenga
- General and Upper GI Surgery Division, University of Verona, Verona, Italy
| | - Simone Giacopuzzi
- General and Upper GI Surgery Division, University of Verona, Verona, Italy
| | - Francesca La Russa
- Department of Medical Oncology, Ospedale S. Maria della Misericordia, Viale Tre Martiri, 140-45100, Rovigo, Italy
| | - Milena Gusella
- Department of Medical Oncology, Ospedale S. Maria della Misericordia, Viale Tre Martiri, 140-45100, Rovigo, Italy
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17
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Hwang J. Beyond HER2: recent advances and future directions in targeted therapies in esophagogastric cancers. J Gastrointest Oncol 2016; 7:763-770. [PMID: 27747090 PMCID: PMC5056259 DOI: 10.21037/jgo.2016.08.13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 06/06/2016] [Indexed: 12/19/2022] Open
Abstract
Esophagogastric cancers (EGCa) are a leading cause of cancer related mortality worldwide. It has been recognized that they represent heterogenous diseases based on histology and anatomy. However, it is also increasingly evident that these are diverse malignancies based on genetic alterations, and this is increasingly making these diseases amenable to targeted therapies. While epidermal growth factor receptor (EGFR) and mTOR inhibitors have failed to prove effective in the treatment of advanced EGCa, vascular endothelial growth factor (VEGF) inihibitor have now been demonstrated to improve survival, at least in the 2nd line setting of adenocarcinomas. Other promising approaches are being investigated, including targeted therapies such as MET and FGFR inhibitors, as well as immunotherapy and agents that may affect synthetic lethality.
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Affiliation(s)
- Jimmy Hwang
- Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC 28204, USA
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18
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Riquelme I, Saavedra K, Espinoza JA, Weber H, García P, Nervi B, Garrido M, Corvalán AH, Roa JC, Bizama C. Molecular classification of gastric cancer: Towards a pathway-driven targeted therapy. Oncotarget 2016; 6:24750-79. [PMID: 26267324 PMCID: PMC4694793 DOI: 10.18632/oncotarget.4990] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 07/17/2015] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer mortality worldwide. Although surgical resection is a potentially curative approach for localized cases of GC, most cases of GC are diagnosed in an advanced, non-curable stage and the response to traditional chemotherapy is limited. Fortunately, recent advances in our understanding of the molecular mechanisms that mediate GC hold great promise for the development of more effective treatment strategies. In this review, an overview of the morphological classification, current treatment approaches, and molecular alterations that have been characterized for GC are provided. In particular, the most recent molecular classification of GC and alterations identified in relevant signaling pathways, including ErbB, VEGF, PI3K/AKT/mTOR, and HGF/MET signaling pathways, are described, as well as inhibitors of these pathways. An overview of the completed and active clinical trials related to these signaling pathways are also summarized. Finally, insights regarding emerging stem cell pathways are described, and may provide additional novel markers for the development of therapeutic agents against GC. The development of more effective agents and the identification of biomarkers that can be used for the diagnosis, prognosis, and individualized therapy for GC patients, have the potential to improve the efficacy, safety, and cost-effectiveness for GC treatments.
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Affiliation(s)
- Ismael Riquelme
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Kathleen Saavedra
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Jaime A Espinoza
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Helga Weber
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Patricia García
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Bruno Nervi
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marcelo Garrido
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alejandro H Corvalán
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
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19
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Pectasides E. Genomic Alterations and Targeted Therapy in Gastric and Esophageal Adenocarcinoma. Clin Ther 2016; 38:1589-99. [PMID: 27041412 DOI: 10.1016/j.clinthera.2016.03.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 03/07/2016] [Accepted: 03/08/2016] [Indexed: 12/18/2022]
Abstract
PURPOSE Gastric and esophageal adenocarcinomas are common and aggressive malignancies. Systemic therapy for these tumors is based primarily on cytotoxic chemotherapy, but outcomes remain poor. Precision medicine, where treatments are tailored to specific molecular abnormalities of tumors, holds great promise for improving outcomes in this disease. METHODS A search was performed in PubMed to identify studies that have characterized the molecular basis of gastric and esophageal adenocarcinoma, as well as clinical trials exploring targeted therapies in this disease. FINDINGS Recent genomic studies have identified potentially targetable genomic alterations in gastroesophageal adenocarcinoma. Specifically, The Cancer Genome Atlas study defined 4 subgroups of gastric cancer, each harboring distinct genomic features. However, development of targeted therapies for gastroesophageal cancer has been challenging. The only biomarker-driven therapy in clinical practice, trastuzumab for the ~15% of patients with human epidermal growth factor receptor 2-positive disease, is modestly effective, extending median overall survival by 2.7 months. Clinical trials of other targeted therapies, including epidermal growth factor receptor, fibroblast growth factor receptor 2, and MET inhibitors, have had disappointing results so far. IMPLICATIONS The availability of genomic tools provides an unprecedented opportunity to develop new rational therapeutic strategies. New trial designs of targeted therapies in biomarker-selected patient populations have the potential to improve outcomes in this lethal disease. As these clinical trials are being developed, it is increasingly important to incorporate correlative studies that will allow us to identify biomarkers of response or resistance to targeted therapies.
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Affiliation(s)
- Eirini Pectasides
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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20
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Huang J, Fan Q, Lu P, Ying J, Ma C, Liu W, Liu Y, Tan F, Sun Y. Icotinib in Patients with Pretreated Advanced Esophageal Squamous Cell Carcinoma with EGFR Overexpression or EGFR Gene Amplification: A Single-Arm, Multicenter Phase 2 Study. J Thorac Oncol 2016; 11:910-7. [PMID: 26980473 DOI: 10.1016/j.jtho.2016.02.020] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 02/23/2016] [Accepted: 02/25/2016] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Epidermal growth factor receptor (EGFR) has been reported to be overexpressed and amplified in a high percentage of patients with esophageal squamous cell carcinoma (ESCC). The activity of icotinib, an EGFR tyrosine kinase inhibitor, was assessed in previously treated ESCC with EGFR overexpression or amplification. METHODS For this phase 2, single-arm, multicenter trial undertaken at six hospitals in China, we included Chinese patients with previously treated, histologically confirmed advanced ESCC and EGFR overexpression (immunohistochemical staining sore of 3+) or amplification (positive fluorescence in situ hybridization result). These patients received oral icotinib (250 mg, three times daily).The primary end point was the proportion of patients with objective responses as assessed by an independent radiology review committee. RESULTS Between December 5, 2013, and May 28, 2015, a total of 281 patients were screened. Fifty-four eligible patients were enrolled. Nine responses were observed, including one complete response and eight partial responses, and 16 patients had stable disease, resulting in a 16.7% objective response rate (95% confidence interval [CI]: 6.7-26.6) and 46.3% disease control rate (95% CI: 33.0-59.6). The median progression-free survival and overall survival times were 52 (95% CI: 40-95) days and 153 (95% CI: 139-218) days, respectively. A total of 43 patients experienced at least one adverse event, but most were only grade 1 to 2 in severity. The most frequent was rash (48.1%), followed by diarrhea (22.2%). CONCLUSIONS Icotinib showed favorable activity in patients with advanced, previously treated ESCC with EGFR overexpression or amplification. These findings suggest further research into EGFR overexpression or amplification for selecting responsive patients.
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Affiliation(s)
- Jing Huang
- Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Qingxia Fan
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Ping Lu
- Department of Oncology, First Affiliated Hospital of Xinxiang Medical University, Xinxiang, People's Republic of China
| | - Jianming Ying
- Department of Pathology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Changwu Ma
- Department of Medical Oncology, Chifeng Municipal Hospital, Chifeng, People's Republic of China
| | - Wei Liu
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Ying Liu
- Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou, People's Republic of China
| | - Fenlai Tan
- Betta Pharmaceuticals Co., Ltd, Hangzhou, People's Republic of China
| | - Yan Sun
- Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
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21
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Expression and Prognostic Significance of Human Epidermal Growth Factor Receptors 1 and 3 in Gastric and Esophageal Adenocarcinoma. PLoS One 2016; 11:e0148101. [PMID: 26844548 PMCID: PMC4742525 DOI: 10.1371/journal.pone.0148101] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 01/13/2016] [Indexed: 01/08/2023] Open
Abstract
Background Gastric and esophageal adenocarcinomas are major global cancer burdens. These cancer forms are characterized by a poor prognosis and a modest response to chemo- radio- and targeted treatment. Hence there is an obvious need for further enhanced diagnostic and treatment strategies. The aim of this study was to examine the expression and prognostic impact of human epidermal growth factor receptor 1 (HER1/EGFR) and 3 (HER3), as well as the occurrence of EGFR and KRAS mutations in gastric and esophageal adenocarcinoma. Methods Immunohistochemical expression of EGFR and HER3 was analysed in all primary tumours and a subset of lymph node metastases in a consecutive cohort of 174 patients with adenocarcinoma of the stomach, cardia and esophagus. The anti-HER3 antibody used was validated by siRNA-mediated knockdown, immunohistochemistry and quantitative real-time PCR. EGFR and KRAS mutation status was analysed by pyrosequencing tecchnology. Results and Discussion High EGFR expression was an independent risk factor for shorter overall survival (OS), whereas high HER3 expression was associated with a borderline significant trend towards a longer OS. KRAS mutations were present in only 4% of the tumours and had no prognostic impact. All tumours were EGFR wild-type. These findings contribute to the ongoing efforts to decide on the potential clinical value of different HERs and druggable mutations in gastric and esophageal adenocarcinomas, and attention is drawn to the need for more standardised investigational methods.
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22
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Kim HS, Kim SM, Kim H, Pyo KH, Sun JM, Ahn MJ, Park K, Keam B, Kwon NJ, Yun HJ, Kim HG, Chung IJ, Lee JS, Lee KH, Kim DJ, Lee CG, Hur J, Chung H, Park JC, Shin SK, Lee SK, Kim HR, Moon YW, Lee YC, Kim JH, Paik S, Cho BC. Phase II clinical and exploratory biomarker study of dacomitinib in recurrent and/or metastatic esophageal squamous cell carcinoma. Oncotarget 2015; 6:44971-84. [PMID: 26462025 PMCID: PMC4792605 DOI: 10.18632/oncotarget.6056] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 09/23/2015] [Indexed: 12/14/2022] Open
Abstract
The purpose of this study was to investigate the clinical activity, safety and predictive biomarkers of dacomitinib, an irreversible pan-HER inhibitor, in patients with recurrent or metastatic esophageal squamous cell carcinoma (R/M-ESCC). Patients, whose diseases were not amenable to curative treatment and had progressed on platinum-based chemotherapy, were treated with dacomitinib 45 mg/day. The primary endpoint was objective response rate by RECISTv 1.1. Predictive biomarker analyses included the characterization of somatic mutations and gene expression using the Ion Torrent AmpliSeq Cancer Hotspot Panel and Nanostring nCounter, and investigation of their relationship with clinical outcomes. Of the 48 evaluable patients, 6 (12.5%) achieved partial responses and 29 (60.4%) had stable disease. The median response duration was 7.1 months. The median progression free survival (PFS) and overall survival (OS) was 3.3 months (95% CI, 2.4-4.3 months) and 6.4 months (95% CI, 4.4-8.4 months). Adverse events were mostly grade 1-2. Gene set enrichment analysis revealed that ERBB signaling pathway is significantly enriched in patients with PFS ≥ 4 months (n = 12) than PFS < 4 months (n = 21) (p < 0.001). Upregulation of ERBB signaling pathway was significantly associated with longer PFS (5.0 vs. 2.9 months, P = 0.016) and OS (10.0 vs. 4.8 months, P = 0.022). The most frequent mutations were TP53 (61%) followed by CDKN2A (8%), MLH1 (8%), FLT3 (8%) and EGFR (8%). Dacomitinib demonstrated clinical efficacy with manageable toxicity in platinum-failed R/M-ESCC. Screening of ERBB pathway-related gene expression profiles may help identify patients who are most likely benefit from dacomitinib.
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Affiliation(s)
- Hyo Song Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Sung-Moo Kim
- Yonsei Cancer Research Institute, JE-UK Laboratory of Molecular Cancer Therapeutics, Seoul, Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Kyoung-Ho Pyo
- Yonsei Cancer Research Institute, JE-UK Laboratory of Molecular Cancer Therapeutics, Seoul, Korea
| | - Jong-Mu Sun
- Department of Hematology-Oncology, Samsung Medical Center, Seoul, Korea
| | - Myung-Ju Ahn
- Department of Hematology-Oncology, Samsung Medical Center, Seoul, Korea
| | - Keunchil Park
- Department of Hematology-Oncology, Samsung Medical Center, Seoul, Korea
| | - Bhumsuk Keam
- Department of Hematology-Oncology, Seoul National University Hospital, Seoul, Korea
| | | | - Hwan Jung Yun
- Division of Hemato-Oncology, Chungnam National University Hospital, Daejeon, Korea
| | - Hoon-Gu Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Gyeongnam Regional Cancer Center, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Ik-Joo Chung
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, South Korea
| | - Jong Seok Lee
- Department of Hematology-Oncology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Kyung Hee Lee
- Department of Hematology-Oncology, Yeungnam University Medical Center, Daegu, South Korea
| | - Dae Joon Kim
- Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Chang-Geol Lee
- Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea
| | - Jin Hur
- Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
| | - Hyunsoo Chung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Chul Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Kwan Shin
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Ryun Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Yong Wha Moon
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Yong Chan Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Joo Hang Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Soonmyung Paik
- Division of Pathology NSABP, Pittsburgh, PA, USA
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Byoung Chul Cho
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
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Woo J, Cohen SA, Grim JE. Targeted therapy in gastroesophageal cancers: past, present and future. Gastroenterol Rep (Oxf) 2015; 3:316-29. [PMID: 26510453 PMCID: PMC4650980 DOI: 10.1093/gastro/gov052] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 09/09/2015] [Indexed: 12/12/2022] Open
Abstract
Gastroesophageal cancer is a significant global problem that frequently presents at an incurable stage and has very poor survival with standard chemotherapy approaches. This review will examine the epidemiology and molecular biology of gastroesophageal cancer and will focus on the key deregulated signaling pathways that have been targeted in the clinic. A comprehensive overview of clinical data highlighting successes and failures with targeted agents will be presented. Most notably, HER2-targeted therapy with the monoclonal antibody trastuzumab has proven beneficial in first-line therapy and has been incorporated into standard practice. Targeting the VEGF pathway has also proven beneficial, and the VEGFR-targeted monoclonal antibody ramucirumab is now approved for second-line therapy. In contrast to these positive results, agents targeting the EGFR and MET pathways have been evaluated extensively in gastroesophageal cancer but have repeatedly failed to show benefit. An increased understanding of the molecular predictors of response to targeted therapies is sorely needed. In the future, improved molecular pathology approaches should subdivide this heterogeneous disease entity to allow individualization of cancer therapy based on integrated and global identification of deregulated signaling pathways. Better patient selection, rational combinations of targeted therapies and incorporation of emerging immunotherapeutic approaches should further improve the treatment of this deadly disease.
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Affiliation(s)
- Janghee Woo
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Division of Medical Oncology, University of Washington, Seattle, WA, USA and
| | - Stacey A Cohen
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Division of Medical Oncology, University of Washington, Seattle, WA, USA and
| | - Jonathan E Grim
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Division of Medical Oncology, University of Washington, Seattle, WA, USA and Hospital and Specialty Medicine, VA Puget Sound Health Care System, Seattle, WA, USA
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Dahle-Smith A, Petty RD. Biomarkers and novel agents in esophago-gastric cancer: are we making progress? Expert Rev Anticancer Ther 2015; 15:1103-19. [DOI: 10.1586/14737140.2015.1071669] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Guo JH, Chen MQ, Chen C, Lu HJ, Xu BH. Efficacy and toxicity of nimotuzumab combined with radiotherapy in elderly patients with esophageal squamous cell carcinoma. Mol Clin Oncol 2015; 3:1135-1138. [PMID: 26623065 DOI: 10.3892/mco.2015.606] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 06/27/2015] [Indexed: 12/25/2022] Open
Abstract
This study was conducted to assess the efficacy and toxicity of nimotuzumab combined with radiotherapy (RT) in elderly patients with esophageal squamous cell carcinoma. The clinical data of 16 esophageal squamous cell carcinoma patients, aged >70 years, who were initially treated with nimotuzumab combined with RT, were collected and retrospectively reviewed. The overall response and treatment toxicity were analyzed using SPSS software. All the patients completed the treatment schedule. The response to treatment was assessed at treatment completion and reassessed after 1-2 months: 1 patient achieved complete response (CR), 10 patients achieved partial response (PR), 4 patients exhibited stable disease and 1 patient developed disease progression and succumbed to radiation pneumonitis (RP) 1 month later. The overall response rate (CR+PR) was 68.8%. All 16 patients experienced grade 1-2 radiation esophagitis; no grade 3-4 toxicities were reported. There was one case of treatment-related mortality due to RP during the study. One patient developed a rash on the forearm. No hematological, gastrointestinal, hepatic or renal toxicities were observed. In conclusion, the toxicity of combined nimotuzumab with RT in elderly patients with esophageal cancer was tolerable. However, due to limitations associated with the retrospective nature of this study, the limited number of enrolled cases and the epidermal growth factor receptor expression determination prior to treatment, the efficacy of this treatment modality requires further investigation.
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Affiliation(s)
- Jin-Hua Guo
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Ming-Qiu Chen
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Cheng Chen
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Hai-Jie Lu
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Ben-Hua Xu
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
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26
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Prins MJD, Ruurda JP, Lolkema MP, Sitarz R, Ten Kate FJW, van Hillegersberg R. The role of biological markers of epithelial to mesenchymal transition in oesophageal adenocarcinoma, an immunohistochemical study. J Clin Pathol 2015; 68:529-35. [PMID: 25855799 DOI: 10.1136/jclinpath-2015-202962] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 03/14/2015] [Indexed: 02/05/2023]
Abstract
BACKGROUND E-cadherin, β-catenin, epidermal growth factor receptor (EGFR), neuronal cadherin (N-cadherin) and Cyclin D1 are involved in epithelial to mesenchymal transition (EMT). However, the prognostic significance of EMT markers in oesophageal adenocarcinoma (OAC) is unknown. Aim of this study was to evaluate the prognostic value of, and the association between different EMT markers in OAC. METHODS Tumour cores of 154 patients with OAC were included in a tissue microarray. Scoring criteria was based on immunohistochemical staining intensity. RESULTS EMT-associated markers were expressed in OAC: reduced membranous E-cadherin and β-catenin were seen in 11.4% and 51.7%, nuclear β-catenin in 19.1% and EGFR and Cyclin D1 overexpression in 56.5% and 27.4% of tumours. Mesenchymal marker N-cadherin was not expressed in OAC. A positive correlation was seen between membranous β-catenin and E-cadherin expression (R=0.209, p=0.001) and between EGFR and Cyclin D1 (R=0.257, p=0.002). In univariate analysis, EGFR overexpression and membranous β-catenin staining were significantly associated with a poor survival (HR 2.145; 95% CI 1.429 to 3.218, p<0.001 and HR 1.665; 95% CI 1.114 to 2.488; p=0.013). However, Cyclin D1 (HR 1.092; 95% CI 0.702 to 1.698; p=0.697), nuclear β-catenin (HR 1.322; 95% CI 0.799 to 2.189; p=0.277) and E-cadherin (HR 1.012; 95% CI 0.554 to 1.851; p=0.968) were not associated with survival. In multivariate analysis, EGFR overexpression was an independent prognostic factor for poor survival (HR 1.678; 95% CI 1.055 to 2.668; p=0.029) together with T stage (HR 2.759; 95% CI 1.356 to 5.576; p=0.005). CONCLUSIONS This study supports the presence of EMT in OAC. Moreover, EGFR overexpression was independently associated with a poor survival.
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Affiliation(s)
- M J D Prins
- Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - J P Ruurda
- Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - M P Lolkema
- Department of Medical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - R Sitarz
- Department of Surgery, Medical University of Lublin, Lublin, Poland
| | - F J W Ten Kate
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - R van Hillegersberg
- Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
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27
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Bartley AN, Hamilton SR. Select biomarkers for tumors of the gastrointestinal tract: present and future. Arch Pathol Lab Med 2014; 139:457-68. [PMID: 25333834 DOI: 10.5858/arpa.2014-0189-ra] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Advances in molecular biomarkers of the gastrointestinal tract have contributed to a decline in the incidence of and mortality from diseases of the gastrointestinal tract. The discovery and clinical validation of new biomarkers are important to personalized cancer therapy, and numerous clinical trials are currently ongoing to help identify individualized therapy affecting these biomarkers and molecular mechanisms they represent. Distinct molecular pathways leading to cancers of the colorectum, esophagus, stomach, small bowel, and pancreas have been identified. Using biomarkers in these pathways to direct patient care, including selection of proper molecular testing for identification of actionable mutations and reporting the results of these biomarkers to guide clinicians and genetic counselors, is paramount. OBJECTIVE To examine and review select clinically actionable biomarkers of the colon, esophagus, stomach, small bowel, and pancreas, including present and future biomarkers with relevant clinical trials. DATA SOURCES Extensive literature review and practical and consultation experience of the authors. CONCLUSIONS Although numerous biomarkers have been identified and are currently guiding patient therapy, few have shown evidence of clinical utility in the management of patients with gastrointestinal cancers. Inconsistent results and discordant proposed algorithms for testing were identified throughout the literature; however, the potential for biomarkers to improve outcomes for patients with gastrointestinal cancer remains high. Continued advances through high-quality studies are needed.
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Affiliation(s)
- Angela N Bartley
- From Molecular Diagnostics, Department of Pathology, St. Joseph Mercy Hospital, Ypsilanti, Michigan (Dr Bartley); and the Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas (Dr Hamilton)
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Drenckhan A, Grob T, Dupree A, Dohrmann T, Mann O, Izbicki JR, Gros SJ. Esophageal carcinoma cell line with high EGFR polysomy is responsive to gefitinib. Langenbecks Arch Surg 2014; 399:879-88. [DOI: 10.1007/s00423-014-1235-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 07/16/2014] [Indexed: 10/25/2022]
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29
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Xu Z, Huo X, Ye H, Tang C, Nandakumar V, Lou F, Zhang D, Dong H, Sun H, Jiang S, Zhang G, Liu Z, Dong Z, Guo B, He Y, Yan C, Wang L, Su Z, Li Y, Gu D, Zhang X, Wu X, Wei X, Hong L, Zhang Y, Yang J, Gong Y, Tang C, Jones L, Huang XF, Chen SY, Chen J. Genetic mutation analysis of human gastric adenocarcinomas using ion torrent sequencing platform. PLoS One 2014; 9:e100442. [PMID: 25025766 PMCID: PMC4098916 DOI: 10.1371/journal.pone.0100442] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 05/28/2014] [Indexed: 12/15/2022] Open
Abstract
Gastric cancer is the one of the major causes of cancer-related death, especially in Asia. Gastric adenocarcinoma, the most common type of gastric cancer, is heterogeneous and its incidence and cause varies widely with geographical regions, gender, ethnicity, and diet. Since unique mutations have been observed in individual human cancer samples, identification and characterization of the molecular alterations underlying individual gastric adenocarcinomas is a critical step for developing more effective, personalized therapies. Until recently, identifying genetic mutations on an individual basis by DNA sequencing remained a daunting task. Recent advances in new next-generation DNA sequencing technologies, such as the semiconductor-based Ion Torrent sequencing platform, makes DNA sequencing cheaper, faster, and more reliable. In this study, we aim to identify genetic mutations in the genes which are targeted by drugs in clinical use or are under development in individual human gastric adenocarcinoma samples using Ion Torrent sequencing. We sequenced 737 loci from 45 cancer-related genes in 238 human gastric adenocarcinoma samples using the Ion Torrent Ampliseq Cancer Panel. The sequencing analysis revealed a high occurrence of mutations along the TP53 locus (9.7%) in our sample set. Thus, this study indicates the utility of a cost and time efficient tool such as Ion Torrent sequencing to screen cancer mutations for the development of personalized cancer therapy.
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Affiliation(s)
- Zhi Xu
- Department of Oncology, The Affiliated Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xinying Huo
- Department of Oncology, The Affiliated Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Hua Ye
- San Valley Biotechnology Incorporated, Beijing, China
| | | | - Vijayalakshmi Nandakumar
- Norris Comprehensive Cancer Center, Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Feng Lou
- San Valley Biotechnology Incorporated, Beijing, China
| | - Dandan Zhang
- San Valley Biotechnology Incorporated, Beijing, China
| | - Haichao Dong
- San Valley Biotechnology Incorporated, Beijing, China
| | - Hong Sun
- San Valley Biotechnology Incorporated, Beijing, China
| | - Shouwen Jiang
- San Valley Biotechnology Incorporated, Beijing, China
| | | | - Zhiyuan Liu
- San Valley Biotechnology Incorporated, Beijing, China
| | - Zhishou Dong
- San Valley Biotechnology Incorporated, Beijing, China
| | - Baishuai Guo
- San Valley Biotechnology Incorporated, Beijing, China
| | - Yan He
- San Valley Biotechnology Incorporated, Beijing, China
| | - Chaowei Yan
- San Valley Biotechnology Incorporated, Beijing, China
| | - Lu Wang
- San Valley Biotechnology Incorporated, Beijing, China
| | - Ziyi Su
- San Valley Biotechnology Incorporated, Beijing, China
| | - Yangyang Li
- San Valley Biotechnology Incorporated, Beijing, China
| | - Dongying Gu
- Department of Oncology, The Affiliated Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xiaojing Zhang
- Department of Oncology, The Affiliated Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xiaomin Wu
- Department of Oncology, The Affiliated Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xiaowei Wei
- Department of Oncology, The Affiliated Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Lingzhi Hong
- Department of Oncology, The Affiliated Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yangmei Zhang
- Department of Oncology, The Affiliated Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jinsong Yang
- Department of Oncology, The Affiliated Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yonglin Gong
- Department of Oncology, The Affiliated Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Cuiju Tang
- Department of Oncology, The Affiliated Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Lindsey Jones
- Norris Comprehensive Cancer Center, Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Xue F. Huang
- Norris Comprehensive Cancer Center, Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Si-Yi Chen
- Norris Comprehensive Cancer Center, Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Jinfei Chen
- Department of Oncology, The Affiliated Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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Dutton SJ, Ferry DR, Blazeby JM, Abbas H, Dahle-Smith A, Mansoor W, Thompson J, Harrison M, Chatterjee A, Falk S, Garcia-Alonso A, Fyfe DW, Hubner RA, Gamble T, Peachey L, Davoudianfar M, Pearson SR, Julier P, Jankowski J, Kerr R, Petty RD. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol 2014; 15:894-904. [PMID: 24950987 DOI: 10.1016/s1470-2045(14)70024-5] [Citation(s) in RCA: 245] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare gefitinib with placebo in previously treated advanced oesophageal cancer. METHODS For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0-2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179. FINDINGS Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3·73 months, 95% CI 3·23-4·50, for gefitinib vs 3·67 months, 95% CI 2·97-4·37, for placebo; hazard ratio [HR] 0·90, 95% CI 0·74-1·09, p=0·29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference -8·61, 95% CI -14·49 to -2·73; n=227; p=0·004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2·69, 95% CI -2·33 to 7·72, n=231, p=0·293), dysphagia (-3·18, 95% CI -8·36 to 2·00, n=231, p=0·228), and eating (-4·11, 95% CI -9·96 to 1·75, n=229, p=0·168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1·57 months, 95% CI 1·23-1·90 in the gefitinib group vs 1·17 months, 95% CI 1·07-1·37 in the placebo group; HR 0·80, 95% CI 0·66-0·96, p=0·020). The most common toxicities were diarrhoea (36 [16%] of 224 patients on gefitinib vs six [3%] of 225 on placebo) and skin toxicity (46 [21%] vs two [1%]), both mostly grade 2. The commonest grade 3-4 toxicities were fatigue (24 [11%] vs 13 [6%] patients) and diarrhoea (13 [6%] vs two [1%]). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0·023). INTERPRETATION The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients. FUNDING Cancer Research UK.
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Affiliation(s)
- Susan J Dutton
- Oxford Clinical Trials Research Unit and Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Oxford, UK.
| | - David R Ferry
- Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, UK; Lilly UK, Erl Wood Manor, Windlesham, UK
| | - Jane M Blazeby
- University Hospitals Bristol NHS Foundation Trust, Bristol, UK; School of Social and Community Medicine, University of Bristol Senate House, Bristol, UK
| | - Haider Abbas
- Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, UK
| | - Asa Dahle-Smith
- University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK
| | - Wasat Mansoor
- Christie Hospital NHS Foundation Trust, Manchester, UK
| | | | | | | | - Stephen Falk
- University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | | | - David W Fyfe
- University Hospitals of Morecombe Bay, Furness General Hospital, Barrow-in-Furness, UK
| | | | - Tina Gamble
- Birmingham Heartlands Hospital, Birmingham, UK
| | - Lynnda Peachey
- Oncology Clinical Trials Office, University of Oxford, Department of Oncology, Old Road Campus Research Building, University of Oxford, Old Road Campus, Oxford, UK
| | - Mina Davoudianfar
- Oncology Clinical Trials Office, University of Oxford, Department of Oncology, Old Road Campus Research Building, University of Oxford, Old Road Campus, Oxford, UK
| | - Sarah R Pearson
- Oncology Clinical Trials Office, University of Oxford, Department of Oncology, Old Road Campus Research Building, University of Oxford, Old Road Campus, Oxford, UK
| | - Patrick Julier
- Oncology Clinical Trials Office, University of Oxford, Department of Oncology, Old Road Campus Research Building, University of Oxford, Old Road Campus, Oxford, UK
| | | | - Rachel Kerr
- Oncology Clinical Trials Office, University of Oxford, Department of Oncology, Old Road Campus Research Building, University of Oxford, Old Road Campus, Oxford, UK
| | - Russell D Petty
- University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK
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Guo YM, Yu WW, Zhu M, Guo CY. Clinicopathological and prognostic significance of epidermal growth factor receptor overexpression in patients with esophageal adenocarcinoma: a meta-analysis. Dis Esophagus 2014; 28:750-6. [PMID: 24961755 DOI: 10.1111/dote.12248] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The prognostic significance of epidermal growth factor receptor (EGFR) overexpression in patients with esophageal adenocarcinoma (EAC) remains controversial. Eligible studies that investigated the association between survival in EAC and the expression status of EGFR were identified by an electronic search of PubMed, EMBASE, and ISI Web of Science. A meta-analysis was performed to clarify the impact of EGFR overexpression on clinicopathological parameters or overall survival (OS) in EAC. A total of seven studies including 1028 patients were subjected to the final analysis. The overall results suggested that overexpression of EGFR was significantly correlated with not only the depth of invasion, lymph node status, and tumors stage of EAC, with a pooled odds ratio of 2.99 (95% confidence interval [CI]: 1.07-8.35; Z = 2.09; P = 0.037), 3.05 (95% CI: 1.77-5.27; Z = 4.00; P < 0.001), and 5.37 (95% CI: 2.49-11.57; Z = 4.29; P < 0.001), respectively, but also the poorer OS with a pooled hazard ratio of 2.20 (95% CI: 1.47-3.31; Z = 3.79; P < 0.001). Overexpression of EGFR correlates with not only the clinicopathological features, but also the worse OS, and it might be useful as a predictive biomarker in clinical practice, yet the clinicopathological and prognostic role of EGFR in EAC still needs further confirmation by well-designed prospective studies.
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Affiliation(s)
- Y-M Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - W-W Yu
- Department of Radiation Oncology, Shanghai Jiao Tong University Affiliated Sixth people's Hospital, Shanghai, China
| | - M Zhu
- Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China
| | - C-Y Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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32
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Moorcraft SY, Chau I. Investigational therapies targeting the ErbB family in oesophagogastric cancer. Expert Opin Investig Drugs 2014; 23:1349-63. [PMID: 24949530 DOI: 10.1517/13543784.2014.930126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The prognosis for patients with oesophagogastric (OG) cancer remains poor, with a median survival of approximately 9 - 11 months for patients with metastatic disease. However, a more personalised approach to treatment, using drugs tailored to the molecular characteristics of patients' tumours, has the potential to improve patient outcomes. Drugs targeting the ErbB family of receptors have been developed, but these have had varying degrees of success in clinical practice. AREAS COVERED The authors provide an overview of the ErbB receptor family with regard to OG cancers. Furthermore, they evaluate the evidence from preclinical and clinical trials of therapeutics targeting this family, including monoclonal antibodies, tyrosine kinase inhibitors and novel agents. EXPERT OPINION Drugs targeting the ErbB family have been evaluated in OG cancer, with a notable success story in the case of trastuzumab, although there have been disappointing failures with anti-EGFR therapy. The response to targeted treatment remains variable and further biomarker research is essential to identify patients most likely to benefit from these therapies. The treatment of OG cancer remains challenging, but new anti-HER2 therapies and combination therapies hold promise for the future.
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Affiliation(s)
- Sing Yu Moorcraft
- The Royal Marsden NHS Foundation Trust, Gastrointestinal Unit, Department of Medicine , Sutton SM2 5PT , UK +44 020 8642 6011 ; +44 020 8643 9414 ;
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33
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Sohal DPS, Rice TW, Rybicki LA, Rodriguez CP, Videtic GMM, Saxton JP, Murthy SC, Mason DP, Phillips BE, Tubbs RR, Plesec T, McNamara MJ, Ives DI, Bodmann JW, Adelstein DJ. Gefitinib in definitive management of esophageal or gastroesophageal junction cancer: a retrospective analysis of two clinical trials. Dis Esophagus 2014; 28:547-51. [PMID: 24849395 DOI: 10.1111/dote.12241] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The role of epidermal growth factor receptor inhibition in resectable esophageal/gastroesophageal junction (E/GEJ) cancer is uncertain. Results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery are updated and retrospectively compared, the second study differing only by the addition of gefitinib (G) to the treatment regimen. Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma, with an endoscopic ultrasound stage of at least T3, N1, or M1a (American Joint Committee on Cancer 6th). Patients in both trials received 5-fluorouracil (1000 mg/m(2) /day) and cisplatin (20 mg/m(2) /day) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250 mg/day, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Clinical characteristics were similar between the 80 patients on the G trial (2003-2006) and the 93 patients on the no-G trial (1999-2003). Minimum follow-up for all patients was 5 years. Multivariable analyses comparing the G versus no-G patients and adjusting for statistically significant covariates demonstrated improved overall survival (hazard ratio [HR] 0.64, 95% confidence interval [CI] = 0.45-0.91, P = 0.012), recurrence-free survival (HR 0.61, 95% CI = 0.43-0.86, P = 0.006), and distant recurrence (HR 0.68, 95% CI = 0.45-1.00, P = 0.05), but not locoregional recurrence. Although this retrospective comparison can only be considered exploratory, it suggests that G may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer.
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Affiliation(s)
- D P S Sohal
- Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, Ohio, USA
| | - T W Rice
- Department of Cardiothoracic Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - L A Rybicki
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
| | - C P Rodriguez
- Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, Ohio, USA
| | - G M M Videtic
- Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - J P Saxton
- Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - S C Murthy
- Department of Cardiothoracic Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - D P Mason
- Department of Cardiothoracic Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - B E Phillips
- Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, Ohio, USA
| | - R R Tubbs
- Department of Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - T Plesec
- Department of Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - M J McNamara
- Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, Ohio, USA
| | - D I Ives
- Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, Ohio, USA
| | - J W Bodmann
- Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, Ohio, USA
| | - D J Adelstein
- Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, Ohio, USA
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Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas. Br J Cancer 2014; 110:1525-34. [PMID: 24569475 PMCID: PMC3960617 DOI: 10.1038/bjc.2014.45] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 12/23/2013] [Accepted: 01/08/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy. METHODS Tumour biopsies from patients (n=14) with TNM stage IB-IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (n=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (n=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for in vitro validation investigations. RESULTS We identified 520 genes with differential expression (Mann-Whitney U, P<0.020) between radiological responding and nonresponding patients. Gene enrichment analysis (DAVID v6.7) was used on this list of 520 genes to identify pathways associated with response and identified the adipocytokine signalling pathway, with higher leptin mRNA associated with lack of radiological response (P=0.011). Similarly, in the independent cohort (n=154), higher leptin protein expression by immunohistochemistry in the tumour cells was associated with lack of histopathological response (P=0.007). Higher leptin protein expression by immunohistochemistry was also associated with improved survival in the absence of neoadjuvant chemotherapy, and patients with low leptin protein-expressing tumours had improved survival when treated by neoadjuvant chemotherapy (P for interaction=0.038). In the gastric adenocarcinoma cell lines, higher leptin protein expression was associated with resistance to cisplatin (P=0.008), but not to oxaliplatin (P=0.988) or 5fluorouracil (P=0.636). The leptin receptor antagonist SHLA increased the sensitivity of AGS Cis5 and OE33 cell lines to cisplatin. CONCLUSIONS In gastro-oesophageal adenocarcinomas, tumour leptin expression is associated with chemoresistance but a better therapy-independent prognosis. Tumour leptin expression determined by immunohistochemistry has potential utility as a predictive marker of resistance to cytotoxic chemotherapy, and a prognostic marker independent of therapy in gastro-oesophageal adenocarcinoma. Leptin antagonists have been developed for clinical use and leptin and its associated pathways may also provide much needed novel therapeutic targets for gastro-oesophageal adenocarcinoma.
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Yamaguchi NH, Mayer IA, Malzyner A, de Andrade CJ, Murad AM, Del Giglio A, Alves V. Gefitinib and celecoxib in advanced metastatic gastrointestinal tumors: a pilot feasibility study. J Gastrointest Oncol 2014; 5:57-66. [PMID: 24490043 DOI: 10.3978/j.issn.2078-6891.2013.056] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Accepted: 11/11/2013] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND This pilot, open-label study examined the safety and tolerability (primary objective) and efficacy (secondary objective) of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, in patients with advanced or refractory gastrointestinal (GI) tumors of epithelial origin. METHODS Patients were administered gefitinib (250 mg/day) plus celecoxib (400 mg twice daily). In the event of toxicity, dose interruptions were permitted and a single celecoxib dose reduction was allowed. RESULTS Thirty patients (median age 60 years) with primary colorectal (25 patients), pancreatic (3 patients), esophageal (1 patient), or gall bladder (1 patient) tumors were recruited, 29 of whom had received prior chemotherapy. Adverse events (AEs) were generally mild and consisted mainly of acne, diarrhea, and nausea. Few severe AEs were noted. There were no withdrawals or deaths due to AEs. Dose reductions for celecoxib were reported for five patients, in three cases due to toxicity. Stable disease was confirmed in 12 patients (40%), with progressive disease in 18 patients (60%). CONCLUSIONS After study completion, safety issues relating to the long-term use of COX-2 inhibitors have been raised. However, in this pilot study, the combination of gefitinib and celecoxib was generally well tolerated in patients with advanced GI cancer.
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Affiliation(s)
- Nise H Yamaguchi
- University of São Paulo Medical School and Institute of Advances in Medicine, São Paulo, Brazil
| | | | - Artur Malzyner
- Hospital Israelita Albert Einstein and Heliopolis Hospital and Clínica de Oncologia Médica, São Paulo, Brazil
| | | | - Andre M Murad
- Oncology Department, Hospital das Clinicas, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Venancio Alves
- University of São Paulo School of Medicine, São Paulo, Brazil
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Kasper S, Schuler M. Targeted therapies in gastroesophageal cancer. Eur J Cancer 2014; 50:1247-58. [PMID: 24495747 DOI: 10.1016/j.ejca.2014.01.009] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 01/07/2014] [Accepted: 01/08/2014] [Indexed: 02/07/2023]
Abstract
Gastroesophageal cancers comprising gastric cancer (GC), and cancers of the distal oesophagus and gastroesophageal junction (GEJ) are a global health threat. In Western populations the incidence of GC is declining which has been attributed to effective strategies of eradicating Helicobacter pylori infection. To the contrary, GEJ cancers are on the rise, with obesity and reflux disease being viewed as major risk factors. During the past decade perioperative chemotherapy, pre- or postoperative radio-chemotherapy, and, in Asian populations, adjuvant chemotherapy have been shown to improve the outcome of patients with advanced GC and GEJ cancers suited for surgery. Less progress has been made in the treatment of metastatic disease. The introduction of trastuzumab in combination with platinum/fluoropyrimidine-based chemotherapy for patients with HER2-positive disease has marked a turning point. Recently, several novel agents targeting growth factor receptors, angiogenic pathways, adhesion molecules and mediators of intracellular signal transduction have been clinically explored. Here we summarise the current status and future developments of molecularly targeted therapies in GC and GEJ cancer.
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Affiliation(s)
- Stefan Kasper
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Martin Schuler
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
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Mohamed A, El-Rayes B, Khuri FR, Saba NF. Targeted therapies in metastatic esophageal cancer: advances over the past decade. Crit Rev Oncol Hematol 2014; 91:186-96. [PMID: 24582516 DOI: 10.1016/j.critrevonc.2014.01.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 01/14/2014] [Accepted: 01/17/2014] [Indexed: 12/29/2022] Open
Abstract
Esophageal cancer is one of the most aggressive malignancies of the upper aerodigestive tract. Despite advances in surgical techniques and multi-modality therapies, the 5-year survival rate remains poor (14%). Over the past decade, efforts have been focused on the field of drug development with the advancement of novel molecularly targeted therapeutic agents. These agents target a variety of cancer relevant pathways such as vascular endothelial growth factor (VEGF) or its receptor, the cyclooxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), and mammalian target of rapamycin (mTOR) pathways. The number of approved targeted agents remains few, with HER-2 inhibitors leading the list for treatment of HER-2 expressing metastatic adenocarcinomas. Novel agents have not yet been widely explored in esophageal cancer. In this review, we will provide a concise and systematic overview of the development of novel targeted therapies currently under investigation for the treatment of metastatic esophageal disease.
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Affiliation(s)
- Amr Mohamed
- Department of Medicine, Morehouse School of Medicine, Atlanta, GA, USA
| | - Bassel El-Rayes
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA
| | - Fadlo R Khuri
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA
| | - Nabil F Saba
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
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Zhang Z, Xiao H, Xie F, Zhang H, Chen C, Xiao H, Yang Z, Wang D, Li Z, Wang G. High-incidence of PTEN mutations in Chinese patients with primary small cell carcinoma of the esophagus. BMC Cancer 2014; 14:19. [PMID: 24422746 PMCID: PMC3938318 DOI: 10.1186/1471-2407-14-19] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 01/06/2014] [Indexed: 12/28/2022] Open
Abstract
Background Primary small cell carcinoma of the esophagus (PSCCE) is a rare and aggressive tumor with poor prognosis. The aim of this study was to investigate the existence of EGFR, KRAS, PIK3CA and PTEN mutations in PSCCE. Methods Clinical–pathological data and paraffin-embedded specimens were collected from 38 patients. Exons 18 to 21 of EGFR, KRAS and PIK3CA status were analyzed by real-time PCR based on ARMS and Scorpion technology in all patients, and the PTEN gene was also screened using real-time PCR and high-resolution melting curve analysis (HRMA). Results Only 1 (2.63%) out of 38 patients had EGFR mutations in L858R missense, and KRAS and PIK3CA were not found in the mutational spot in all patients. However, PTEN mutations presented in 14 (36.84%) out of 38 patients, including exon 5 coding for PTEN missense mutation (n =4, 10.53%), exon 6 (n =7, 18.42%), concurrent exon 5 and exon 6 (n =2, 5.26%), and exon 8 (n =1, 2.63%). Concurrent mutations of these genes were not detected in all samples. No statistically significant associations were found between the clinicopathological features and the mutation status of PTEN. Conclusions The incidence of PTEN mutations in Chinese patients with PSCCE was higher than that of previous reports in other histological subtypes of esophageal cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Ge Wang
- Cancer Center, Institute of Surgical Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
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Chemotherapeutic and targeted strategies for locally advanced and metastatic esophageal cancer. J Thorac Oncol 2014; 8:673-84. [PMID: 23591158 DOI: 10.1097/jto.0b013e31828b5172] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION : Esophageal cancer represents a major health care problem worldwide and its prevalence is rapidly increasing. A key challenge in the treatment of both locally advanced and metastatic disease is to improve our understanding of the underlying molecular biology. Herein we discuss the most active chemotherapies and targeted agents for esophageal cancer, and explore potential differences in the disease between Eastern and Western countries. METHODS : We reviewed the literature for trials involving chemotherapy and targeted agents in locally advanced and metastatic disease in the last 20 years. The search was supplemented by a review of the abstracts presented at the annual American Society of Clinical Oncology meetings from 1992 to 2012. RESULTS : Neoadjuvant chemo-radiation followed by surgery remains standard of care for operable disease. Definitive chemo-radiation can be considered for locally advanced squamous cell tumors. Platinum-based combination chemotherapy is preferable in the first-line metastatic setting. Recently, HER2, EGFR, and VEGF-targeted agents have been extensively investigated as single agents or in combination with chemotherapy. Several new targets are being explored. CONCLUSIONS : There have been incremental improvements in our understanding of the molecular biology of esophageal cancer, and ethnic differences between Asian and Western populations are becoming apparent. Next-generation sequencing has failed to demonstrate significant oncogenic drivers; however, the addition of trastuzumab to chemotherapy for HER2-amplified tumors has been validated in the metastatic setting and is undergoing investigation in operable disease. Epigenetic therapeutics may provide additional benefit in future years for this difficult-to-treat disease.
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Weaver JMJ, Ross-Innes CS, Fitzgerald RC. The '-omics' revolution and oesophageal adenocarcinoma. Nat Rev Gastroenterol Hepatol 2014; 11:19-27. [PMID: 23982683 DOI: 10.1038/nrgastro.2013.150] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Oesophageal adenocarcinoma (OAC) is the eighth most common cancer type worldwide with a dismal 5-year survival. Barrett oesophagus, the replacement of the normal squamous epithelia with glandular cells, is the first step in the pathway towards OAC. Although most patients with OAC present de novo, the presence of the easily detectable OAC precursor lesion, Barrett oesophagus, enables the possibility of early detection of high-risk patients who are more likely to progress. Currently, identification of high-risk patients depends on histopathological assessment of dysplasia with no regards to molecular pathogenesis. In the future, screening and risk stratification initiatives for Barrett oesophagus that incorporate molecular profiles might permit improved early diagnosis and intervention strategies with the possibility of preventing OAC. For the majority of patients presenting de novo at an advanced stage, combining so-called -omics datasets with current clinical staging algorithms might enable OACs to be better classified according to distinct molecular programmes, thereby leading to better targeted treatment strategies as well as cancer monitoring regimes. This Review discusses how the latest advances in -omics technologies have improved our understanding of the development and biology of OAC, and how this development might alter patient management in the future.
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Affiliation(s)
- Jamie M J Weaver
- MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK
| | - Caryn S Ross-Innes
- MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK
| | - Rebecca C Fitzgerald
- MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK
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Ku GY, Ilson DH. Emerging tyrosine kinase inhibitors for esophageal cancer. Expert Opin Emerg Drugs 2013; 18:219-30. [PMID: 23725567 DOI: 10.1517/14728214.2013.805203] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Because of the poor prognosis for patients with esophagogastric cancers (EGCs), increasing attention has focused on targeted agents. AREAS COVERED Targets include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), Her2, mammalian target of rapamycin (mTOR), and MET. We briefly discuss preclinical data and the rationale for targeting these pathways and summarize the results of clinical trials of tyrosine kinase inhibitors (TKIs) against these targets. EXPERT OPINION While anti-EGFR therapy has been extensively investigated, completed Phase III trials suggest that this is not a promising target. A Phase III trial of an anti-VEGF antibody failed to show improvement in the primary endpoint of overall survival but response rates and progression-free survival were improved; a Phase III trial of an anti-VEGF receptor 2 antibody in second-line therapy did show improved survival. As such, Phase II and III evaluations of anti-VEGF TKIs are ongoing. The only Food and Drug Administration-approved targeted therapy in EGC is trastuzumab, an anti-Her2 antibody, and the results of a Phase III evaluation of lapatinib, an anti-Her2 TKI, are awaited. Phase III evaluation of an mTOR inhibitor has been negative. Finally, MET inhibition appears to have significant clinical potential and early testing of MET TKIs is underway.
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Affiliation(s)
- Geoffrey Y Ku
- Memorial Sloan-Kettering Cancer Center, Department of Medicine, Gastrointestinal Oncology Service, 300 East 66th Street, New York, NY 10065, USA
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Abstract
PURPOSE OF REVIEW Our current review aims to outline recent progress in the development of modern targeted therapeutic regimens for esophageal cancer. RECENT FINDINGS Esophageal cancers demonstrate marked molecular heterogeneity. Modern technology increasingly allows us to identify subgroups of patients whose tumors fit particular molecular profiles. Tumor-based human epidermal growth factor receptor 2 (HER-2) analysis has become a standard part of the work-up for patients with tumors of the esophagogastric junction. The anti-HER-2 antibody, trastuzumab, when added to a chemotherapeutic regimen combining a fluoropyrimidine and platinum, provides a survival benefit for those patients with HER-2 overexpression and/or amplification. Despite large coordinated efforts to establish the efficacy of additional targeted therapeutics, to this point minimal additional benefit has been realized in affecting prominent molecular targets, such as vascular endothelial growth factor and epidermal growth factor receptor, in esophageal cancer. Multiple targets of interest remain under investigation with some early encouraging data. These targets include mammalian target of rapamycin, c-MET, insulin like growth factor 1 receptor and cytotoxic T-lymphocyte antigen 4. Additional improvements in therapy may stem from improved patient selection for combinations of standard cytotoxic regimens, such as platinum-based regimens. SUMMARY Targeted therapeutics have yielded early benefit, but further progress will require a deeper understanding of this disease, improved identification of subpopulations who may derive greater benefit, and continued multicenter efforts to conduct the necessary clinical investigations.
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Nagaraja V, Eslick GD. Advances in biomarkers for esophageal cancer. Expert Rev Anticancer Ther 2013; 13:1169-1180. [PMID: 24134419 DOI: 10.1586/14737140.2013.844953] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
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Hong L, Han Y, Brain L. Epidermal growth factor receptor: an important target in esophageal cancer. Expert Opin Ther Targets 2013; 17:1179-85. [PMID: 23855932 DOI: 10.1517/14728222.2013.820709] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Even after complete tumor removal by surgery, the clinical outcomes remain poor in patients with advanced esophageal cancer, justifying the need for new treatment options. Epidermal growth factor receptor (EGFR) is a molecular target for antibody-based therapy in various cancer types, and it may play important roles in the development of esophageal cancer. AREAS COVERED This review evaluates the expression, function, and mechanism of EGFR in esophageal cancer and analyzes its value for the prognosis and therapy of esophageal cancer. Future developments toward the clinical applications of EGFR to cancer treatment are also envisaged. EXPERT OPINION EGFR may function as an ideal therapeutic target for esophageal cancer. Further investigation of epidermal growth-factor-receptor-mediated pathways will push insight into the novel strategies of target therapy for esophageal cancer. More clinical trials should be performed to promote the success of therapeutic-clinical use of EGFR and its targets in esophageal cancer.
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Affiliation(s)
- Liu Hong
- Fourth Military Medical University, Xijing Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology , Xi'an, 710032, Shaanxi Province , China +86 29 84773974 ; +86 29 82539041 ;
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Forde PM, Kelly RJ. Genomic alterations in advanced esophageal cancer may lead to subtype-specific therapies. Oncologist 2013; 18:823-32. [PMID: 23853247 PMCID: PMC3720637 DOI: 10.1634/theoncologist.2013-0130] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Accepted: 05/06/2013] [Indexed: 12/18/2022] Open
Abstract
The development of targeted agents for metastatic esophageal or gastroesophageal junction (GEJ) tumors has been limited when compared with that for other common tumors. To date, the anti-human epidermal growth factor receptor-2 (HER-2) antibody, trastuzumab, in combination with chemotherapy, is the only approved novel agent for these cancers, and its use is limited to the small population of patients whose tumors overexpress HER-2. Despite recent progress in the field, median overall survival remains only 8-12 months for patients with stage IV esophageal or GEJ cancer. In this article, we examine the molecular aberrations thought to drive the development and spread of esophageal cancer and identify promising targets for specific tumor inhibition. Data from clinical studies of targeted agents are reviewed, including epidermal growth factor receptor antibodies, tyrosine kinase inhibitors, HER-2, and vascular endothelial growth factor-directed therapy. Current and future targets include MET, fibroblast growth factor receptor, and immune-based therapies. Evidence from trials to date suggests that molecularly unselected patient cohorts derive minimal benefit from most target-specific agents, suggesting that future collaborative investigation should focus on preselected molecular subgroups of patients with this challenging heterogeneous disease.
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Affiliation(s)
- Patrick M. Forde
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Ronan J. Kelly
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
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Abstract
Esophageal cancer comprises two different histological forms - squamous cell carcinoma (SCC) and adenocarcinoma (AC). While the incidence of AC has increased steeply in Western countries during the last few years, the incidence of SCC is fairly stable. Both forms differ in pathogenesis and response to chemotherapy and radiation therapy. Plenty of studies have evaluated new chemotherapy combination regimens in the neoadjuvant, adjuvant, and palliative setting. In addition, new radiation and chemoradiation protocols have been investigated. Finally, molecular-targeted therapy has been included in several new randomized prospective trials. Therefore, this review presents new data on this topic and critically discusses promising approaches towards a more effective treatment in a disease with a grim prognosis.
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Affiliation(s)
- Marcus W Wiedmann
- Department of Internal Medicine I, St Mary’s Hospital, Berlin, Germany
- Division of Gastroenterology and Rheumatology, Department of Medicine, Neurology and Dermatology, University Hospital of Leipzig, Leipzig, Germany
| | - Joachim Mössner
- Division of Gastroenterology and Rheumatology, Department of Medicine, Neurology and Dermatology, University Hospital of Leipzig, Leipzig, Germany
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Hou W, Qin X, Zhu X, Fei M, Liu P, Liu L, Moon H, Zhang P, Greshock J, Bachman KE, Ye BC, Wang H, Zang CYQ. Lapatinib inhibits the growth of esophageal squamous cell carcinoma and synergistically interacts with 5-fluorouracil in patient-derived xenograft models. Oncol Rep 2013; 30:707-14. [PMID: 23708506 DOI: 10.3892/or.2013.2500] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Accepted: 04/19/2013] [Indexed: 11/05/2022] Open
Abstract
Lapatinib is a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2) tyrosine kinase domains. To explore the potential utility of lapatinib for the treatment of esophageal squamous cell carcinoma (ESCC), we examined the expression profiles of EGFR and HER2 in tumor tissues and in paired adjacent non-neoplastic tissues from patients with ESCC. We evaluated the antitumor effects of lapatinib alone or in combination with oxaliplatin or 5-fluorouracil (5-FU) on a panel of primary ESCC cells in vitro with various levels of EGFR and HER2 expression. The in vivo effect of lapatinib alone or in combination with oxaliplatin or 5-FU was evaluated using a primary ESCC xenograft model. EGFR was overexpressed in 80.9% (76/94) of the ESCC samples, while 24.5% (23/94) of the samples overexpressed HER2. EGFR and HER2 co-overexpression was detected in 22.3% of samples (21/94). In vitro, the primary ESCC cells were more sensitive to lapatinib combined with 5-FU or oxaliplatin than to lapatinib alone. Lapatinib in combination with 5-FU had more potent antitumor effects in the primary ESCC xenograft model, and markedly reduced the phosphorylation of EGFR and HER2, compared with lapatinib alone or in combination with oxaliplatin. These data indicate that lapatinib has activity in EGFR- and/or HER2-expressing ESCC primary cells, and that lapatinib in combination with 5-FU may be a promising treatment strategy for patients with ESCC.
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Affiliation(s)
- Wenmin Hou
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, PR China
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Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AFC, Wotherspoon A, Saffery C, Middleton G, Wadsley J, Ferry D, Mansoor W, Crosby T, Coxon F, Smith D, Waters J, Iveson T, Falk S, Slater S, Peckitt C, Barbachano Y. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol 2013; 14:481-9. [PMID: 23594787 PMCID: PMC3669518 DOI: 10.1016/s1470-2045(13)70096-2] [Citation(s) in RCA: 568] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. METHODS In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. FINDINGS Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥ 3 neutropenia 35 [13%] vs 74 [28%]). INTERPRETATION Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. FUNDING Amgen, UK National Institute for Health Research Biomedical Research Centre.
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Affiliation(s)
- Tom Waddell
- The Royal Marsden NHS Foundation Trust, London and Surrey, UK
| | - Ian Chau
- The Royal Marsden NHS Foundation Trust, London and Surrey, UK
| | | | - David Gonzalez
- The Royal Marsden NHS Foundation Trust, London and Surrey, UK
| | | | | | - Claire Saffery
- The Royal Marsden NHS Foundation Trust, London and Surrey, UK
| | | | | | | | - Wasat Mansoor
- Christie Hospitals NHS Foundation Trust, Manchester, UK
| | | | - Fareeda Coxon
- Northern Centre for Cancer Care, Newcastle-upon-Tyne, UK
| | - David Smith
- Clatterbridge Centre for Oncology, Wirral, UK
| | | | - Timothy Iveson
- Southampton University Hospitals NHS Foundation Trust, Southampton, UK
| | - Stephen Falk
- Bristol Haematology and Oncology Centre, Bristol, UK
| | | | - Clare Peckitt
- The Royal Marsden NHS Foundation Trust, London and Surrey, UK
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Sano A, Sakurai S, Kato H, Suzuki S, Yokobori T, Sakai M, Tanaka N, Inose T, Sohda M, Nakajima M, Fukai Y, Miyazaki T, Ojima H, Hosoya Y, Enomoto T, Kanda T, Ajioka Y, Kuwano H. Expression of receptor tyrosine kinases in esophageal carcinosarcoma. Oncol Rep 2013; 29:2119-26. [PMID: 23546020 DOI: 10.3892/or.2013.2371] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 12/17/2012] [Indexed: 11/06/2022] Open
Abstract
Esophageal carcinosarcoma (ECS) is a rare malignant neoplasm associated with a poor patient prognosis. It is characterized by the presence of both malignant epithelial and mesenchymal components. Molecular-targeted therapy of several receptor tyrosine kinases (RTKs) has been reported to be effective in the treatment of various malignant tumors, including carcinosarcoma of several organs. This study aimed to assess the therapeutic potential of targeting RTKs in ECS. Overexpression of RTKs was assessed in 21 ECS cases by immunohistochemistry (IHC). Positively stained cases were further examined for RTK gene mutations and amplifications by direct sequencing analysis and fluorescence in situ hybridization. In epithelial components, KIT, platelet-derived growth factor receptor (PDGFR)A, PDGFRB, MET, epidermal growth factor receptor (EGFR) and HER-2 were overexpressed in 1 (4.8%), 1 (4.8%), 0 (0%), 11 (52.4%), 13 (61.9%) and 2 (9.5%) cases, respectively. In the mesenchymal components the corresponding numbers of cases were 2 (9.5%), 2 (9.5%), 0 (0%), 12 (57.1%), 11 (52.4%) and 0 (0%). No mutations in the c-kit, PDGFRA and c-met genes were found. Among 19 EGFR-positive tumors, 2 had EGFR missense mutations (T790A, exon 20) only in the mesenchymal component. Gene amplification or high polysomy of c-kit, PDGFRA, c-met and EGFR was observed in 1 (33.3%), 0 (0%), 3 (18.8%) and 10 (52.6%) cases, respectively. In conclusion, various RTKs, particularly MET and EGFR were overexpressed in ECSs suggesting that molecular-targeted therapies directed to MET, EGFR or other RTKs may be effective in inhibiting the growth or progression of the epithelial and/or mesenchymal component of ECS.
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Affiliation(s)
- Akihiko Sano
- Department of Gastroenterological Surgery, Gunma Prefectural Cancer Center, Ohta, Gunma 373-8550, Japan
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Abstract
Although medical treatment has been shown to improve quality of life and prolong survival, no significant progress has been made in the treatment of advanced gastric cancer (AGC) within the last two decades. Thus, the optimum standard first-line chemotherapy regimen for AGC remains debatable, and most responses to chemotherapy are partial and of short duration; the median survival is approximately 7 to 11 months, and survival at 2 years is exceptionally > 10%. Recently, remarkable progress in tumor biology has led to the development of new agents that target critical aspects of oncogenic pathways. For AGC, many molecular targeting agents have been evaluated in international randomized studies, and trastuzumab, an anti-HER-2 monoclonal antibody, has shown antitumor activity against HER-2-positive AGC. However, this benefit is limited to only ~20% of patients with AGC (patients with HER-2-positive AGC). Therefore, there remains a critical need for both the development of more effective agents and the identification of molecular predictive and prognostic markers to select those patients who will benefit most from specific chemotherapeutic regimens and targeted therapies.
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Affiliation(s)
- Jong Gwang Kim
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
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