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1
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Varlamova EG, Gudkov SV, Blinova EV, Blinov DS, Turovsky EA. Anticancer signal transduction pathways of selenium nanoparticles in mouse colorectal cancer model. Biochem Biophys Res Commun 2025; 769:151962. [PMID: 40347624 DOI: 10.1016/j.bbrc.2025.151962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/23/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
Despite significant advances in the treatment of colon cancer, this disease is extremely common, often requiring serious surgery followed by long-term drug treatment. Colon and rectal cancer remain dangerous forms of cancer due to the high degree of metastasis. The development and study of the effectiveness of anticancer drugs based on nanoparticles is an urgent task of modern biomedicine. Of particular interest are attempts to move research from the in vitro level to the in vivo level of preclinical studies. In the presented study, mice were subcutaneously implanted with MC-38 cell line, a tumor was grown, and selenium nanoparticles (SeNPs) with a diameter of 100 nm obtained using the laser ablation method were administered intraperitoneally. Using morphometric measurements, it was found that injections of 1 μg/g or 10 μg/g SeNPs inhibited weight loss of mice during cancer development, reduced tumor size by 2-2.5 times, and suppressed metastasis by 1.5-3 times. Analysis of selenium levels in mouse blood, liver and tumor samples by atomic absorption spectrometry after the end of SeNPs treatment showed that the nanoparticles increased selenium levels in the blood and liver of mice without a significant dose-dependence, whereas in tumors a dose-dependent increase in selenium concentration was detected from the concentration of nanoparticles, with 10 μg/g SeNPs causing a more pronounced increase in selenium concentration. Using PCR and Western blot analysis, it was possible to establish that SeNPs injections led to an increase in the expression of genes encoding anti-inflammatory and anti-hypoxic proteins, but reduced the expression of antioxidant selenium-containing proteins and proteins responsible for the proliferation of cancer cells. Both concentrations of SeNPs led to similar effects, but increasing the concentration of nanoselenium to 10 μg/g affected the expression of a larger number of genes and the effects on expression were more "bright". Thus, the complex of presented experiments showed that injections of selenium nanoparticles in concentrations of 1 μg/g or 10 μg/g are capable to transport by the bloodstream and accumulating in the highest concentration in colon adenocarcinoma, compared with liver, which indicates the targeting of SeNPs in relation to tumors even without functionalization by specific molecules. As a result, there was a change in the expression patterns of genes and a number of proteins, and as a result, there was a decrease in tumor volume, normalization of mouse weight and maintenance of positive dynamics throughout the entire observation period.
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Affiliation(s)
- Elena G Varlamova
- Institute of Cell Biophysics of the Russian Academy of Sciences, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", 142290, Pushchino, Russia.
| | - Sergey V Gudkov
- Prokhorov General Physics Institute of the Russian Academy of Sciences, 38 Vavilove st., 119991, Moscow, Russia
| | | | - Dmitrii S Blinov
- All-Union Research Center for Biological Active Compounds Safety, 23 Kirova St., 142450, StarajaKupavna, Russia
| | - Egor A Turovsky
- Institute of Cell Biophysics of the Russian Academy of Sciences, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", 142290, Pushchino, Russia.
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2
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Zheng Y, Dou G, Liu S, Meng Z, Tsao EI, Yu G, Zhu X, Gu R, Wu Z, Sun Y, Han P, Gan H. Preclinical Pharmacokinetics and Biodistribution of LR004, a Novel Antiepidermal Growth Factor Receptor Monoclonal Antibody. Molecules 2024; 29:545. [PMID: 38276624 PMCID: PMC10821095 DOI: 10.3390/molecules29020545] [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: 12/08/2023] [Revised: 01/12/2024] [Accepted: 01/20/2024] [Indexed: 01/27/2024] Open
Abstract
LR004 is a novel chimeric (human/mouse) monoclonal antibody developed for the treatment of advanced colorectal carcinoma with detectable epidermal growth factor receptor (EGFR) expression. We aimed to investigate the preclinical pharmacokinetics (PK) and in vivo biodistribution of LR004. The PK profiles of LR004 were initially established in rhesus monkeys. Subsequently, 125I radionuclide-labeled LR004 was developed and the biodistribution, autoradiography, and NanoSPECT/CT of 125I-LR004 in xenograft mice bearing A431 tumors were examined. The PK data revealed a prolonged half-life and nonlinear PK characteristics of LR004 within the dose range of 6-54 mg/kg. The radiochemical purity of 125I-LR004 was approximately 98.54%, and iodination of LR004 did not affect its specific binding activity to the EGFR antigen. In a classical biodistribution study, 125I-LR004 exhibited higher uptake in highly perfused organs than in poorly perfused organs. Prolonged retention properties of 125I-LR004 in tumors were observed at 4 and 10 days. Autoradiography and NanoSPECT/CT confirmed the sustained retention of 125I-LR004 at the tumor site in xenograft mice. These findings demonstrated the adequate tumor targeting capabilities of 125I-LR004 in EGFR-positive tumors, which may improve dosing strategies and future drug development.
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Affiliation(s)
- Ying Zheng
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (Y.Z.); (G.D.); (S.L.); (Z.M.); (X.Z.); (R.G.); (Z.W.); (Y.S.); (P.H.)
- Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Guifang Dou
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (Y.Z.); (G.D.); (S.L.); (Z.M.); (X.Z.); (R.G.); (Z.W.); (Y.S.); (P.H.)
| | - Shuchen Liu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (Y.Z.); (G.D.); (S.L.); (Z.M.); (X.Z.); (R.G.); (Z.W.); (Y.S.); (P.H.)
| | - Zhiyun Meng
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (Y.Z.); (G.D.); (S.L.); (Z.M.); (X.Z.); (R.G.); (Z.W.); (Y.S.); (P.H.)
| | - Eric I. Tsao
- Synermore Biologics Co., Ltd., Suzhou 215000, China;
| | - Gang Yu
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China;
| | - Xiaoxia Zhu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (Y.Z.); (G.D.); (S.L.); (Z.M.); (X.Z.); (R.G.); (Z.W.); (Y.S.); (P.H.)
| | - Ruolan Gu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (Y.Z.); (G.D.); (S.L.); (Z.M.); (X.Z.); (R.G.); (Z.W.); (Y.S.); (P.H.)
| | - Zhuona Wu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (Y.Z.); (G.D.); (S.L.); (Z.M.); (X.Z.); (R.G.); (Z.W.); (Y.S.); (P.H.)
| | - Yunbo Sun
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (Y.Z.); (G.D.); (S.L.); (Z.M.); (X.Z.); (R.G.); (Z.W.); (Y.S.); (P.H.)
| | - Peng Han
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (Y.Z.); (G.D.); (S.L.); (Z.M.); (X.Z.); (R.G.); (Z.W.); (Y.S.); (P.H.)
| | - Hui Gan
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (Y.Z.); (G.D.); (S.L.); (Z.M.); (X.Z.); (R.G.); (Z.W.); (Y.S.); (P.H.)
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3
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Song YQ, Yan XD, Wang Y, Wang ZZ, Mao XL, Ye LP, Li SW. Role of ferroptosis in colorectal cancer. World J Gastrointest Oncol 2023; 15:225-239. [PMID: 36908317 PMCID: PMC9994046 DOI: 10.4251/wjgo.v15.i2.225] [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: 09/19/2022] [Revised: 12/15/2022] [Accepted: 01/09/2023] [Indexed: 02/14/2023] Open
Abstract
Colorectal cancer (CRC) is the second deadliest cancer and the third-most common malignancy in the world. Surgery, chemotherapy, and targeted therapy have been widely used to treat CRC, but some patients still develop resistance to these treatments. Ferroptosis is a novel non-apoptotic form of cell death. It is an iron-dependent non-apoptotic cell death characterized by the accumulation of lipid reactive oxygen species and has been suggested to play a role in reversing resistance to anticancer drugs. This review summarizes recent advances in the prognostic role of ferroptosis in CRC and the mechanism of action in CRC.
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Affiliation(s)
- Ya-Qi Song
- Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai 317000, Zhejiang Province, China
| | - Xiao-Dan Yan
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Yi Wang
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Zhen-Zhen Wang
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Xin-Li Mao
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Li-Ping Ye
- Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai 317000, Zhejiang Province, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Shao-Wei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
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Moench R, Gasser M, Nawalaniec K, Grimmig T, Ajay AK, de Souza LCR, Cao M, Luo Y, Hoegger P, Ribas CM, Ribas-Filho JM, Malafaia O, Lissner R, Hsiao LL, Waaga-Gasser AM. Platelet-derived growth factor (PDGF) cross-signaling via non-corresponding receptors indicates bypassed signaling in colorectal cancer. Oncotarget 2022; 13:1140-1152. [PMID: 36264073 PMCID: PMC9584432 DOI: 10.18632/oncotarget.28281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Platelet-derived growth factor (PDGF) signaling, besides other growth factor-mediated signaling pathways like vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), seems to play a crucial role in tumor development and progression. We have recently provided evidence for upregulation of PDGF expression in UICC stage I-IV primary colorectal cancer (CRC) and demonstrated PDGF-mediated induction of PI3K/Akt/mTOR signaling in CRC cell lines. The present study sought to follow up on our previous findings and explore the alternative receptor cross-binding potential of PDGF in CRC. Our analysis of primary human colon tumor samples demonstrated upregulation of the PDGFRβ, VEGFR1, and VEGFR2 genes in UICC stage I-III tumors. Immunohistological analysis revealed co-expression of PDGF and its putative cross-binding partners, VEGFR2 and EGFR. We then analyzed several CRC cell lines for PDGFRα, PDGFRβ, VEGFR1, and VEGFR2 protein expression and found these receptors to be variably expressed amongst the investigated cell lines. Interestingly, whereas Caco-2 and SW480 cells showed expression of all analyzed receptors, HT29 cells expressed only VEGFR1 and VEGFR2. However, stimulation of HT29 cells with PDGF resulted in upregulation of VEGFR1 and VEGFR2 expression despite the absence of PDGFR expression and mimicked the effect of VEGF stimulation. Moreover, PDGF recovered HT29 cell proliferation under simultaneous treatment with a VEGFR or EGFR inhibitor. Our results provide some of the first evidence for PDGF cross-signaling through alternative receptors in colorectal cancer and support anti-PDGF therapy as a combination strategy alongside VEGF and EGF targeting even in tumors lacking PDGFR expression.
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Affiliation(s)
- Romana Moench
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg 97080, Bavaria, Germany
| | - Martin Gasser
- Department of Surgery I, University of Wuerzburg, Wuerzburg 97080, Bavaria, Germany
| | - Karol Nawalaniec
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Tanja Grimmig
- Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg 97080, Bavaria, Germany
| | - Amrendra K Ajay
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | | | - Minghua Cao
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Yueming Luo
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Petra Hoegger
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Wuerzburg 97074, Bavaria, Germany
| | - Carmen M Ribas
- Mackenzie Evangelical Faculty of Paraná, Curitiba 80730-000, Parana, Brazil
| | | | - Osvaldo Malafaia
- Mackenzie Evangelical Faculty of Paraná, Curitiba 80730-000, Parana, Brazil
| | - Reinhard Lissner
- Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg 97080, Bavaria, Germany
| | - Li-Li Hsiao
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Co-senior investigators
| | - Ana Maria Waaga-Gasser
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg 97080, Bavaria, Germany.,Co-senior investigators
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Chen H, Qi Q, Wu N, Wang Y, Feng Q, Jin R, Jiang L. Aspirin promotes RSL3-induced ferroptosis by suppressing mTOR/SREBP-1/SCD1-mediated lipogenesis in PIK3CA-mutant colorectal cancer. Redox Biol 2022; 55:102426. [PMID: 35963119 PMCID: PMC9389304 DOI: 10.1016/j.redox.2022.102426] [Citation(s) in RCA: 106] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/29/2022] [Accepted: 07/30/2022] [Indexed: 02/07/2023] Open
Abstract
Ferroptosis, a new form of regulated cell death triggered by the iron-dependent peroxidation of phospholipids, is associated with cellular metabolism, redox homeostasis, and various signaling pathways related to cancer. Aspirin is a widely used non-steroidal anti-inflammatory drug (NSAID) and has been reported to show therapeutic benefit in cancers harboring oncogenic PIK3CA, which encodes the catalytic p110α subunit of phosphoinositide 3-kinase (PI3K). In this study, we found that aspirin sensitized cancer cells harboring oncogenic activation of PIK3CA to ferroptosis induction. Mechanistically, aspirin inhibited protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, suppressed downstream sterol regulatory element-binding protein 1 (SREBP-1) expression, and attenuated stearoyl-CoA desaturase-1 (SCD1)-mediated lipogenesis of monounsaturated fatty acids, thus promoting RSL3-induced ferroptosis in colorectal cancer (CRC) cells. Moreover, genetic ablation of SREBP-1 or SCD1 conferred cancer cells greater sensitivity to ferroptosis induction. Conversely, ectopic expression of SREBP-1 or SCD1 restored ferroptosis resistance in CRC cells and abolished the effect of aspirin on RSL3-induced cytotoxicity. Additionally, the synergistic effects of aspirin and RSL3 were confirmed in a xenograft mouse model. The combined use of aspirin and RSL3 resulted in significant tumor suppression. Our work demonstrated that aspirin enhanced the cytotoxic effect of RSL3 in PIK3CA-mutant cancers, and the combination of aspirin and ferroptosis inducer displayed promising therapeutic effects in cancer treatment.
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Affiliation(s)
- Hao Chen
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Qinqin Qi
- Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Nan Wu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Ying Wang
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Qian Feng
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Rong Jin
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Lei Jiang
- Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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Xiong Q, Zeng Z, Yang Y, Wang Y, Xu Y, Zhou Y, Liu J, Zhang Z, Qiu M, Zhu Q. KRAS Gene Copy Number as a Negative Predictive Biomarker for the Treatment of Metastatic Rectal Cancer With Cetuximab: A Case Report. Front Oncol 2022; 12:872630. [PMID: 35734602 PMCID: PMC9207953 DOI: 10.3389/fonc.2022.872630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/14/2022] [Indexed: 02/05/2023] Open
Abstract
Background Close to one third of colorectal cancer (CRC) patients are diagnosed with metastatic CRC (mCRC). Patients with wild-type RAS and BRAF usually receive anti-EGFR monoclonal antibody therapy containing cetuximab. Overall, 30–50% of mCRC patients are reported to harbor RAS mutations, and RAS mutation status should be assessed when considering EGFR inhibitor treatment according to mCRC biomarker guidelines. Of note, 0.67–2% of patients with CRC harbored a KRAS amplification. Here we reported a case of advanced rectal cancer with wild-type RAS and BRAF in a male patient who harbored a KRAS amplification during anti-EGFR treatment. Case Presentation A 46-year-old man was diagnosed with rectal adenocarcinoma with liver metastases (cT3NxM1a, stage IVA). After receiving first-line irinotecan- fluorouracil chemotherapy (FOLFIRI) plus cetuximab, second-line capecitabine- oxaliplatin chemotherapy (XELOX) plus bevacizumab, and third-line regorafenib, he rechallenged FOLFIRI and cetuximab for seven cycles, achieving a prolonged survival of at least 5 months. The KRAS copy number of circulating tumor DNA (ctDNA) was assessed during treatment. Notably, apart from serum carbohydrate antigen 199 (CA199) and carcinoembryonic antigen (CEA), the change of plasm Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) copy number appeared to strongly correlate with treatment response. Conclusion Our findings suggest that the dynamic change of KRAS copy number on ctDNA during treatment might be a negative predictive biomarker. Additionally, RAS and BRAF wild-type mCRC patients who are resistant to first-line FOLFIRI plus cetuximab therapy may respond well to the FOLFIRI plus cetuximab “rechallenged” strategy.
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Affiliation(s)
- Qunli Xiong
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhu Zeng
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Yang
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Ya Wang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Yongfeng Xu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Ying Zhou
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinlu Liu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiwei Zhang
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Meng Qiu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Qing Zhu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
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7
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Joharatnam-Hogan N, Chambers P, Dhatariya K, Board R. A guideline for the outpatient management of glycaemic control in people with cancer. Diabet Med 2022; 39:e14636. [PMID: 34240470 DOI: 10.1111/dme.14636] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/02/2021] [Accepted: 07/06/2021] [Indexed: 12/17/2022]
Abstract
Individuals with cancer are at increased risk of developing new-onset diabetes mellitus and hyperglycaemia, and an estimated 20% of people with cancer already have an underlying diagnosis of diabetes mellitus. People with both cancer and diabetes may have an increased risk of toxicities, hospital admissions and morbidity, with hyperglycaemia potentially attenuating the efficacy of chemotherapy often secondary to dose reductions and early cessation. Numerous studies have demonstrated that hyperglycaemia is prognostic of worse overall survival and risk of cancer recurrence. These guidelines aim to provide the oncology/haemato-oncology and diabetes multidisciplinary teams with the tools to manage people with diabetes commencing anti-cancer/glucocorticoid therapy, as well as identifying individuals without a known diagnosis of diabetes who are at risk of developing hyperglycaemia and new-onset diabetes.
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Affiliation(s)
| | - Pinkie Chambers
- University College London Hospital NHS Foundation Trust, London, UK
| | - Ketan Dhatariya
- Norfolk and Norwich Hospitals NHS Foundation Trust, London, UK
| | - Ruth Board
- Lancashire Teaching Hospitals NHS Foundation Trust, London, UK
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8
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Yang J, Mo J, Dai J, Ye C, Cen W, Zheng X, Jiang L, Ye L. Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer. Cell Death Dis 2021; 12:1079. [PMID: 34775496 PMCID: PMC8590697 DOI: 10.1038/s41419-021-04367-3] [Citation(s) in RCA: 192] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 10/22/2021] [Accepted: 10/27/2021] [Indexed: 12/13/2022]
Abstract
Cetuximab is approved for the treatment of metastatic colorectal cancer (mCRC) with RAS wild-type. Nevertheless, the prognosis remains poor and the effectiveness of cetuximab is limited in KRAS mutant mCRC. Recently, emerging evidence has shown that ferroptosis, a newly discovered form of nonapoptotic cell death, is closely related to KRAS mutant cells. Here, we further investigated whether cetuximab-mediated regulation of p38/Nrf2/HO-1 promotes RSL3-induced ferroptosis and plays a pivotal role in overcoming drug resistance in KRAS mutant colorectal cancer (CRC). In our research, we used two KRAS mutant CRC cell lines, HCT116 and DLD-1, as models of intrinsic resistance to cetuximab. The viability of cells treated with the combination of RSL3 and cetuximab was assessed by the CCK-8 and colony formation assays. The effective of cetuximab to promote RSL3-induced ferroptosis was investigated by evaluating lipid reactive oxygen species accumulation and the expression of the malondialdehyde and the intracellular iron assay. Cetuximab therapy contributed to regulating the p38/Nrf2/HO-1 axis, as determined by western blotting and transfection with small interfering RNAs. Cetuximab promoted RSL3-induced ferroptosis by inhibiting the Nrf2/HO-1 in KRAS mutant CRC cells, and this was further demonstrated in a xenograft nude mouse model. Our work reveals that cetuximab enhances the cytotoxic effect of RSL3 on KRAS mutant CRC cells and that cetuximab enhances RSL3-induced ferroptosis by inhibiting the Nrf2/HO-1 axis through the activation of p38 MAPK.
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Affiliation(s)
- Jiawen Yang
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, People's Republic of China
| | - Jiajie Mo
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, People's Republic of China
| | - Juji Dai
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, People's Republic of China
| | - Chenqiao Ye
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, People's Republic of China
| | - Wei Cen
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, People's Republic of China
| | - Xuzhi Zheng
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, People's Republic of China
| | - Lei Jiang
- Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, People's Republic of China.
| | - Lechi Ye
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, People's Republic of China.
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9
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Current Treatment Landscape for Third- or Later-Line Therapy in Metastatic Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2021. [DOI: 10.1007/s11888-021-00469-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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10
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Nakajima H, Kotani D, Bando H, Kato T, Oki E, Shinozaki E, Sunakawa Y, Yamazaki K, Yuki S, Nakamura Y, Yamanaka T, Yoshino T, Ohta T, Taniguchi H, Kagawa Y. REMARRY and PURSUIT trials: liquid biopsy-guided rechallenge with anti-epidermal growth factor receptor (EGFR) therapy with panitumumab plus irinotecan for patients with plasma RAS wild-type metastatic colorectal cancer. BMC Cancer 2021; 21:674. [PMID: 34098908 PMCID: PMC8186219 DOI: 10.1186/s12885-021-08395-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 05/23/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Previous clinical trials have demonstrated the potential efficacy of rechallenge with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) for patients with RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). Moreover, post hoc biomarker analyses of clinical trials has suggested that RAS status in circulating tumor DNA (ctDNA) has a high probability to select patients who could benefit from anti-EGFR mAb rechallenge. METHODS This trial is composed of 2 phases: a monitoring phase (REMARRY) and a trial phase (PURSUIT). A monitoring phase, the REMARRY study, aims to evaluate the dynamics of plasma RAS status during the subsequent treatments after refractory to anti-EGFR therapy in patients with mCRC with RAS/BRAF V600E wild-type tumors who have progressed after a response to previous anti-EGFR therapy, using a highly sensitive digital polymerase chain reaction OncoBEAM RAS CRC kit in a central laboratory (Sysmex, Japan). A trial phase, the PURSUIT trial, is a multicenter, single-arm phase II trial to assess the efficacy and safety of rechallenge therapy with panitumumab plus irinotecan in patients without RAS mutations in ctDNA (plasma RAS negative) in the REMARRY study. Key eligibility criteria of the PURSUIT trial include RAS/BRAF V600E wild-type mCRC in tumor tissue refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; progression after complete or partial response to previous anti-EGFR therapy; plasma RAS negative (defined as plasma mutant allele frequencies [MAF] of all RAS ≤ 0.1%) within 28 days prior to enrollment; 4 months or more between the last administration of previous anti-EGFR mAb and the start of protocol treatment; and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. The primary endpoint is the confirmed objective response rate (ORR). The target sample size of the PURSUIT trial is 50 patients. Biomarker analyses will be performed in parallel using the OncoBEAM RAS CRC kit and a next-generation sequencing-based ctDNA analysis (Guardant360). DISCUSSION Our trial aims to confirm the clinical benefit of anti-EGFR mAb rechallenge therapy in patients with plasma RAS negative. Moreover, through biomarker analyses, our trial will shed light on which patients would benefit from rechallenge in addition to being plasma RAS negative. TRIAL REGISTRATION The REMARRY study: UMIN, UMIN000036424 . Registered date: April 5, 2019. The PURSUIT trial: jRCT, jRCTs031190096 . Registered date: October 1, 2019.
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Affiliation(s)
- Hiromichi Nakajima
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Daisuke Kotani
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hideaki Bando
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Takeshi Kato
- Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Shinozaki
- Department of Gastroenterology, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Kentaro Yamazaki
- Divison of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Satoshi Yuki
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Yoshiaki Nakamura
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan
| | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takashi Ohta
- Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan
| | - Hiroya Taniguchi
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yoshinori Kagawa
- Department of Colorectal Surgery, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka, Japan.
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11
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Hwang K, Yoon JH, Lee JH, Lee S. Recent Advances in Monoclonal Antibody Therapy for Colorectal Cancers. Biomedicines 2021; 9:39. [PMID: 33466394 PMCID: PMC7824816 DOI: 10.3390/biomedicines9010039] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/31/2020] [Accepted: 12/31/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide. Recent advances in recombinant DNA technology have led to the development of numerous therapeutic antibodies as major sources of blockbuster drugs for CRC therapy. Simultaneously, increasing numbers of therapeutic targets in CRC have been identified. In this review, we first highlight the physiological and pathophysiological roles and signaling mechanisms of currently known and emerging therapeutic targets, including growth factors and their receptors as well as immune checkpoint proteins, in CRC. Additionally, we discuss the current status of monoclonal antibodies in clinical development and approved by US Food and Drug Administration for CRC therapy.
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Affiliation(s)
| | | | | | - Sukmook Lee
- Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Korea; (K.H.); (J.H.Y.); (J.H.L.)
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12
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Readministration of Cancer Drugs in a Patient with Chemorefractory Metastatic Colorectal Cancer. Case Rep Oncol Med 2020; 2020:2351810. [PMID: 32655959 PMCID: PMC7330645 DOI: 10.1155/2020/2351810] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 06/03/2020] [Accepted: 06/11/2020] [Indexed: 11/22/2022] Open
Abstract
A 63-year-old woman was admitted to our institution for severe pain in her right lower abdomen caused by the perforation of cecal cancer. She underwent emergency surgery, from which she was diagnosed with cecal carcinoma with liver, lung, and lymph node metastases. As she was taking aspirin to prevent cerebral infarction, anti-vascular endothelial growth factor (receptor) antibody and regorafenib therapy were not used. Thus, we started a modified FOLFOX 6+cetuximab regimen. This first-line treatment initially achieved a partial response (PR), but she then developed progressive disease (PD) after 14 months. We changed the regimen to FOLFIRI, followed by trifluridine/tipiracil, but her progression-free survival periods were 2.7 months and 1 month, respectively. Although we cycled through the available array of standard cancer drugs, the patient showed a good performance status, and some benefit from treatment still seemed plausible. We readministered the 5-fluorouracil oral preparation S-1, which maintained stable disease (SD) for 7 months. After PD emerged, we readministered the anti-epidermal growth factor receptor (EGFR) antibody panitumumab for 7.5 months of SD. Finally, 39 months after her diagnosis, she died from rapidly progressing disease. However, her relatively long survival implies that readministering drugs similar to those used in previous regimens might benefit patients with metastatic colorectal cancer.
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13
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Piccirillo MC, Avallone A, Carlomagno C, Maiello E, Rosati G, Alabiso O, Nasti G, De Placido S, Latiano TP, Bilancia D, Ottaiano A, De Stefano A, Romano C, Silvestro L, Nappi A, Cassata A, Giordano P, Iaffaioli RV, Normanno N, Perrone F, Daniele B. Multicenter Single-Arm, Two-Stage Phase 2 Study of Panitumumab in Patients With Cetuximab-Refractory Metastatic Colorectal Cancer: The PACER Trial. Clin Colorectal Cancer 2020; 19:270-276. [PMID: 32631788 DOI: 10.1016/j.clcc.2020.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 01/23/2020] [Accepted: 05/22/2020] [Indexed: 11/26/2022]
Abstract
PURPOSE To assess whether panitumumab is active in patients with cetuximab-refractory metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Eligible patients had pretreated RAS (renin-angiotensin system) wild-type mCRC that progressed after cetuximab treatment, after having shown either objective response or stable disease. A minimax two-stage design was applied, with progression-free rate at 2 months as the primary end point. At least 12 of 28 and 21 of 41 successes at the first and second stage, respectively, were required for a positive result. Panitumumab 6 mg/kg was provided every 2 weeks, until progression or unacceptable toxicity. RESULTS Overall, 52 patients with KRAS (Kirsten rat sarcoma viral oncogene) wild-type disease were enrolled, but 11 were found to have mutated disease after all-RAS retesting. Among 41 eligible patients, median time since diagnosis was 38 months, and 71% experienced an objective response to previous cetuximab. First stage was passed with 12 of 28 patients alive without progression at 2 months. At the second stage, 17 of 41 patients were alive without progression at 2 months. At a median follow-up of 21.8 months, 35 patients experienced disease progression, and 26 died. Median progression-free survival was 2.1 months (95% confidence interval, 1.8-3.6) and median overall survival 6.8 months (95% confidence interval, 4.6-16.6). Most of the patients experienced no adverse reactions; 25% of patients had grade 3 rash. CONCLUSION According to our study design, panitumumab was not effective in patients with cetuximab-refractory RAS wild-type mCRC.
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Affiliation(s)
- Maria Carmela Piccirillo
- Unità Sperimentazioni Cliniche, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Antonio Avallone
- Oncologia Clinica Sperimentale Addome, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Chiara Carlomagno
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Napoli, Italy
| | - Evaristo Maiello
- Oncologia Medica, IRCCS, Casa Sollievo Sofferenza, S. Giovanni Rotondo (FG), Italy
| | | | | | - Guglielmo Nasti
- Oncologia Clinica Sperimentale Addome, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Sabino De Placido
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Napoli, Italy
| | - Tizana Pia Latiano
- Oncologia Medica, IRCCS, Casa Sollievo Sofferenza, S. Giovanni Rotondo (FG), Italy
| | | | - Alessandro Ottaiano
- Oncologia Clinica Sperimentale Addome, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Alfonso De Stefano
- Oncologia Clinica Sperimentale Addome, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Carmela Romano
- Oncologia Clinica Sperimentale Addome, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Lucrezia Silvestro
- Oncologia Clinica Sperimentale Addome, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Anna Nappi
- Oncologia Clinica Sperimentale Addome, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Antonino Cassata
- Oncologia Clinica Sperimentale Addome, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | | | - Rosario Vincenzo Iaffaioli
- Oncologia Clinica Sperimentale Addome, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Nicola Normanno
- Biologia Cellulare e Bioterapie, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Francesco Perrone
- Unità Sperimentazioni Cliniche, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
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14
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Parseghian CM, Napolitano S, Loree JM, Kopetz S. Mechanisms of Innate and Acquired Resistance to Anti-EGFR Therapy: A Review of Current Knowledge with a Focus on Rechallenge Therapies. Clin Cancer Res 2019; 25:6899-6908. [PMID: 31263029 PMCID: PMC6891150 DOI: 10.1158/1078-0432.ccr-19-0823] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/16/2019] [Accepted: 06/26/2019] [Indexed: 02/06/2023]
Abstract
Innate and acquired resistance to anti-EGFR therapy (EGFRi) is a major limitation in the treatment of metastatic colorectal cancer (mCRC). Although RAS genes are the most commonly mutated innate and acquired oncogenes in cancer, there are a number of other mechanisms that limit the effectiveness of EGFRi. Patients with innate resistance have been found to contain BRAFV600E mutations, and possibly MET, MEK, PIK3CA, PTEN, and HER2 alterations. Meanwhile, BRAFV600E mutations may also be involved in acquired resistance to EGFRi, in addition to EGFR ectodomain mutations, MET alterations, and possibly HER2 amplification. In addition, paracrine effects and cell-fate mechanisms of resistance are being increasingly described as contributing to acquired resistance. Utilization of circulating tumor DNA has been paramount in monitoring the dynamic nature of acquired resistance and has helped to guide treatment decisions, particularly in the EGFRi rechallenge setting. Herein, we provide an in-depth review of EGFRi-resistance mechanisms and describe the current therapeutic landscape in the hopes of identifying effective rechallenge strategies.
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Affiliation(s)
- Christine M Parseghian
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Stefania Napolitano
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
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15
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Taieb J, Jung A, Sartore-Bianchi A, Peeters M, Seligmann J, Zaanan A, Burdon P, Montagut C, Laurent-Puig P. The Evolving Biomarker Landscape for Treatment Selection in Metastatic Colorectal Cancer. Drugs 2019; 79:1375-1394. [PMID: 31347092 PMCID: PMC6728290 DOI: 10.1007/s40265-019-01165-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The approval of targeted therapies for metastatic colorectal cancer (mCRC) has led to important improvements in patient outcomes. However, it is still necessary to increase individualisation of treatments based on tumour genetic profiles to optimise efficacy, while minimising toxicity. As such, there is currently great focus on the discovery and validation of further biomarkers in mCRC, with many new potential prognostic and predictive markers being identified alongside developments in patient molecular profiling technologies. Here, we review data for validated and emerging biomarkers impacting treatment strategies in mCRC. We completed a structured literature search of the PubMed database to identify relevant publications, limiting for English-language publications published between 1 January 2014 and 11 July 2018. In addition, we performed a manual search of the key general oncology and CRC-focused congresses to identify abstracts reporting emerging mCRC biomarker data, and of ClinicalTrials.gov to identify ongoing clinical trials investigating emerging biomarkers in mCRC and/or molecular-guided clinical trials. There is solid evidence supporting the use of BRAF status as a prognostic biomarker and DYPD, UGT1A1, RAS, and microsatellite instability as predictive biomarkers in mCRC. There are a number of emerging biomarkers that may prove to be clinically relevant in the future to have prognostic (HPP1 methylation), predictive (HER3, microRNAs, anti-angiogenic markers, and CRC intrinsic subtypes), or both prognostic and predictive values (HER2, CpG island methylator phenotype, tumour mutational load, gene fusions, and consensus molecular subtypes). As such, new biomarker-led treatment strategies in addition to anti-epidermal growth factor receptor and anti-angiogenetic treatments are being explored. Biomarkers that are not recommended to be tested in clinical practice or are unlikely to be imminently clinically relevant for mCRC include thymidylate transferase, ERCC1, PIK3CA, and PTEN. We highlight the clinical utility of existing and emerging biomarkers in mCRC and provide recommended treatment strategies according to the biomarker status. An update on ongoing molecular-guided clinical trials is also provided.
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Affiliation(s)
- Julien Taieb
- Sorbonne Paris Cité, Paris Descartes University, Georges Pompidou European Hospital, Paris, France.
| | - Andreas Jung
- Pathology Institute, Ludwig Maximilians University of Munich, Munich, Germany
- German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Marc Peeters
- Department of Oncology, Antwerp University Hospital/Antwerp University, Edegem, Belgium
| | - Jenny Seligmann
- Division of Cancer Studies and Pathology, St James's Institute of Oncology, Leeds, UK
| | - Aziz Zaanan
- Sorbonne Paris Cité, Paris Descartes University, Georges Pompidou European Hospital, Paris, France
| | - Peter Burdon
- European Medical, Amgen (Europe) GmbH, Rotkreuz, Switzerland
| | - Clara Montagut
- Medical Oncology Department, Hospital del Mar-IMIM, CIBERONC, HM Delfos, Barcelona, Spain
| | - Pierre Laurent-Puig
- Sorbonne Paris Cité, Paris Descartes University, Georges Pompidou European Hospital, Paris, France
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16
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Rawla P, Barsouk A, Hadjinicolaou AV, Barsouk A. Immunotherapies and Targeted Therapies in the Treatment of Metastatic Colorectal Cancer. Med Sci (Basel) 2019; 7:E83. [PMID: 31366129 PMCID: PMC6723550 DOI: 10.3390/medsci7080083] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 07/27/2019] [Accepted: 07/28/2019] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer deaths, and while mortality has largely improved in the developed world, five-year survival for metastatic disease remains dismally low at only 15%. Fortunately, nearly a dozen targeted therapies and immunotherapies have been FDA approved in the past decade for certain patient profiles with metastatic CRC (mCRC), and many others are under development. Checkpoint inhibitors such as pembrolizumab have proven effective at extending survival for mismatch repair (MMR)-deficient and high microsatellite instability (MSI) mCRC patients. In combination with chemotherapy in first- and second-line treatment, antiangiogenic (anti-vascular endothelial growth factor (anti-VGEF)) agent bevacizumab has been shown to increase mCRC survival. Anti-epidermal growth factor receptor (anti-EGFR) agents panitumumab and cetuximab, in combination with chemotherapy, have also prolonged survival among KRAS and all RAS wild-type mCRC patients. Among these patients, anti-EGFR therapy has been found to be more efficacious than bevacizumab. Improved selectivity has allowed small-molecule receptor tyrosine kinase (RTK) inhibitors to target VEGF and EGFR with greater efficacy and tolerability. Combinations of immunotherapies, RTKs, monoclonal antibodies, and cytotoxic drugs are being investigated to provide broad-spectrum protection against relapse by simultaneously targeting many cancer hallmarks. Lastly, human epidermal growth factor receptor 2 (HER2) therapy has shown promise for HER2-positive mCRC patients, though larger clinical trials are required to secure FDA approval.
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Affiliation(s)
- Prashanth Rawla
- Department of Medicine, Sovah Health, Martinsville, VA 24112, USA.
| | - Adam Barsouk
- Hillman Cancer Center, University of Pittsburgh, PA 15232, USA
| | - Andreas V Hadjinicolaou
- Academic Clinical Post-doctoral Fellow and Gastroenterology Resident, MRC Cancer Unit and Department of Gastroenterology, University of Cambridge, Cambridge CB2 0XZ, UK
| | - Alexander Barsouk
- Hematologist-Oncologist, Allegheny Health Network, Pittsburgh, PA 15212, USA
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17
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Clinical Pharmacokinetics and Pharmacodynamics of the Epidermal Growth Factor Receptor Inhibitor Panitumumab in the Treatment of Colorectal Cancer. Clin Pharmacokinet 2019; 57:455-473. [PMID: 28853050 PMCID: PMC5856878 DOI: 10.1007/s40262-017-0590-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Despite progress in the treatment of metastatic colorectal cancer (mCRC) in the last 15 years, it is still a condition with a relatively low 5-year survival rate. Panitumumab, a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is able to prolong survival in patients with mCRC. Panitumumab is used in different lines of therapy in combination with chemotherapy, and as monotherapy for the treatment of wild-type (WT) RAS mCRC. It is administered as an intravenous infusion of 6 mg/kg every 2 weeks and has a t½ of approximately 7.5 days. Elimination takes place via two different mechanisms, and immunogenicity rates are low. Only RAS mutations have been confirmed as a negative predictor of efficacy with anti-EGFR antibodies. Panitumumab is generally well tolerated and has a manageable toxicity profile, despite a very high prevalence of dermatologic side effects. This article presents an overview of the clinical pharmacokinetics and pharmacodynamics of panitumumab, including a description of the studies that led to its approval in the different lines of therapy of mCRC.
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18
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Mauri G, Pizzutilo EG, Amatu A, Bencardino K, Palmeri L, Bonazzina EF, Tosi F, Carlo Stella G, Burrafato G, Scaglione F, Marsoni S, Siravegna G, Bardelli A, Siena S, Sartore-Bianchi A. Retreatment with anti-EGFR monoclonal antibodies in metastatic colorectal cancer: Systematic review of different strategies. Cancer Treat Rev 2019; 73:41-53. [PMID: 30616224 DOI: 10.1016/j.ctrv.2018.12.006] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Revised: 12/22/2018] [Accepted: 12/24/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Despite advances in precision oncology and immunotherapy of tumors, little progress has been made in metastatic colorectal cancer (mCRC) in recent years. Therefore, making the most of available therapies is a necessity. Several studies, based on the pulsatile behavior of RAS clones under EGFR blockade, investigated whether readministration of EGFR-targeted agents is effective beyond second line. METHODS A systematic review of studies of retreatment with anti-EGFR monoclonal antibodies has been performed from January 2005 to December 2018 according to PRISMA criteria from PubMed, ESMO and ASCO meetings libraries and Clinicaltrial.gov. Efficacy has been evaluated as objective response rate and survival in available publications. In addition, type and incidence of side effects occurring during on anti-EGFR retreatment have been considered. RESULTS 26 publications have been retrieved, of which 20 full-text articles and 6 abstracts and categorized as for the retreatment strategy into five groups: rechallenge (n = 10), reintroduction (n = 4), sequence (n = 5), dose escalation (n = 1) and mixed (n = 6). Data of efficacy displayed high heterogeneity across different strategies (objective response rate, ORR = 0.0-53.8%; disease control rate, DCR = 24.0-89.7%), with best results in the setting of rechallenge (ORR = 2.9-53.8%; DCR = 40.0-89.7%). CONCLUSIONS Rechallenge with anti-EGFR provides clinical benefit in molecularly selected mCRC patients beyond second line. Further ctDNA-guided studies comparing this option of treatment with current approved advanced line treatments are warranted.
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Affiliation(s)
- Gianluca Mauri
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Università degli Studi di Milano, Dipartimento di Oncologia ed Emato-Oncologia, Milano, Italy
| | - Elio Gregory Pizzutilo
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Università degli Studi di Milano, Dipartimento di Oncologia ed Emato-Oncologia, Milano, Italy
| | - Alessio Amatu
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Katia Bencardino
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Laura Palmeri
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | | | - Federica Tosi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giulia Carlo Stella
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giovanni Burrafato
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Francesco Scaglione
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Università degli Studi di Milano, Dipartimento di Oncologia ed Emato-Oncologia, Milano, Italy
| | - Silvia Marsoni
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; FIRC Institute of Molecular Oncology (IFOM), Milan, Italy
| | - Giulia Siravegna
- Candiolo Cancer Insitute - FPO, IRCCS, Candiolo, Turin, Italy; Department of Oncology, University of Torino, Candiolo, Turin, Italy
| | - Alberto Bardelli
- Candiolo Cancer Insitute - FPO, IRCCS, Candiolo, Turin, Italy; Department of Oncology, University of Torino, Candiolo, Turin, Italy
| | - Salvatore Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Università degli Studi di Milano, Dipartimento di Oncologia ed Emato-Oncologia, Milano, Italy
| | - Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Università degli Studi di Milano, Dipartimento di Oncologia ed Emato-Oncologia, Milano, Italy.
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19
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Modest DP, Pant S, Sartore-Bianchi A. Treatment sequencing in metastatic colorectal cancer. Eur J Cancer 2019; 109:70-83. [PMID: 30690295 DOI: 10.1016/j.ejca.2018.12.019] [Citation(s) in RCA: 227] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Accepted: 12/18/2018] [Indexed: 12/17/2022]
Abstract
Metastatic colorectal cancer (mCRC) remains incurable in most cases, but survival has improved with advances in cytotoxic chemotherapy and targeted agents. However, the optimal use and sequencing of these agents across multiple lines of treatment is unclear. Here, we review current treatment approaches and optimal treatment sequencing across the first-, second- and third-line settings in mCRC, including biological aspects affecting sequencing and rechallenge. Effective first-line therapy is a key determinant of treatment outcomes and should be selected after considering both clinical factors and biological markers, notably RAS and BRAF. The second-line regimen choice depends on the systemic therapies given in first-line. Anti-angiogenic agents (e.g. bevacizumab, ramucirumab and aflibercept) are indicated for most patients, whereas epidermal growth factor receptor (EGFR) inhibitors do not improve survival in the second-line setting. Molecular profiling is important in third-line treatment, with options in RAS wild-type patients including EGFR inhibitors (cetuximab or panitumumab), regorafenib and trifluridine/tipiracil. Immunotherapy with pembrolizumab or nivolumab ± ipilimumab may be considered for patients with high microsatellite instability disease. Targeting HER2/neu amplification shows promise for the subset of CRC tumours displaying this abnormality. Sequencing decisions are complicated by the potential for any treatment break or de-escalation to evoke a distinct clinical progression type. Ongoing trials are investigating the optimal sequencing and timing of therapies for mCRC. Molecular profiling has established new targets, and increasing knowledge of tumour evolution under drug pressure will possibly impact on sequencing.
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Affiliation(s)
- D P Modest
- Department of Medicine III, University Hospital, LMU Munich, Germany.
| | - S Pant
- Department of Investigational Cancer Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - A Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore, 3, 20162, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy
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20
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Bekaii-Saab T, Kim R, Kim TW, O'Connor JM, Strickler JH, Malka D, Sartore-Bianchi A, Bi F, Yamaguchi K, Yoshino T, Prager GW. Third- or Later-line Therapy for Metastatic Colorectal Cancer: Reviewing Best Practice. Clin Colorectal Cancer 2018; 18:e117-e129. [PMID: 30598357 DOI: 10.1016/j.clcc.2018.11.002] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/08/2018] [Accepted: 11/09/2018] [Indexed: 02/05/2023]
Abstract
An increasing number of patients with metastatic colorectal cancer (mCRC) are able to receive 3 or more lines of therapy. Treatments in this setting can include regorafenib (an oral multikinase inhibitor), trifluridine/tipiracil hydrochloride (TAS-102), antibodies that target epidermal growth factor receptor for patients with RAS wild-type tumors (if no prior exposure), and, where approved, anti-programmed cell death protein 1 inhibitors for patients with microsatellite instability-high mCRC. Although guidelines describe the available treatment options, few insights are provided to guide selection and sequencing. In this article, we share expert opinion from diverse geographic regions, to offer guidance for best practice when selecting and managing third-line treatment for mCRC. Various factors, including performance status, age, and tumor sidedness, can be used to guide treatment selection. Biomarkers, such as RAS, BRAF, and microsatellite instability, can be useful for treatment stratification. Management of adverse events, to maintain quality of life, is a key consideration and is crucial to best practice in this setting. Common toxicities associated with third-line treatments are hand-foot skin reaction, fatigue, diarrhea, and cytopenias. Patients who receive third-line and later-line treatments should be monitored for these events, especially during the first 2 cycles. Dose modifications can also be used to manage toxicities and to minimize the effect on quality of life, while maximizing treatment benefit. Clinical trials of emerging agents, new treatment combinations, and novel therapies continue the efforts to improve outcomes for patients with mCRC. Sharing expert opinions on best practice for treatment selection and management can ultimately improve outcomes for patients with mCRC.
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Affiliation(s)
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL
| | - Tae Won Kim
- Department of Oncology, ASAN Medical Center, University of Ulsan, Seoul, South Korea
| | - Juan Manuel O'Connor
- Department Clinical Oncology, Clinical Oncology Instituto Alexander Fleming, Buenos Aires, Argentina
| | - John H Strickler
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC
| | - David Malka
- Department of Cancer Medicine, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Feng Bi
- Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Gerald W Prager
- Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University Vienna, Vienna, Austria.
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21
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Tanioka H, Asano M, Yoshida R, Waki N, Uno F, Ishizaki M, Yamashita K, Morishita Y, Nagasaka T. Cetuximab retreatment in patients with metastatic colorectal cancer who exhibited a clinical benefit in response to prior cetuximab: A retrospective study. Oncol Lett 2018; 16:3674-3680. [PMID: 30127977 PMCID: PMC6096178 DOI: 10.3892/ol.2018.9127] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 04/05/2018] [Indexed: 12/13/2022] Open
Abstract
Clinical benefits of cetuximab retreatment in patients with metastatic colorectal (mCRC) have been reported. In the present study, the effect of cetuximab retreatment on predictive markers was investigated by evaluating the clinical benefit of initial cetuximab treatment prior to cetuximab retreatment. Between November 2012 and March 2017, 14 patients with KRAS proto-oncogene GTPase exon 2 wild-type mCRC who exhibited a clinical benefit (confirmed stable disease for at least 6 months or a clinical response) to an initial cetuximab-based regimen, who received multiple lines of chemotherapy following disease progression and ultimately received a second cetuximab and irinotecan regimen, were retrospectively analyzed. For retreatment, patients received bi-weekly irinotecan (120-150 mg/m2) combined with cetuximab (400 mg/m2 as an initial dose, followed by 250 mg/m2, weekly). The median age of the 14 patients (11 males, 3 females) was 68 years (32-77). The median progression-free survival (PFS) following prior cetuximab-based therapy was 6.6 months (range, 4.1-18.4). Initial cetuximab treatment was administered as a first-line treatment in 11 patients, a second-line treatment in 1 patient and a third-line treatment in 2 patients. The median interval time between the last cycle of initial cetuximab-based therapy and the first cycle of cetuximab retreatment was 13.1 months (range, 6.0-37.1). The objective response rate of cetuximab retreatment was 21.4% and the median PFS was 4.4 months (95% confidence interval, 1.4-5.6). The Spearman's correlation coefficient for the PFS following retreatment and duration of initial cetuximab-based regimens demonstrated a more marked correlation compared with that between the PFS following retreatment and the interval time between the two regimens (r=0.45, P=0.11 vs. r=0.08, P=0.79). Cetuximab retreatment may provide clinical benefit to patients with mCRC who were good responders with longer periods of initial cetuximab-based therapy.
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Affiliation(s)
- Hiroaki Tanioka
- Department of Medical Oncology, Okayama Rosai Hospital, Okayama 702-8055, Japan.,Department of Clinical Oncology, Kawasaki Medical School Hospital, Okayama 701-0192, Japan
| | - Motoi Asano
- Department of Medical Oncology, Okayama Rosai Hospital, Okayama 702-8055, Japan
| | - Ryousuke Yoshida
- Department of Surgery, Okayama Rosai Hospital, Okayama 702-8055, Japan
| | - Naohisa Waki
- Department of Surgery, Okayama Rosai Hospital, Okayama 702-8055, Japan
| | - Futoshi Uno
- Department of Surgery, Okayama Rosai Hospital, Okayama 702-8055, Japan
| | - Masahiro Ishizaki
- Department of Surgery, Okayama Rosai Hospital, Okayama 702-8055, Japan
| | - Kazuki Yamashita
- Department of Surgery, Okayama Rosai Hospital, Okayama 702-8055, Japan
| | - Yuki Morishita
- Department of Pharmacy, Okayama Rosai Hospital, Okayama 702-8055, Japan
| | - Takeshi Nagasaka
- Department of Clinical Oncology, Kawasaki Medical School Hospital, Okayama 701-0192, Japan
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22
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Martinez-Perez J, Riesco-Martinez MC, Garcia-Carbonero R. The safety of trifluridine and tipiracil for the treatment of metastatic colorectal cancer. Expert Opin Drug Saf 2018; 17:643-650. [DOI: 10.1080/14740338.2018.1475557] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Julia Martinez-Perez
- Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital, Madrid, Spain
| | - M. Carmen Riesco-Martinez
- Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital, Madrid, Spain
| | - Rocio Garcia-Carbonero
- Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital, Madrid, Spain
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23
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McGregor M, Price TJ. Panitumumab in the treatment of metastatic colorectal cancer, including wild-type RAS, KRAS and NRAS mCRC. Future Oncol 2018; 14:2437-2459. [PMID: 29737864 DOI: 10.2217/fon-2017-0711] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The humanized monoclonal antibody panitumumab, targeted against EGFR, plays an important role in patients with metastatic colorectal cancer. This article reviews the body of evidence for panitumumab which demonstrates significant benefits across multiple lines of therapy in those without an extended RAS mutation. The use of panitumumab with RAS mutations is not beneficial and possibly harmful. Panitumumab is well tolerated with manageable toxicities. The role of panitumumab continues to evolve as understanding of sequencing of therapies grows. There is evidence for use as maintenance therapy and conversion therapy for unresectable liver metastases. Future research is likely to focus on biomarkers for improved patient selection and the development of novel therapeutic strategies to overcome resistance.
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Affiliation(s)
- Mark McGregor
- Medical Oncology, Adelaide Oncology & Haematology, North Adelaide, Australia.,Medical Oncology, Flinders Medical Centre, Adelaide, Australia
| | - Timothy J Price
- Medical Oncology, Adelaide Oncology & Haematology, North Adelaide, Australia.,Medical Oncology, The Queen Elizabeth Hospital & University of Adelaide, Woodville, Adelaide, Australia
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24
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Goldberg RM, Montagut C, Wainberg ZA, Ronga P, Audhuy F, Taieb J, Stintzing S, Siena S, Santini D. Optimising the use of cetuximab in the continuum of care for patients with metastatic colorectal cancer. ESMO Open 2018; 3:e000353. [PMID: 29765773 PMCID: PMC5950648 DOI: 10.1136/esmoopen-2018-000353] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 03/19/2018] [Accepted: 03/21/2018] [Indexed: 12/17/2022] Open
Abstract
The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in combination with chemotherapy is a standard of care in the first-line treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC) and has demonstrated efficacy in later lines. Progressive disease (PD) occurs when tumours develop resistance to a therapy, although controversy remains about whether PD on a combination of chemotherapy and targeted agents implies resistance to both components. Here, we propose that some patients may gain additional clinical benefit from the reuse of cetuximab after having PD on regimens including cetuximab in an earlier treatment line. We conducted a non-systematic literature search in PubMed and reviewed published and ongoing clinical trials, focusing on later-line cetuximab reuse in patients with mCRC. Evidence from multiple studies suggests that cetuximab can be an efficacious and tolerable treatment when continued or when fit patients with mCRC are retreated with it after a break from anti-EGFR therapy. Furthermore, on the basis of available preclinical and clinical evidence, we propose that longitudinal monitoring of RAS status may identify patients suitable for such a strategy. Patients who experience progression on cetuximab plus chemotherapy but have maintained RAS wt tumour status may benefit from continuation of cetuximab with a chemotherapy backbone switch because they have probably developed resistance to the chemotherapeutic agents rather than the biologic component of the regimen. Conversely, patients whose disease progresses on cetuximab-based therapy due to drug-selected clonal expansion of RAS-mutant tumour cells may regain sensitivity to cetuximab following a defined break from anti-EGFR therapy. Looking to the future, we propose that RAS status determination at disease progression by liquid, needle or excisional biopsy may identify patients eligible for cetuximab continuation and rechallenge. With this approach, treatment benefit can be extended, adding to established continuum-of-care strategies in patients with mCRC.
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Affiliation(s)
- Richard M Goldberg
- Cancer Signature Program, West Virginia University Cancer Institute, Morgantown, West Virginia, USA
| | - Clara Montagut
- Gastrointestinal Cancer, Department of Medical Oncology, Hospital del Mar-IMIM, Barcelona, Spain
| | - Zev A Wainberg
- University of California Los Angeles David Geffen School of Medicine, Division of Hematology/Oncology, Department of Medicine, Los Angeles, California, USA
| | | | | | - Julien Taieb
- Hôpital Européen Georges-Pompidou, APHP, Paris Descartes University, Sorbonne Paris Cité, Department of GI Oncology, Paris, France
| | - Sebastian Stintzing
- University Hospital, Ludwig-Maximilians-University Munich, Department of Medicine III, Munich, Germany
| | - Salvatore Siena
- Università degli Studi di Milano, Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Department of Hematology and Oncology, Milan, Italy
| | - Daniele Santini
- Unit of Medical Oncology, Università Campus Bio-Medico, Rome, Italy
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25
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Izzedine H, Perazella MA. Adverse kidney effects of epidermal growth factor receptor inhibitors. Nephrol Dial Transplant 2018; 32:1089-1097. [PMID: 28339780 DOI: 10.1093/ndt/gfw467] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Accepted: 12/15/2016] [Indexed: 12/17/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) is implicated in various malignancies. The past decade has seen the development and widespread use of EGFR inhibitors for the successful treatment of such cancers. Available EGFR inhibitors include small molecule tyrosine-kinase inhibitors and monoclonal antibodies. Class-related renal adverse events result in dual toxicity including tubular/electrolyte disorders and glomerulopathies. Tubular injury is common and mainly due to monoclonal antibodies while glomerulopathy is rare and related to various anti-EGFR agents. The exact pathogenesis of anti-EGFR agents associated with kidney disorders remains to be elucidated.
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Affiliation(s)
- Hassan Izzedine
- Department of Nephrology, Monceau Park International Clinic, Paris, France
| | - Mark A Perazella
- Department of Nephrology, Yale University School of Medicine, New Haven, CT, USA
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26
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Yee K. Redefining Later-Line Therapy in Metastatic Colorectal Cancer. EUROPEAN MEDICAL JOURNAL 2017. [DOI: 10.33590/emj/10311880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer death in the world, accounting for approximately 1.4 million new cases and almost 700,000 deaths in 2012.1 The objective of the symposium was to provide an overview of the current treatment landscape in terms of later-line therapy in metastatic CRC (mCRC) and to discuss the evidence for the various options available, including rechallenge and therapies such as trifluridine (FTD)/tipiracil (TPI) (Lonsurf®; also known as TAS-102) and regorafenib (Stivarga®). The symposium started by examining the clinical value of third-line treatment in patients with mCRC and providing an insight into the mechanism of action of FTD/TPI, and a comparison with that of 5-fluorouracil (5-FU). The safety and efficacy of FTD/ TPI was then discussed together with the practical management of patients on treatment. The speakers tackled the issue of rechallenge and reintroduction as an option in the third-line, reviewing the pros and cons, and the available studies providing information on the safety and efficacy of the different options in later lines, concluding that there is a lack of robust evidence for rechallenge as a clinical decision. This was followed by a review of the compelling evidence for the use of treatments such as FTD/TPI and regorafenib in the third-line, with documented evidence for efficacy.
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27
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Peng J, Wei K, Zhao X, Yang K, Wang H, Zhang Y, Guo M, He J, Wu H, Li Y, Zhao N, Huang Q, Fu W. Wild‑type blocking pcr coupled with internal competitive amplified fragment improved the detection of rare mutation of KRAS. Mol Med Rep 2017; 16:2726-2732. [PMID: 28677778 PMCID: PMC5547944 DOI: 10.3892/mmr.2017.6883] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 06/08/2017] [Indexed: 01/01/2023] Open
Abstract
Mutant KRAS proto-oncogene GTPase (KRAS) serves an important role in predicting the development, diagnosis, treatment and efficacy of targeted drug therapies for colorectal cancer. To improve the detection efficacy of trace amount of mutant KRAS, the locked nucleic acid-based method was modified in the present study. Internal competitive amplification fragments were used to improve the inhibition of wild-type KRAS with a wild-type blocking (WTB) probe and specifically amplify the trace amounts of mutant KRAS. The modified method, quantitative clamp-based polymerase chain reaction technology using WTB coupled with internal competitive reference to enhance the amplification specificity, named WIRE-PCR, completely blocked the amplification of wild-type KRAS in 50–150 ng DNA templates. The added internal competitive amplified fragments were amplified together with the target gene, which were used to reduce base mismatch due to the high number of cycles in PCR and quantify the total amount of DNA. The results demonstrated that WIRE-PCR facilitated the detection of mutated alleles at a single molecular level. In the colorectal biopsies from 50 patients with suspected colorectal cancer, 18 cases (36%) contained mutant KRAS, and the amount of mutant DNA accounted for 18.6–64.2% of the total DNA. WIRE-PCR is a simple, rapid and low-cost quantitative analysis method for the detection of trace amounts of the mutant KRAS.
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Affiliation(s)
- Jia Peng
- Department of Laboratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
| | - Kun Wei
- Department of Laboratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
| | - Xiang Zhao
- Department of Laboratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
| | - Ke Yang
- Department of Laboratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
| | - Huan Wang
- Department of Laboratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
| | - Yang Zhang
- Department of Laboratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
| | - Mei Guo
- Department of Laboratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
| | - Jing He
- Department of Laboratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
| | - Haiyan Wu
- Department of Laboratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
| | - Yongchuan Li
- Department of Laboratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
| | - Na Zhao
- Department of Laboratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
| | - Qing Huang
- Department of Laboratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
| | - Weiling Fu
- Department of Laboratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
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28
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Lubner SJ, Uboha NV, Deming DA. Primary and acquired resistance to biologic therapies in gastrointestinal cancers. J Gastrointest Oncol 2017; 8:499-512. [PMID: 28736637 PMCID: PMC5506279 DOI: 10.21037/jgo.2017.01.16] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 11/09/2016] [Indexed: 12/11/2022] Open
Abstract
Improvements in the understanding of cancer biology have led to therapeutic advances in the treatment of gastrointestinal cancers. Drugs which target the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways have led the way in colon cancer. Monoclonal antibodies (mAbs) such as bevacizumab, ramucirumab, cetuximab, and panitumumab, have improved progression free survival and overall survival (OS) for colorectal cancers and were quickly adopted. Human epidermal growth factor receptor 2 (HER2) has demonstrated significant benefit for gastroesophageal cancers and in the setting of HER2 amplification, trastuzumab in combination with chemotherapy has become the standard of care. However, responses have not been as durable nor as robust as once hoped. Mechanisms of resistance for each of these biologic compounds have been hypothesized and are in the process of being better elucidated. This review will approach the innate and acquired mechanisms of resistance of the above compounds. Additionally, we will explore some ongoing clinical trials to capitalize on the mechanisms of resistance in the hopes of retaining the promise of targeting these pathways.
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Affiliation(s)
- Sam J Lubner
- Department of Medicine, Hematology-Oncology Section, University of Wisconsin Carbone Cancer Center, Madison, WI 53792, USA
| | - Nataliya V Uboha
- Department of Medicine, Hematology-Oncology Section, University of Wisconsin Carbone Cancer Center, Madison, WI 53792, USA
| | - Dustin A Deming
- Department of Medicine, Hematology-Oncology Section, University of Wisconsin Carbone Cancer Center, Madison, WI 53792, USA
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29
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Sartore-Bianchi A, Siena S, Tonini G, Bardelli A, Santini D. Overcoming dynamic molecular heterogeneity in metastatic colorectal cancer: Multikinase inhibition with regorafenib and the case of rechallenge with anti-EGFR. Cancer Treat Rev 2016; 51:54-62. [PMID: 27865140 DOI: 10.1016/j.ctrv.2016.10.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 10/21/2016] [Accepted: 10/23/2016] [Indexed: 12/25/2022]
Abstract
In metastatic colorectal cancer (mCRC), fluorouracil-based combination therapy with oxaliplatin or irinotecan is the mainstay of first-line treatment. Patient survival has been significantly improved with the introduction of monoclonal antibodies against VEGF (bevacizumab), VEGFR2 (ramucirumab) or EGFR (cetuximab or panitumumab) in first- and second-line therapies. However, all patients treated with chemotherapy and targeted therapies will eventually relapse, and recently the emergence of alterations in EGFR, RAS, BRAF, ERB-B2, MET and possibly in other genes has been shown to jeopardize response to EGFR blockade. In chemorefractory patients, multikinase inhibition with regorafenib has proved to be effective and rechallenge with chemotherapy or anti-EGFR agents is empirically pursued. This review will critically discuss how the evolving knowledge of mechanisms of resistance driven by intratumoural dynamic molecular heterogeneity can impact on rational choice of treatments in this setting.
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Affiliation(s)
- Andrea Sartore-Bianchi
- Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda, 20162 Milan, Italy
| | - Salvatore Siena
- Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda, 20162 Milan, Italy; Department of Oncology, Università degli Studi di Milano, 20122 Milan, Italy
| | - Giuseppe Tonini
- Department of Medical Oncology, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Alberto Bardelli
- Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy; Department of Oncology, University of Torino, 10043 Torino, Italy
| | - Daniele Santini
- Department of Medical Oncology, Campus Bio-Medico University of Rome, 00128 Rome, Italy.
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30
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Ohhara Y, Fukuda N, Takeuchi S, Honma R, Shimizu Y, Kinoshita I, Dosaka-Akita H. Role of targeted therapy in metastatic colorectal cancer. World J Gastrointest Oncol 2016; 8:642-55. [PMID: 27672422 PMCID: PMC5027019 DOI: 10.4251/wjgo.v8.i9.642] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 06/21/2016] [Accepted: 07/20/2016] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is a significant cause of cancer-related morbidity and mortality all over the world. Improvements of cytotoxic and biologic agents have prolonged the survival in metastatic CRC (mCRC), with a median overall survival of approximately 2 years and more in the past two decades. The biologic agents that have proven clinical benefits in mCRC mainly target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). In particular, bevacizumab targeting VEGF and cetuximab and panitumumab targeting EGFR have demonstrated significant survival benefits in combination with cytotoxic chemotherapy in the first-line, second-line, or salvage setting. Aflibercept, ramucirumab, and regorafenib are also used in second-line or salvage therapy. Recent retrospective analyses have shown that KRAS or NRAS mutations were negative predictive markers for anti-EGFR therapy. Based on the evidence from large randomized clinical trials, personalized therapy is necessary for patients with mCRC according to their tumor biology and characteristics. The aim of this paper was to summarize the results of the major randomized clinical trials and highlight the benefits of the molecular targeted agents in patients with mCRC.
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31
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Goldman JW, Mendenhall MA, Rettinger SR. Hyperglycemia Associated With Targeted Oncologic Treatment: Mechanisms and Management. Oncologist 2016; 21:1326-1336. [PMID: 27473045 DOI: 10.1634/theoncologist.2015-0519] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 06/09/2016] [Indexed: 12/15/2022] Open
Abstract
: Molecularly targeted cancer therapy has rapidly changed the landscape of oncologic care, often improving patients' prognosis without causing as substantial a quality-of-life decrement as cytotoxic chemotherapy does. Nevertheless, targeted agents can cause side effects that may be less familiar to medical oncologists and that require the attention and expertise of subspecialists. In this review, we focus on hyperglycemia, which can occur with use of new anticancer agents that interact with cell proliferation pathways. Key mediators of these pathways include the tyrosine kinase receptors insulin growth factor receptor 1 (IGF-1R) and epidermal growth factor receptor (EGFR), as well as intracellular signaling molecules phosphatidylinositol 3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR). We summarize available information on hyperglycemia associated with agents that inhibit these molecules within the larger context of adverse event profiles. The highest incidence of hyperglycemia is observed with inhibition of IGF-1R or mTOR, and although the incidence is lower with PI3K, AKT, and EGFR inhibitors, hyperglycemia is still a common adverse event. Given the interrelationships between the IGF-1R and cell proliferation pathways, it is important for oncologists to understand the etiology of hyperglycemia caused by anticancer agents that target those pathways. We also discuss monitoring and management approaches for treatment-related hyperglycemia for some of these agents, with a focus on our experience during the clinical development of the EGFR inhibitor rociletinib. IMPLICATIONS FOR PRACTICE Treatment-related hyperglycemia is associated with several anticancer agents. Many cancer patients may also have preexisting or undiagnosed diabetes or glucose intolerance. Screening can identify patients at risk for hyperglycemia before treatment with these agents. Proper monitoring and management of symptoms, including lifestyle changes and pharmacologic intervention, may allow patients to continue benefiting from use of anticancer agents.
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Affiliation(s)
- Jonathan W Goldman
- Division of Hematology and Oncology, David Geffen School of Medicine at UCLA, Santa Monica, California, USA
| | - Melody A Mendenhall
- Division of Hematology and Oncology, David Geffen School of Medicine at UCLA, Santa Monica, California, USA
| | - Sarah R Rettinger
- Endocrinology Medical Group of Orange County, Inc., Orange, California, USA
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32
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Sforza V, Martinelli E, Ciardiello F, Gambardella V, Napolitano S, Martini G, della Corte C, Cardone C, Ferrara ML, Reginelli A, Liguori G, Belli G, Troiani T. Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer. World J Gastroenterol 2016; 22:6345-61. [PMID: 27605871 PMCID: PMC4968117 DOI: 10.3748/wjg.v22.i28.6345] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 06/11/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
The prognosis of patients with metastatic colorectal cancer (mCRC) remain poor despite the impressive improvement of treatments observed over the last 20 years that led to an increase in median overall survival from 6 mo, with the only best supportive care, to approximately 30 mo with the introduction of active chemotherapy drugs and targeted agents. The monoclonal antibodies (moAbs) cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), undoubtedly represent a major step forward in the treatment of mCRC, given the relevant efficacy in terms of progression-free survival, overall survival, response rate, and quality of life observed in several phase III clinical trials among different lines of treatment. However, the anti-EGFR moAbs were shown only to be effective in a subset of patients. For instance, KRAS and NRAS mutations have been identified as biomarkers of resistance to these drugs, improving the selection of patients who might derive a benefit from these treatments. Nevertheless, several other alterations might affect the response to these drugs, and unfortunately, even the responders eventually become resistant by developing secondary (or acquired) resistance in approximately 13-18 mo. Several studies highlighted that the landscape of responsible alterations of both primary and acquired resistance to anti-EGFR drugs biochemically converge into MEK-ERK and PIK3CA-AKT pathways. In this review, we describe the currently known mechanisms of primary and acquired resistance to anti-EGFR moAbs together with the various strategies evaluated to prevent, overcame or revert them.
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Bertino EM, McMichael EL, Mo X, Trikha P, Davis M, Paul B, Grever M, Carson WE, Otterson GA. A Phase I Trial to Evaluate Antibody-Dependent Cellular Cytotoxicity of Cetuximab and Lenalidomide in Advanced Colorectal and Head and Neck Cancer. Mol Cancer Ther 2016; 15:2244-50. [PMID: 27458141 DOI: 10.1158/1535-7163.mct-15-0879] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 06/28/2016] [Indexed: 12/17/2022]
Abstract
mAbs can induce antibody-dependent cellular cytotoxicity (ADCC) via the innate immune system's ability to recognize mAb-coated cancer cells and activate immune effector cells. Lenalidomide is an immunomodulatory agent with the capacity to stimulate immune cell cytokine production and ADCC activity. This phase I trial evaluated the combination of cetuximab with lenalidomide for the treatment of advanced colorectal and head and neck squamous cell cancers (HNSCC). This trial included patients with advanced colorectal cancer or HNSCC. Treatment consisted of cetuximab 500 mg/m(2) i.v. every two weeks with lenalidomide given orally days 1-21 on a 28-day cycle. Three dose levels of lenalidomide were evaluated (15, 20, 25 mg). Correlative studies included measurement of ADCC, FcγRIIIA polymorphism genotyping, measurement of serum cytokine levels, and flow cytometric analysis of immune cell subtypes. Twenty-two patients were enrolled (19 colorectal cancer, 3 HNSCC). Fatigue was the only dose-limiting toxicity. One partial response was observed and 8 patients had stable disease at least 12 weeks. The recommended phase II dose is cetuximab 500 mg/m(2) with lenalidomide 25 mg daily, days 1-21. Correlative studies demonstrated a dose-dependent increase in natural killer cytotoxic activity with increasing doses of lenalidomide. Cetuximab and lenalidomide were well tolerated. There was a lenalidomide dose-dependent increase in ADCC with higher activity in patients enrolled in cohort 3 than those enrolled in cohorts 1/2. Although response was not a primary endpoint, there was evidence of antitumor activity for the combination therapy. Further investigation of lenalidomide as an immunomodulator in solid tumors is warranted. Mol Cancer Ther; 15(9); 2244-50. ©2016 AACR.
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Affiliation(s)
- Erin M Bertino
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
| | - Elizabeth L McMichael
- Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio
| | - Xiaokui Mo
- Center for Biostatistics, The Ohio State University, Columbus, Ohio
| | - Prashant Trikha
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Melanie Davis
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Bonnie Paul
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Michael Grever
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - William E Carson
- Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio
| | - Gregory A Otterson
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
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Dienstmann R, Salazar R, Tabernero J. Overcoming Resistance to Anti-EGFR Therapy in Colorectal Cancer. Am Soc Clin Oncol Educ Book 2016:e149-56. [PMID: 25993166 DOI: 10.14694/edbook_am.2015.35.e149] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Our understanding of the genetic and nongenetic molecular alterations associated with anti-epidermal growth factor receptor (EGFR) therapy resistance in colorectal cancer (CRC) has markedly expanded in recent years. Mutations in RAS genes (KRAS/NRAS exons 2, 3, or 4) predict a lack of clinical benefit when anti-EGFR monoclonal antibodies (mAbs) are added to chemotherapy. Genetic events in additional nodes of the mitogen-activated protein kinase (MAPK)-phosphoinositide 3-kinase (PI3K) pathways that bypass EGFR signaling, such as BRAF or PIK3CA mutations or KRAS, ERBB2, or MET amplifications, also may confer resistance to cetuximab or panitumumab. Polymorphisms that block antibody binding as a result of EGFR extracellular domain mutations have been reported. Nongenetic mechanisms, including compensatory activation of receptor tyrosine kinases HER3 and MET, together with high expression of the ligands amphiregulin, transforming growth factor alpha heregulin, and hepatocyte growth factor in the tumor microenvironment also are thought to be involved in resistance. In one-third of the samples, more than one genetic event can be found, and nongenetic events most likely coexist with gene alterations. Furthermore, activation of a gene expression signature of epithelial-mesenchymal transition has been associated with reduced cellular dependence on EGFR signaling. Collectively, this body of work provides convincing evidence that the molecular heterogeneity of CRC plays an important role in the context of resistance to anti-EGFR therapy. Herein, we discuss how this knowledge has been translated into drug development strategies to overcome primary and acquired anti-EGFR resistance, with rational combinations of targeted agents in genomically selected populations, second-generation EGFR inhibitors, and other agents expected to boost the immune response at the tumor site.
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Affiliation(s)
- Rodrigo Dienstmann
- From the Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, WA; Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Medical Oncology, Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Ramon Salazar
- From the Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, WA; Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Medical Oncology, Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Josep Tabernero
- From the Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, WA; Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Medical Oncology, Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain
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Marks E, Rizvi SM, Sarwani N, Yang Z, El-Deiry WS. A case of heterogeneous sensitivity to panitumumab in cetuximab-refractory colorectal adenocarcinoma metastases. Cancer Biol Ther 2016; 16:377-82. [PMID: 25695537 DOI: 10.1080/15384047.2015.1004927] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
We present the case of a 43-year-old-man with wild-type KRAS and BRAF colorectal adenocarcinoma that was metastatic to the liver and lung. The patient initially received neoadjuvant chemotherapy with FOLFOX and bevacizumab, followed by surgical resection of the primary tumor and hepatic metastases. His disease recurred shortly after surgery and he was treated with FOLFIRI plus the anti-EGFR antibody cetuximab. After this regimen failed to arrest his disease progression, treatment with FOLFIRI in combination with another anti-EGFR antibody, panitumumab was started. While on this therapy, the patient's lung nodules remained largely stable but metastatic lesions within the liver continued to progress. Our case highlights the differences between panitumumab and cetuximab, and contemplates the possible explanations for this patient's apparently heterogeneous disease progression within the liver despite stabilization of multiple pulmonary nodules.
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Affiliation(s)
- Eric Marks
- a Penn State College of Medicine and Penn State Hershey Cancer Institute ; Hershey , PA USA
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Patel SB, Gill D, Garrido-Laguna I. Profile of panitumumab as first-line treatment in patients with wild-type KRAS metastatic colorectal cancer. Onco Targets Ther 2015; 9:75-86. [PMID: 26770060 PMCID: PMC4706127 DOI: 10.2147/ott.s68558] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Targeted therapies against EGFR, vascular endothelial growth factor, and vascular endothelial growth factor receptor have expanded treatment options for patients with metastatic colorectal cancer (mCRC). Unfortunately, biomarkers to identify patients that are most likely to derive benefit from targeted therapies in this disease are still needed. Indeed, only RAS mutations have been identified as predictive of lack of benefit from monoclonal antibodies against EGFR in patients with mCRC. Panitumumab is a fully humanized monoclonal antibody against EGFR. In this study, we review data to support the use of panitumumab in combination with a chemotherapy backbone, in the first line setting in patients with RAS wild-type mCRC. Ongoing efforts are aimed at identifying smaller subsets of patients within the RAS wild-type group that will derive the largest benefit from anti-EGFR therapy. In the meantime, treatment with anti-EGFR therapy should be reserved for patients with RAS wild-type mCRC.
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Affiliation(s)
- Shiven B Patel
- Department of Internal Medicine, Oncology Division and Center for Investigational Therapeutics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - David Gill
- Department of Internal Medicine, Oncology Division and Center for Investigational Therapeutics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Ignacio Garrido-Laguna
- Department of Internal Medicine, Oncology Division and Center for Investigational Therapeutics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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Current and Future Approaches to Target the Epidermal Growth Factor Receptor and Its Downstream Signaling in Metastatic Colorectal Cancer. Clin Colorectal Cancer 2015; 14:203-18. [DOI: 10.1016/j.clcc.2015.05.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 05/20/2015] [Accepted: 05/22/2015] [Indexed: 01/27/2023]
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Liu X, George GC, Tsimberidou AM, Naing A, Wheler JJ, Kopetz S, Fu S, Piha-Paul SA, Eng C, Falchook GS, Janku F, Garrett C, Karp D, Kurzrock R, Zinner R, Raghav K, Subbiah V, Hess K, Meric-Bernstam F, Hong DS, Overman MJ. Retreatment with anti-EGFR based therapies in metastatic colorectal cancer: impact of intervening time interval and prior anti-EGFR response. BMC Cancer 2015; 15:713. [PMID: 26474549 PMCID: PMC4609167 DOI: 10.1186/s12885-015-1701-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 10/07/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND This retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval. METHODS Eighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival. RESULTS Retreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156). CONCLUSION Our data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed.
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Affiliation(s)
- X Liu
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - G C George
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - A M Tsimberidou
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - A Naing
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - J J Wheler
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - S Kopetz
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit # 426, Houston, TX, 77030, USA.
| | - S Fu
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - S A Piha-Paul
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - C Eng
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit # 426, Houston, TX, 77030, USA.
| | - G S Falchook
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - F Janku
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - C Garrett
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit # 426, Houston, TX, 77030, USA.
| | - D Karp
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - R Kurzrock
- Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, CA, USA.
| | - R Zinner
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - K Raghav
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit # 426, Houston, TX, 77030, USA.
| | - V Subbiah
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - K Hess
- Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - F Meric-Bernstam
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - D S Hong
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - M J Overman
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit # 426, Houston, TX, 77030, USA.
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Oronsky BT, Oronsky AL, Lybeck M, Oronsky NC, Scicinski JJ, Carter C, Day RM, Rodriguez Orengo JF, Rodriguez-Torres M, Fanger GF, Reid TR. Episensitization: Defying Time's Arrow. Front Oncol 2015; 5:134. [PMID: 26125013 PMCID: PMC4464068 DOI: 10.3389/fonc.2015.00134] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 05/27/2015] [Indexed: 12/17/2022] Open
Abstract
The development of cancer is driven by complex genetic and epigenetic changes that result in aberrant and uncontrolled cellular growth. Epigenetic changes, in particular, are implicated in the silencing or activation of key genes that control cellular growth and apoptosis and contribute to transformative potential. The purpose of this review is to define and assess the treatment strategy of “episensitization,” or the ability to sensitize cancer cells to subsequent therapy by resetting the epigenetic infrastructure of the tumor. One important facet is resensitization by epigenetic mechanisms, which goes against the norm, i.e., challenges the long-held doctrine in oncology that the reuse of previously tried and failed therapies is a clinically pointless endeavor. Thus, episensitization is a hybrid term, which covers recent clinically relevant observations and refers to the epigenomic mechanism of resensitization. Among the many formidable challenges in the treatment of cancer, the most inevitable is the development of acquired therapeutic resistance. Here, we present the basic principles behind episensitization and highlight the evidence suggesting that epigenetically mediated histone hypoacetylation and DNA hypermethylation events may reverse clinical drug resistance. The potential reversibility of epigenetic changes and the microenvironmental impact of epigenetic control on gene expression may mediate a return to a baseline state of treatment susceptibility. Episensitization is a novel and highly practical management strategy both to prevent the practice of permanent treatment discontinuation with the occurrence of resistance, which rapidly exhausts remaining options in the pharmaceutical armamentarium and to significantly extend patient survival. Accordingly, this review highlights several epigenetic agents including decitabine, vorinostat, entinostat, 5-azacitidine, oncolytic viruses, and RRx-001.
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Affiliation(s)
| | | | | | | | | | - Corey Carter
- Walter Reed National Military Medical Center, National Cancer Institute , Bethesda, MD , USA
| | - Regina M Day
- Uniformed Services University of the Health Sciences , Bethesda, MD , USA
| | | | | | | | - Tony R Reid
- Moores Cancer Center, University of California San Diego , La Jolla, CA , USA
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Rihawi K, Giampieri R, Scartozzi M, Pusceddu V, Bonotto M, Fasola G, Cascinu S, Aprile G. Role and mechanisms of resistance of epidermal growth factor receptor antagonists in the treatment of colorectal cancer. Expert Opin Investig Drugs 2015; 24:1185-98. [DOI: 10.1517/13543784.2015.1054479] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Panitumumab after Progression on Cetuximab in KRAS Wild-type Metastatic Colorectal Cancer Patients: a Single Institution Experience. TUMORI JOURNAL 2015; 101:524-8. [DOI: 10.5301/tj.5000356] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2015] [Indexed: 12/17/2022]
Abstract
Aims and background Few data describe the activity of panitumumab after cetuximab-irinotecan-based regimen failure in patients with KRAS wild-type metastatic colorectal cancer (WT MCRC). Methods The aim of this study is to assess if panitumumab has some activity in this setting. Results We retrospectively analyzed 25 patients with KRAS WT MCRC who received panitumumab from July 2009 to January 2013 after progression on cetuximab. All patients had previously received cetuximab and irinotecan (20 patients) or oxaliplatin (5 patients). We withdrew cetuximab for intolerance in 4 patients (16%). Twenty-one patients (84%) who had previously responded to cetuximab (overall response rate [ORR] plus stable disease ≥5 months) received panitumumab off-label after progression on cetuximab because they were strongly motivated to continue treatment without chemotherapy. The median number of cycles of panitumumab was 7 (range 1-54). Only 20 patients were evaluable for ORR (5 patients received 1-2 cycles and then died). We observed 1 (5%) partial response, 5 (25%) stable disease, median duration 9 months. Median progression-free survival (PFS) and overall survival (OS) were 5 (3-28) and 8 (5-41) months, respectively. All patients were evaluable for toxicity. No patients developed anemia or neutropenia. One patient (4%) developed grade 2 thrombocytopenia, 8 patients (32%) grade 2-3 dry skin or rash, and 2 patients (8%) grade 2 nausea-vomiting (Common Terminology Criteria for Adverse Events version 4.03). Conclusions Our data, with all the limits of a retrospective analysis, show longer PFS and OS as compared to other series in the same setting, demonstrating that panitumumab has treatment effectiveness in patients with KRAS WT MCRC who progressed on prior cetuximab. Further confirmatory prospective studies with a larger series of patients are necessary.
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Dienstmann R, Patnaik A, Garcia-Carbonero R, Cervantes A, Benavent M, Roselló S, Tops BBJ, van der Post RS, Argilés G, Skartved NJØ, Hansen UH, Hald R, Pedersen MW, Kragh M, Horak ID, Braun S, Van Cutsem E, Tolcher AW, Tabernero J. Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer. Cancer Discov 2015; 5:598-609. [PMID: 25962717 DOI: 10.1158/2159-8290.cd-14-1432] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 03/25/2015] [Indexed: 02/06/2023]
Abstract
UNLABELLED Tumor growth in the context of EGFR inhibitor resistance may remain EGFR-dependent and is mediated by mechanisms including compensatory ligand upregulation and de novo gene alterations. Sym004 is a two-antibody mixture targeting nonoverlapping EGFR epitopes. In preclinical models, Sym004 causes significant EGFR internalization and degradation, which translates into superior growth inhibition in the presence of ligands. In this phase I trial, we observed grade 3 skin toxicity and hypomagnesemia as mechanism-based dose-limiting events during dose escalation. In dose-expansion cohorts of 9 and 12 mg/kg of Sym004 weekly, patients with metastatic colorectal cancer and acquired EGFR inhibitor resistance were enrolled; 17 of 39 patients (44%) had tumor shrinkage, with 5 patients (13%) achieving partial response. Pharmacodynamic studies confirmed marked Sym004-induced EGFR downmodulation. MET gene amplification emerged in 1 patient during Sym004 treatment, and a partial response was seen in a patient with EGFR(S492R) mutation that is predictive of cetuximab resistance. SIGNIFICANCE Potent EGFR downmodulation with Sym004 in patients with metastatic colorectal cancer and acquired resistance to cetuximab/panitumumab translates into significant antitumor activity and validates the preclinical hypothesis that a proportion of tumors remains dependent on EGFR signaling. Further clinical development and expanded correlative analyses of response patterns with secondary RAS/EGFR mutations are warranted.
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Affiliation(s)
- Rodrigo Dienstmann
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Center affiliated to the RTICC (ISCiii), Spain. Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Amita Patnaik
- START South Texas Accelerated Research Therapeutics, San Antonio, Texas
| | - Rocio Garcia-Carbonero
- Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla (HUVR, CSIC, Universidad de Sevilla), Center affiliated to the RTICC (ISCiii), Sevilla, Spain
| | - Andrés Cervantes
- Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain
| | - Marta Benavent
- Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla (HUVR, CSIC, Universidad de Sevilla), Center affiliated to the RTICC (ISCiii), Sevilla, Spain
| | - Susana Roselló
- Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain
| | - Bastiaan B J Tops
- Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Rachel S van der Post
- Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Guillem Argilés
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Center affiliated to the RTICC (ISCiii), Spain
| | | | | | | | | | | | | | | | - Eric Van Cutsem
- Digestive Oncology Department, University Hospitals Leuven and KULeuven, Leuven, Belgium
| | - Anthony W Tolcher
- START South Texas Accelerated Research Therapeutics, San Antonio, Texas
| | - Josep Tabernero
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Center affiliated to the RTICC (ISCiii), Spain.
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Valentine J, Belum VR, Duran J, Ciccolini K, Schindler K, Wu S, Lacouture ME. Incidence and risk of xerosis with targeted anticancer therapies. J Am Acad Dermatol 2015; 72:656-67. [PMID: 25637330 DOI: 10.1016/j.jaad.2014.12.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Revised: 12/03/2014] [Accepted: 12/08/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND Many targeted therapies used in the treatment of cancer can lead to the development of xerosis, but the incidence and relative risk of xerosis have not been ascertained. OBJECTIVE We conducted a systematic review and metaanalysis of clinical trials, to ascertain the incidence and risk of developing xerosis after taking anticancer drugs. METHODS The PubMed (1966-October 2013), Web of Science (January 1998-October 2013), and American Society of Clinical Oncology abstracts (2004-2013) databases were searched for clinical trials of 58 targeted agents. Results were calculated using random or fixed effects models. RESULTS The incidences of all- and high-grade xerosis were 17.9% (95% confidence interval [CI]: 15.6-20.4%) and 1.0% (95% CI: 0.9-1.5%), respectively. The risk of developing all-grade xerosis was 2.99 (95% CI: 2.0-4.3), and it varied across different drugs (P < .001). LIMITATIONS The reporting of xerosis may vary among clinicians and institutions, and the incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions. CONCLUSION Patients receiving targeted therapies have a significant risk of developing xerosis. Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality of life impairment.
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Affiliation(s)
- Johannah Valentine
- Department of Dermatology, Naval Medical Center San Diego, San Diego, California
| | | | - Juanita Duran
- Department of Dermatology, Universidad del Rosario, Bogota, Colombia
| | - Kathryn Ciccolini
- Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Katja Schindler
- Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Shenhong Wu
- Division of Hematology and Oncology, Stony Brook University Cancer Center, Stony Brook, New York; Division of Hematology and Oncology, Department of Medicine, Northport Veterans Affairs Medical Center, Northport, New York
| | - Mario E Lacouture
- Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
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Lv Y, Yang Z, Zhao L, Zhao S, Han J, Zheng L. The efficacy and safety of adding bevacizumab to cetuximab- or panitumumab-based therapy in the treatment of patients with metastatic colorectal cancer (mCRC): a meta-analysis from randomized control trials. Int J Clin Exp Med 2015; 8:334-45. [PMID: 25785004 PMCID: PMC4358459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2014] [Accepted: 01/07/2015] [Indexed: 06/04/2023]
Abstract
OBJECTIVE To estimate the efficacy and safety of adding bevacizumab to cetuximab- or panitumumab-based therapy in the treatment of patients with metastatic colorectal cancer (mCRC), using a meta-analysis of randomized controlled trials. METHODS A literature search for randomized clinical trials (RCTs) was performed through Pubmed, Embase, and Web of Science (up to May 22, 2014). The outcome measures were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events. Two investigators identified eligible studies and extracted data independently. The quality of the included studies was assessed by the Jadad score. Hazard ratios (HR), risk ratio (RR), and 95% confidence intervals (Cls) were calculated and pooled. RESULTS A total of 4 RCTs with 2069 patients were included in this meta-analysis. The addition of bevacizumab to cetuximab- or panitumumab-based therapy did not significantly prolonged PFS, when compared with antibody alone. The subgroup analysis of adding bevacizumab to cetuximab-based therapy also suggested no significant benefit in PFS or in OS. Patients who received the combined therapy did not have a higher ORR (RR = 0.98, 95% CI: 0.89-1.07; P = 0.608). The incidence of grade 3/4 adverse events was not significantly higher in the bevacizumab and cetuximab/panitumumab group. CONCLUSION The addition of bevacizumab to cetuximab- or panitumumab-based therapy did not improve PFS and OS resulting in better ORR. Thus, the combined therapy of bevacizumab with cetuximab or panitumumab is not recommended for the treatment of mCRC. However, larger scale RCTs are needed to confirm these findings.
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Affiliation(s)
- Yingqian Lv
- Department of Oncology, The Second Hospital of Hebei Medical University Shijiazhuang 050000, Hebei, China
| | - Zixin Yang
- Department of Oncology, The Second Hospital of Hebei Medical University Shijiazhuang 050000, Hebei, China
| | - Li Zhao
- Department of Oncology, The Second Hospital of Hebei Medical University Shijiazhuang 050000, Hebei, China
| | - Shan Zhao
- Department of Oncology, The Second Hospital of Hebei Medical University Shijiazhuang 050000, Hebei, China
| | - Jinzhu Han
- Department of Oncology, The Second Hospital of Hebei Medical University Shijiazhuang 050000, Hebei, China
| | - Likang Zheng
- Department of Oncology, The Second Hospital of Hebei Medical University Shijiazhuang 050000, Hebei, China
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Maletzki C, Gock M, Randow M, Klar E, Huehns M, Prall F, Linnebacher M. Establishment and characterization of cell lines from chromosomal instable colorectal cancer. World J Gastroenterol 2015; 21:164-176. [PMID: 25574089 PMCID: PMC4284332 DOI: 10.3748/wjg.v21.i1.164] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 06/26/2014] [Accepted: 07/24/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To generate novel tumor models for preclinical validation of biomarkers that allow drug response prediction and individual therapeutic decisions. METHODS Cell line establishment was conducted by both direct in vitro culturing and in vivo xenografting followed by in vitro culturing procedure. A comprehensive characterization was subsequently performed. This included quality control, consisting of the confirmation of human and colorectal cancer (CRC) origin by DNA fingerprint and epithelial cell adhesion molecule (EpCAM) staining, as well as mycoplasma and human virus testing. Phenotypic analysis was done by light microscopy and multicolor flow cytometry. Histopathological examination (β-catenin and cytokeratin staining) was conducted in direct comparison to parental tumor tissues. Extensive molecular-pathological profiling included mutation analysis for CRC-associated driver mutations, assessment of chromosomal and microsatellite instability, and the grade of CpG island methylation. Additionally, an array-based comparative genomic hybridization analysis was performed. Drug responsiveness was assessed for a panel of classical and novel substances in clinical use for the treatment of solid cancers. Finally, tumorigenicity of the cell lines was tested by xenografting into immunocompromised nude mice. RESULTS Herein we describe the establishment of three ultra-low passage cell lines from two individual patients suffering from sporadic CRC. One cell line was derived directly from an early stage case (HROC18), whereas two cell lines could be established both direct from patient material and after xenografting from a late stage tumor (HROC32). All cell lines were free of contaminating mycoplasma and viruses. Molecular-pathological analysis allowed all cell lines to be classified as chromosomal instable (CIN(+)). They were aneuploid, with CpG island promoter methylation and microsatellite instability being absent. The following mutational profile was observed both in the cell lines and the parental tumor tissue: HROC18: APC(mut), p53(mut), K-ras(wt); HROC32: APC(wt), p53(mut), K-ras(mut). All cell lines were characterized as epithelial (EpCAM(+)) cells, showing distinct morphology and migration speed, but comparable growth kinetics. The cell lines showed different patterns of response towards clinically approved and novel drugs, with HROC18 being more resistant than HROC32 cells. Finally, in vivo tumorigenicity was demonstrated. CONCLUSION We successfully established and characterized novel ultra-low passage patient-derived CRC models as useful instruments for analyzing biological characteristics associated with the CIN(+) phenotype.
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Lien K, Berry S, Ko YJ, Chan KKW. The use of EGFR inhibitors in colorectal cancer: is it clinically efficacious and cost-effective? Expert Rev Pharmacoecon Outcomes Res 2014; 15:81-100. [PMID: 25400031 DOI: 10.1586/14737167.2015.982100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cetuximab (Erbitux) and panitumumab (Vectibix) are monoclonal antibodies to the EGFR. They are used as monotherapy or in combination with cytotoxic chemotherapy and increase both progression-free survival and overall survival in patients with wild-type RAS metastatic colorectal cancer. The most common side effects of therapy are dermatological, including skin (acneiform) rash, pruritus and hair changes. Despite their clinical activity, cost-effectiveness of the two drugs should be addressed in a discussion of their usage in everyday care. This study provides an up-to-date review of the clinical efficacy and cost-effectiveness of anti-EGFR inhibitors.
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Affiliation(s)
- Kelly Lien
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
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Ciombor KK, Goldberg RM. Current evidence and controversies in the incorporation of biologics for metastatic colorectal cancer. Hepat Oncol 2014; 1:331-345. [PMID: 30190967 PMCID: PMC6095158 DOI: 10.2217/hep.14.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
With the advent of new drugs and therapeutic combinations for metastatic colorectal cancer, the prognosis for this often incurable disease is improving. In addition to traditional cytotoxic chemotherapeutics, targeted biologic therapies, such as cetuximab, panitumumab, bevacizumab, aflibercept and regorafenib, are significantly impacting the treatment of this disease. Recent investigations have focused on determination of the optimal usage of these biologic therapies, but many controversies still exist. Specifically, emerging data regarding appropriate combinations of cytotoxics and biologics in each metastatic colorectal cancer treatment setting, the superiority of particular biologics as single agents or in combination with chemotherapy, dual biologic therapy, use of biologics for conversion or maintenance therapies, and predictive biomarker discovery for biologics are addressed in this article, as these issues are rapidly changing our approach to the treatment of the patient with metastatic colorectal cancer.
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Affiliation(s)
- Kristen K Ciombor
- Division of Medical Oncology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210-1280, USA
- The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
| | - Richard M Goldberg
- Division of Medical Oncology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210-1280, USA
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Stremitzer S, Sebio A, Stintzing S, Lenz HJ. Panitumumab safety for treating colorectal cancer. Expert Opin Drug Saf 2014; 13:843-51. [PMID: 24766434 DOI: 10.1517/14740338.2014.915024] [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] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Panitumumab is a human IgG2 mAb against the EGFR, inhibiting tumor cell proliferation, survival and angiogenesis. It has demonstrated clinical efficacy in metastatic colorectal cancer (CRC) in combination with chemotherapy in first- and second-line settings and as monotherapy in third-line setting. Recently, mutations in the RAS genes have been shown to be predictive of lack of efficacy, panitumumab should be restricted to patients with RAS wild-type (wt) tumors. AREAS COVERED This review focuses on main efficacy results of panitumumab in metastatic CRC in first-, second- and third-line settings in combination with chemotherapy or as monotherapy. Additionally, we have covered safety aspects of this agent in these indications, especially in K-RAS and all RAS wt patients. These safety aspects refer to the most common toxicities (i.e., acne-like skin rash, diarrhea and hypomagnesaemia). EXPERT OPINION Panitumumab adds to the armamentarium of effective agents in the treatment of metastatic CRC. Due to its human origin, panitumumab is a well-tolerated agent with low rates of infusional reactions. Skin toxicity is frequent and should be pre-emptively treated. Other common toxicities related to panitumumab treatment, such as diarrhea and hypomagnesaemia, should be closely monitored to ensure early treatment or substitution.
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Affiliation(s)
- Stefan Stremitzer
- University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Division of Medical Oncology , 1441 Eastlake Avenue, Los Angeles, CA, 90033 , USA +1 323 865 3967 ; +1 323 865 0061 ;
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Goffin JR, Zbuk K. Epidermal growth factor receptor: pathway, therapies, and pipeline. Clin Ther 2014; 35:1282-303. [PMID: 24054705 DOI: 10.1016/j.clinthera.2013.08.007] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Revised: 08/16/2013] [Accepted: 08/21/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND The epidermal growth factor receptor (EGFR) pathway is important in tumor growth, survival, and metastasis and is now the target of several therapeutic agents. OBJECTIVES This paper seeks to review the EGFR pathway, the study and use of EGFR-directed agents in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC), and related new drug development. METHODS PubMed was searched for English-language articles by MeSH and title terms of EGFR published from 2006 to 2013, using the limits of clinical trials as well as reviews. Reference lists were assessed for relevant articles, and guidelines were searched. Clinicaltrials.gov and meeting abstracts were queried for investigational agents. Eligible papers included those concerning EGFR biology, NSCLC or CRC studies involving EGFR-directed agents, and/or investigational drugs targeting EGFR and/or associated pathways. RESULTS The activity of oral tyrosine kinase inhibitors (TKIs) against EGFR has improved survival in NSCLC, and these agents particularly effective in cancers with an EGFR mutation. Resistance to TKIs is most commonly related to a second, T790M, mutation, or to MET amplification, with newer agents directed against these mechanisms. Conversely, in CRC, TKIs have been ineffective, whereas monoclonal antibodies have improved survival. Both primary and secondary KRAS mutations in CRC abrogate mAb effectiveness. Several targets, including MET, BRAF, and PI3K, may serve useful in combination with anti-EGFR drugs. CONCLUSIONS Exploitation of EGFR-directed therapies has offered improvement in survival and quality of life in NSCLC and CRC. New therapies directed at EGFR may offer further improvements. However, resistance mechanisms suggest that combination therapies or multitargeted agents will be crucial in making significant future advances.
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Affiliation(s)
- John R Goffin
- Department of Oncology, Faculty of Health Sciences, McMaster University, Hamilton, Canada.
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Sebio A, Stintzing S, Stremitzer S, Zhang W, Lenz HJ. Panitumumab: leading to better overall survival in metastatic colorectal cancer? Expert Opin Biol Ther 2014; 14:535-48. [DOI: 10.1517/14712598.2014.894502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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