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HER2 amplification

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https://www.readbyqxmd.com/read/29338072/targeting-her2-in-colorectal-cancer-the-landscape-of-amplification-and-short-variant-mutations-in-erbb2-and-erbb3
#1
Jeffrey S Ross, Marwan Fakih, Siraj M Ali, Julia A Elvin, Alexa B Schrock, James Suh, Jo-Anne Vergilio, Shakti Ramkissoon, Eric Severson, Sugganth Daniel, David Fabrizio, Garrett Frampton, James Sun, Vincent A Miller, Philip J Stephens, Laurie M Gay
BACKGROUND: In contrast to lung cancer, few precision treatments are available for colorectal cancer (CRC). One rapidly emerging treatment target in CRC is ERBB2 (human epidermal growth factor receptor 2 [HER2]). Oncogenic alterations in HER2, or its dimerization partner HER3, can underlie sensitivity to HER2-targeted therapies. METHODS: In this study, 8887 CRC cases were evaluated by comprehensive genomic profiling for genomic alterations in 315 cancer-related genes, tumor mutational burden, and microsatellite instability...
January 16, 2018: Cancer
https://www.readbyqxmd.com/read/29333901/her2-positive-bilateral-metachronous-primary-breast-carcinoma-a-case-report
#2
Jinghao Yao, Jing Liu, Yawei Li, Yumei Li, Qiong Wu, Yan Yang
Human epidermal growth factor receptor 2 (HER2) positive is a unique molecular subtype of breast cancer (BC) characterized by high malignancy and poor prognosis. Bilateral primary breast cancer (BPBC) harboring HER2 gene amplification is available to be detected among the BC survivors due to the increasing use of anti-HER2 adjuvant therapy. However, owing to the paucity of cases reported, knowledge of treating HER2-positive BPBC patients including the clinical behavior, histopathologic characteristics, anti-HER2 therapeutic response and disease outcome are not fully understood...
January 15, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29330210/trastuzumab-plus-pertuzumab-resistance-does-not-preclude-response-to-lapatinib-plus-trastuzumab-in-her2-amplified-colorectal-cancer
#3
Marwan G Fakih
Human epidermal growth factor 2 (HER2) amplification represents a distinct molecular subgroup of colorectal cancers that is associated with anti-epidermal growth factor receptor resistance and sensitivity to dual HER2 targeting. Although clinical trials have reported activity for trastuzumab/pertuzumab and trastuzumab/lapatinib combinations, there are no reports on lapatinib plus trastuzumab activity after resistance to trastuzumab plus pertuzumab. Presented are three cases of HER2 amplified colorectal cancer that developed acquired refractoriness to trastuzumab pertuzumab with subsequent clinical benefit to lapatinib plus trastuzumab, highlighting the potential for HER2 tyrosine kinase inhibition plus trastuzumab in overcoming trastuzumab/pertuzumab resistance...
January 12, 2018: Oncologist
https://www.readbyqxmd.com/read/29326029/neoadjuvant-treatment-with-trastuzumab-and-pertuzumab-plus-palbociclib-and-fulvestrant-in-her2-positive-er-positive-breast-cancer-na-pher2-an-exploratory-open-label-phase-2-study
#4
Luca Gianni, Giancarlo Bisagni, Marco Colleoni, Lucia Del Mastro, Claudio Zamagni, Mauro Mansutti, Milvia Zambetti, Antonio Frassoldati, Raffaella De Fato, Pinuccia Valagussa, Giuseppe Viale
BACKGROUND: In the neoadjuvant setting, blockade of HER2 plus use of an aromatase inhibitor in patients with HER2-positive and oestrogen receptor (ER)-positive breast cancer leads to a pathological complete response in 21% of patients. Convergence of HER2 and ER signals on RB1 suggests that a combined pharmacological intervention directed to these targets could be synergistic. To test this approach, we combined palbociclib to block RB1, fulvestrant to block ER, and trastuzumab with pertuzumab to block HER2 in patients with HER2-positive, ER-positive breast cancer...
January 8, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29325228/effects-of-trastuzumab-and-afatinib-on-kinase-activity-in-gastric-cancer-cell-lines
#5
Simone Keller, Gwen Zwingenberger, Karolin Ebert, Jan Hasenauer, Jacqueline Wasmuth, Dieter Maier, Ivonne Haffner, Katrin Schierle, Gregor Weirich, Birgit Luber
The molecular mechanism of action of the HER2-targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream-acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI-N87, MKN1 and MKN7) using proteome profiling...
January 11, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29323058/assessment-of-topoisomerase-ii-alpha-gene-status-by-dual-color-chromogenic-in-situ-hybridization-in-a-set-of-iraqi-patients-with-invasive-breast-carcinoma
#6
Rasha Abd Alraouf Neama, Manal A Habib, Sahira A Ali, Ali H Al-Khafaji, Mohammed F Alqanbar
BACKGROUND: The human epidermal growth factor receptor 2(HER2) proto-oncogene is overexpressed or amplified in approximately 15%-25% of invasive breast cancers. Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A) gene encoding an enzyme that is a major target of anthracyclines. Hence, the determination of genetic alteration (amplification or deletion) of both genes is considered as an important predictive factor that determines the response of breast cancer patients to treatment...
October 2017: Indian Journal of Pathology & Microbiology
https://www.readbyqxmd.com/read/29320459/the-landscape-of-small-non-coding-rnas-in-triple-negative-breast-cancer
#7
Yan Guo, Hui Yu, Jing Wang, Quanhu Sheng, Shilin Zhao, Ying-Yong Zhao, Brian D Lehmann
Triple-negative breast cancer (TNBC) is an operational term for breast cancers lacking targetable estrogen receptor expression and HER2 amplifications. TNBC is, therefore, inherently heterogeneous, and is associated with worse prognosis, greater rates of metastasis, and earlier onset. TNBC displays mutational and transcriptional diversity, and distinct mRNA transcriptional subtypes exhibiting unique biology. High-throughput sequencing has extended cancer research far beyond protein coding regions that include non-coding small RNAs, such as miRNA, isomiR, tRNA, snoRNAs, snRNA, yRNA, 7SL, and 7SK...
January 10, 2018: Genes
https://www.readbyqxmd.com/read/29302045/mir-200c-inhibits-tgf-%C3%AE-induced-emt-to-restore-trastuzumab-sensitivity-by-targeting-zeb1-and-zeb2-in-gastric-cancer
#8
Xinliang Zhou, Xinyi Men, Riyang Zhao, Jing Han, Zhisong Fan, Yudong Wang, Yalei Lv, Jing Zuo, Lianmei Zhao, Meixiang Sang, Xian-De Liu, Baoen Shan
Gastric cancer is the fifth most common malignancy in the world, with Eastern Asia as one of areas with the highest incidence rates. Trastuzumab, a HER2-targeting antibody, combined with chemotherapy has been successfully employed for the gastric cancer patients with HER2 overexpression/amplification. However, trastuzumab resistance is a major problem in clinical practice. Here we observed that the trastuzumab-resistant gastric cancer cell line NCI-N87/TR expressed high levels of epithelial-mesenchymal transition factors and demonstrated increased migration and invasion capability compared with NCI-N87 cells...
January 4, 2018: Cancer Gene Therapy
https://www.readbyqxmd.com/read/29298799/targeting-her2-aberrations-in-non-small-cell-lung-cancer-with-osimertinib
#9
Shengwu Liu, Shuai Li, Josephine Hai, Xiaoen Wang, Ting Chen, Max M Quinn, Peng Gao, Yanxi Zhang, Hongbin Ji, Darren Cross, Kwok-Kin Wong
PURPOSE: HER2 (or ERBB2) aberrations, including both amplification and mutations, have been classified as oncogenic drivers that contribute to 2-6 percent of lung adenocarcinomas. HER2 amplification is also an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). However, due to limited preclinical studies and clinical trials, currently there is still no available standard of care for lung cancer patients with HER2 aberrations. To fulfill the clinical need for targeting HER2 in non-small cell lung cancer (NSCLC) patients, we performed a comprehensive pre-clinical study to evaluate the efficacy of a third-generation TKI, osimertinib (AZD9291)...
January 3, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29286417/building-up-a-high-throughput-screening-platform-to-assess-the-heterogeneity-of-her2-gene-amplification-in-breast-cancers
#10
Giulia Ercoli, Gianluca Lopez, Camilla Ciapponi, Chiara Corti, Luca Despini, Donatella Gambini, Letterio Runza, Concetta Blundo, Amedeo Sciarra, Nicola Fusco
Targeted therapies against the human epidermal growth factor receptor 2 (HER2) have radically changed the outcome of patients with HER2-positive breast cancers. However, a minority of cases displays a heterogeneous distribution of HER2-positive cells, which generates major clinical challenges. To date, no reliable and standardized protocols for the characterization and quantification of HER2 heterogeneous gene amplification in large cohorts have been proposed. Here, we present a high-throughput methodology to simultaneously assess the HER2 status across different topographic areas of multiple breast cancers...
December 5, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29285234/targeted-next-generation-sequencing-in-chinese-colorectal-cancer-patients-guided-anti-egfr-treatment-and-facilitated-precision-cancer-medicine
#11
Helei Hou, Dong Liu, Chuantao Zhang, Yanxia Jiang, Guifang Lu, Na Zhou, Xiaonan Yang, Xiaoping Zhang, Zhuokun Li, Hongmei Zhu, Zhaoyang Qian, Xiaochun Zhang
Objective: Colorectal cancer (CRC) patients with both RAS and BRAF wild-type tumors determined by non-next generation sequencing (NGS) testing may still not respond due to the presence of additional mutated genes such as PIK3CA or PTEN. In this study, a broad, hybrid capture-based NGS assay was used to identify RAS, BRAF and additional targetable genetic alterations from Chinese CRC tissues. Methods: Fifty-seven cases of CRC were enrolled, and all the patients signed the informed consent...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29281678/the-natural-compound-jatrophone-interferes-with-wnt-%C3%AE-catenin-signaling-and-inhibits-proliferation-and-emt-in-human-triple-negative-breast-cancer
#12
Iram Fatima, Ikbale El-Ayachi, Ling Taotao, M Angeles Lillo, Raya Krutilina, Tiffany N Seagroves, Tomasz W Radaszkiewicz, Miroslav Hutnan, Vitezslav Bryja, Susan A Krum, Fatima Rivas, Gustavo A Miranda-Carboni
Metastatic breast cancer is the leading cause of worldwide cancer-related deaths among women. Triple negative breast cancers (TNBC) are highly metastatic and are devoid of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are unresponsive to Herceptin and/or anti-estrogen therapies and too often become highly chemoresistant when exposed to standard chemotherapy. TNBCs frequently metastasize to the lung and brain. We have previously shown that TNBCs are active for oncogenic Wnt10b/β-catenin signaling and that WNT10B ligand and its downstream target HMGA2 are predictive of poorer outcomes and are strongly associated with chemoresistant TNBC metastatic disease...
2017: PloS One
https://www.readbyqxmd.com/read/29278885/egfr-and-akt1-overexpression-are-mutually-exclusive-and-associated-with-a-poor-survival-in-resected-gastric-adenocarcinomas
#13
Iacopo Petrini, Monica Lencioni, Enrico Vasile, Lorenzo Fornaro, Lorenzo Belluomini, Giulia Pasquini, Laura Ginocchi, Chiara Caparello, Gianna Musettini, Caterina Vivaldi, Sara Caponi, Sergio Ricci, Agenese Proietti, Gabriella Fontanini, Antonio Giuseppe Naccarato, Vincenzo Nardini, Stefano Santi, Alfredo Falcone
PURPOSE: The evaluation of molecular targets in gastric cancer has demonstrated the predictive role of HER2 amplification for trastuzumab treatment in metastatic gastric cancer. Besides HER2, other molecular targets are under evaluation in metastatic gastric tumors. However, very little is known about their role in resected tumors. We evaluated the expression of HER2, EGFR, MET, AKT1 and phospho-mTOR in resected stage II-III adenocarcinomas. METHODS: Ninety-two patients with resected stomach (63%) or gastro-esophageal adenocarcinomas (27%) were evaluated...
December 15, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/29277796/evaluation-of-expression-of-human-epidermal-growth-factor-receptor-2-her2-in-gastric-and-gastroesophageal-junction-adenocarcinoma-using-ihc-and-dual-ish
#14
Carolina Dominguez, Marilin Rosa, Taara B George, Jose Pimiento, Gregory Y Lauwers, Domenico Coppola
BACKGROUND/AIM: Trastuzumab® is used for human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. Our aim was to compare HER2 expression by immunohistochemistry (IHC) and dual in situ hybridization (DISH) in early-stage vs. late-stage gastric and GEJ tumors. MATERIALS AND METHODS: Fifty early-stage and 50 late-stage gastric tumors and a similar number of early-stage and late-stage GEJ tumors were studied...
January 2018: Anticancer Research
https://www.readbyqxmd.com/read/29223982/pazopanib-sensitivity-in-a-patient-with-breast-cancer-and-fgfr1-amplification
#15
Fiona Tsui-Fen Cheng, Fu Ou-Yang, Nina Lapke, Kai-Che Tung, Yen-Kung Chen, Yuh-Yu Chou, Shu-Jen Chen
Treatment options for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer and resistance to endocrine therapy remain limited. An interesting therapeutic target in these patients is fibroblast growth factor receptor 1 (FGFR1). FGFR1 is amplified in approximately 11% of patients with breast cancer, especially those with HR+ disease. This report presents a patient with metastatic HR+ HER2- breast cancer harboring an FGFR1 amplification who was resistant to endocrine therapy but responded to pazopanib, a multi-tyrosine kinase inhibitor with FGFR-inhibiting activity...
December 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29223420/her2-confers-resistance-to-foretinib-inhibition-of-met-amplified-esophageal-adenocarcinoma-cells
#16
Alexei A Goltsov, Bingliang Fang, Tej K Pandita, Dipen M Maru, Stephen G Swisher, Wayne L Hofstetter
BACKGROUND: Recent genomic studies indicated that esophageal adenocarcinoma (EAC) is driven by amplification of c-MET or HER2 or both in a subset of patients. We studied the effect of MET targeting by the small molecule inhibitor foretinib in EAC cells and the interplay between MET and HER2 signaling. METHODS: We measured the expression levels and phosphorylation status of MET and HER2 proteins in EAC cell lines using Western blot analysis. The expression levels of MET and HER2 were manipulated by transfecting cells with specific siRNA or a plasmid expressing HER2...
December 6, 2017: Annals of Thoracic Surgery
https://www.readbyqxmd.com/read/29211816/clinical-outcome-and-molecular-characterisation-of-chemorefractory-metastatic-colorectal-cancer-patients-with-long-term-efficacy-of-regorafenib-treatment
#17
Erika Martinelli, Vincenzo Sforza, Claudia Cardone, Anna Capasso, Anna Nappi, Giulia Martini, Stefania Napolitano, Anna Maria Rachiglio, Nicola Normanno, Salvatore Cappabianca, Alfonso Reginelli, Maurizio Di Bisceglie, Tiziana Pia Latiano, Evaristo Maiello, Michele Orditura, Fernando De Vita, Floriana Morgillo, Fortunato Ciardiello, Teresa Troiani
HASH(0x42cc170) Background: To investigate the potential predictors of response to regorafenib, in chemorefractory metastatic colorectal cancer (mCRC) patients with long-term efficacy from regorafenib treatment. Methods: Retrospective, single institution analysis of patients with chemorefractory mCRC treated with regorafenib, in clinical practice setting. 123 patients were treated and stratified into two groups according to number of cycles received (<7 and ≥7)...
2017: ESMO Open
https://www.readbyqxmd.com/read/29209536/activating-her2-mutations-as-emerging-targets-in-multiple-solid-cancers
#18
REVIEW
Claire M Connell, Gary J Doherty
The epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases activates signalling pathways regulating cellular proliferation and survival. HER2 is a non-ligand-binding member of this family and exerts its activity through heterodimerisation with other EGFR family members. HER2 functional activation promotes oncogenesis, leading to the investigation of HER2-directed agents in cancers with HER2 alterations. This has been best characterised in the context of HER2 gene amplification in breast and gastro-oesophageal cancers, for which HER2-directed drugs form part of standard treatment regimens...
2017: ESMO Open
https://www.readbyqxmd.com/read/29208673/biomarkers-of-primary-resistance-to-trastuzumab-in-her2-positive-metastatic-gastric-cancer-patients-the-amnesia-case-control-study
#19
Filippo Pietrantonio, Giovanni Fucà, Federica Morano, Annunziata Gloghini, Simona Corso, Giuseppe Aprile, Federica Perrone, Ferdinando De Vita, Elena Tamborini, Gianluca Tomasello, Ambra V Gualeni, Elena Ongaro, Adele Busico, Elisa Giommoni, Chiara C Volpi, Maria Maddalena Laterza, Salvatore Corallo, Michele Prisciandaro, Maria Antista, Alessandro Pellegrinelli, Lorenzo Castagnoli, Serenella Maria Pupa, Giancarlo Pruneri, Filippo G De Braud, Silvia Giordano, Chiara Cremolini, Maria Di Bartolomeo
PURPOSE: Refining the selection of HER2 positive metastatic gastric cancer patients candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways. EXPERIMENTAL DESIGN: We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications...
December 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29207318/her2-copy-number-of-circulating-tumour-dna-functions-as-a-biomarker-to-predict-and-monitor-trastuzumab-efficacy-in-advanced-gastric-cancer
#20
Haixing Wang, Beifang Li, Zhentao Liu, Jifang Gong, Lin Shao, Jun Ren, Yunyun Niu, Shiping Bo, Zhongwu Li, Yumei Lai, Sijia Lu, Jing Gao, Lin Shen
BACKGROUND: HER2 status is significant to trastuzumab therapy; however, it is difficult to determine HER2 status accurately with few pieces of biopsies from advanced gastric cancer (AGC) due to highly heterogeneity and invasive behaviour, which will be investigated in this study. METHODS: Fifty-six patients with AGC were included in this study. Primary tumour tissues and matched plasmas before medication from 36 patients were retrospectively collected, and the other 20 patients with primary tumour tissues and paired plasmas were prospectively collected...
December 2, 2017: European Journal of Cancer
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