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Πέμπτη 30 Μαΐου 2019

Amplification, also known as the over-expression of the ERBB2 gene, occurs in approximately 15-30% of breast cancers.[8][14] It is strongly associated with increased disease recurrence and a poor prognosis.[15] Over-expression is also known to occur in ovarian,[16] stomach, adenocarcinoma of the lung[17] and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma,[18][19] e.g. HER-2 is over-expressed in approximately 7-34% of patients with gastric cancer[20][21] and in 30% of salivary duct carcinomas.[22] HER2 is colocalised and most of the time, coamplified with the gene GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and esophageal tumours. HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.[23][24] Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.[25] Mutations Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression. HER2 is found in a variety of tumours and some of these tumours carry point mutations in the sequence specifying the transmembrane domain of HER2. Substitution of a valine for a glutamic acid in the transmembrane domain can result in the constitutive dimerisation of this protein in the absence of a ligand.[26] HER2 mutations have been found in non-small-cell lung cancers (NSCLC) and can direct treatment.[27]Receptor tyrosine-protein kinase erbB-2, also known as CD340 (cluster of differentiation 340), proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human), is a protein that in humans is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene isolated from avian genome. It is also frequently called HER2 (from human epidermal growth factor receptor 2) or HER2/neu.[5][6][7] HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or over-expression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. In recent years the protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients.[8]

Biomarkers

Molecular markers used to guide treatment, assess prognosis, or detect relapse.

HER2

Studies presented at the AACR meeting demonstrated how the registry can be used to evaluate how cancer patients with rare tumor markers respond to treatments.
Based on the findings, MD Anderson is already using HER2 status to recommend patients for clinical trials instead of EGFR drugs and authors recommend others follow suit.
The researchers also reported that combining an ER-directed therapy with an irreversible HER2 kinase inhibitor could overcome resistance.
New data on Kadcyla and Tecentriq will help doctors further refine precision medicine options for breast cancer patients with unmet needs.
In the I-SPY 2 TRIAL, a subset of TNBC patients with elevated HER2 and EGFR phosphorylation responded to treatment with the HER2-inhibitor neratinib.
The updated guidelines confirm HER2 gene amplification assessed by ISH and protein overexpression assessed by IHC are primary predictors of responsiveness to HER2 therapy.
The analysis of HER2 and HER3 mutation carriers emphasizes how these studies can lead both to broadening and to narrowing of the patient populations for targeted drugs.
At the AACR annual meeting, researchers presented results from the Phase II SUMMIT trial investigating the pan-HER-targeted therapy neratinib.

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