HER-2 (HER2/neu)

Human epidermal growth factor receptor that is a cell surface protein composed of an extracellular domain, a transmembrane domain and an intracellular domain with tyrosine kinase activity.

HER2 is a tyrosine kinase receptor of the ErbB family and is associated with cell signaling pathways that lead to cell proliferation, differentiation, and inhibition of apoptosis.

HER2/neu is located on chromosome 17q21 and encodes the HER2protein,

HER2 oncogene amplification results in HER2 overexpression, enhancing signal propagation, and leads to uncontrolled cellular preparation and chromosomal instability, and tumorigenesis.

The epidermal growth factor receptor (EGFR) family of transmembrane tyrosine kinase receptors include HER1, HER2/NEU, HER 3, and HER4, each with extracellular ligand binding domain, lipophilic transmembrane domain, and an intracellular domain with tyrosine kinase activity that leads to activation of downstream pathways including: RAS/MAPK, PIK3K/AKT (m-TOR) pathways,which induce, proliferation, differentiation, migration, and survival.

HER2 is critical for cell survival and is important in biological processes mediated by the MAPK and PI3K pathways, such as cell growth, survival, and differentiation.

HER2 amplification and overexpression enhances and prolongs signals that trigger malignant transformation, which are associated with poor clinical outcomes in breast, ovarian, gastric, and prostate cancers.

HER2 is a key molecule in the activation of HER signaling pathways, as it is the preferred dimerization partner for other HER receptors.

H ER2 containing heterodimers have the highest mitogenic potential among all HER complexes.

A member of the EGFR family.

Referred to as ERBB2.

Commonly used nomenclature for this family of receptors is ERBB.

Homodmerization or heterodimerization with any other receptor of the HER family activates its intracellular kinase, resulting in the autophosphylorylation of tyrosine residues on its intracellular cytoplasmic domain.

The transmembrane receptor HER2, composing of an extracellular domain and a sub-membrane tyrosine kinase activity, allowed for the development of 2 therapeutic approaches targeting the HER2 receptor directly: monoclonal antibodies and tyrosine kinase inhibitors.

Activation of the extracellular domain leads to confirmational changes initiating reactions resulting in protein kinase activation.

Member of erbB family of transmembrane receptor tyrosine kinases.

The human epidermal growth factor receptor (EGFR) family is composed of four members: HER1 or EGFR, HER2, HER3, and HER4.

HER2 is the only member that does not have a ligand.

HER2 over expression results in activation of downstream growth factors signaling pathways, which can ultimately result in oncogenesis.

HER2 amplification or overexpression is associated with the worse outcome and worst prognosis in breast cancer.

Encodes a tyrosine kinase receptor that mediates signaling functions in normal and malignant epithelial cells.

ERBB tyrosine receptor kinases subsequently activate several intra cellular pathways critical for cellular function and survival, including PI3K-AKT, RAS-MAPK, and mTOR pathways.

Hyper activation or overexpression of these receptors lead to uncontrolled cell growth and proliferation, and eventually oncogenesis.

A family of four transmembrane receptor tyrosine kinases that control cellular growth, differentiation and survival.

HER2 aberrations have been found in numerous solid tumors, including gastrointestinal and lung cancers aside from breast cancer.

Localized to chromosome 17q.

Amplified and/or the protein is overexpressed in approximately 15-20% of primary breast cancers.

HER2 positive breast cancer cells have 100 times the usual number of HER2 receptors than normal breast cells, and they are located on the outside of the cell.

There are thousands of HER2 receptors in the normal breast cell, while HER-2 positive ones may have millions of receptors.

Overexpression of HER-2 receptors leads to aggressive growth and spread greater than in HER2 negative cells.

Cardiomyocytes have HER2 receptors.

HER2 positive tumors can be stratified into two different genomic groups, and explains why some Her2 positive tumors do not respond to HER2 targeted therapies.

HER2 amplification drives cellular proliferation, promotes angiogenesis, and enhances cell survival pathways promoting a more aggressive tumor biology that has a worse prognosis.

Signal transduction occurs as a result of receptor dimerization between members of the HER family.

The HER2-HER3 heterodimer is critical for the activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target or rapamycin (mTOR) pathway.

HER receptors signal through several pathways, but the 2 main pathways are P13K/Akt/mTOR and Ras/Raf/MAPK pathways.

Regulates cell prolfeeration, apoptosis, and drug resistance.

Results in resistance to anti-EGFR antibodies.

Immunohistochemistry testing evaluates expiration of the HER2 protein, which is a receptor that sits on the surface of the cell.

Results are reported as no staining versus 1+, 2+, or 3+, according to the number of cells that are stained for the protein and the intensity of the staining.

Immunohistochemistry tests for protein expression on the cell surface and is scored based on intensity, pattern, and percentage of cells stained.

in situ hybridization assay test for gene amplification and is scored on the HER2 ratio signals over the number of chromosome 17 centromere signals per cell and the average copy number.

HER2 positive disease is considered a 3 when it is at high-intensity in at least 30% of the cells.

HER2 can be measured by gene amplification with fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH).

These methods count the copies of genes, not HER2 protein, localized in the nucleus.

The number is considered amplified when there are at least 2.2 copies.

HER2 at negativity is defined as fluorescence in situ hybridization (FISH) ratio of less than two or 8% positivity below 10% by immunohistochemistry.

Overexpression of the HER2 protein and amplification of HER2 gene, or both occur in 15-25% of patients with breast cancer and indicate aggressive tumor activity.

Overexpression in breast cancer and gastric cancer associated with a worse prognosis and more aggressive disease course.

HER2 amplification is found in approximately 3-4% of all cases of colorectal cancer.

Colorectal rectal cancer HER2 amplification is seen approximately in 2 to 3% of unselected patients with colorectal cancer.

The HER2 amplification rate is higher among patients with RAS wild type disease at approximately 5 to 6%, and lower among patients with RAS mutant disease, at approximately 1 to 2%.

HER2 amplification is a negative predictor of response to anti-epidermal growth factor receptor (EGFR) therapy and In such patients cetuximab and panitumumab are generally avoided.

HER2 positive breast tumors metastasize three times more often to the lungs, liver and brain compared to HER2-negative tumors and three times less often to the bone.

In a study of 83 patients with breast cancer the median overall survival for patients with HER2 positive disease from diagnosis of brain metastases was 17.1 months compared with 5.2 months for patients with HER2 negative breast cancer patients with CNS disease (Eichler AF).

Much higher rate of recurrence among patients with T1abN0 breast cancers HER2 positive compared to HER2 negative tumors: increased risk 2-5 fold, at 5 years with an absolute risk of 10-23% despite small size of cancers (Curigliano, G, Gonzalez-Agulo AM).

In patients with larger tumors and or node positive with HER2 positive lesions the recurrence rate is much higher than in smaller lesions, node negative or HER2 negative tumors.

With current era therapies HER2 positive tumor prognosis has improved.

Presently, HER2 positive tumors of the breast associated with hormone positive breast cancers has a prognosis almost mimicking the outcome of patients with HR positive HER2 neg tumors.

HER family involved in cell-cell stromal communication mainly through signal transduction.

Signal transduction refers to ligands, or external growth factors, that affect the transcription of various genes, by phosphorylating or dephosphorylating transmembrane proteins and intracellular signaling intermediates.

HER-2 overexpression and post surgical growth stimulation of breast cancer cells.

Overexpression has some influence on probability of sensitivity to some chemotherapy agents.

Up to 60% of patients with overexpression do not respond to trastuzumab.

Premenopausal women with HER-2 positive breast cancer have an increased risk of brain metastases.

Combination of lapatinib plus trastuzumab compared to lapatinib alone in women with HER2+ metastatic breast cancer that had progressed on multiple lines of treatment: combination superior in progression free survival compared to lapatinib alone, median overall survival in the combination arm 60.7 weeks compared to lapatinib alone at 41.4 weeks (Blackwell KL).

In a phase 3 study randomized Clinical Evaluating of Pertuzumab and Trastuzumab (CLEOPATRA) trial of 800 meet patients with metastatic HER2 positive breast cancer adding pertuzumab to a combination of trastuzumab and docetaxel chemotherapy stated progression free survival by a median of 6.1 months compared to the combination therapy plus placebo.

Trastuzumab and pertuzumab are monoclonal antibodies that bind to the HER2 receptor protein in different locations.

In the phase II NeoSphere trial 417 patients with newly diagnosed HER-2 positive early stage breast cancer were randomized to one of for treatment arms: Trastuzumab plus docetaxel, pertuzamab plus trastuzumab plus docetaxel, pertuzumab plus trastuzumab or pertuzumab plus docetaxel-Patient’s had locally advanced for early breast cancer and were treated neo-adjuvantly-patient who received docetaxel, pertuzumab plus trastuzumab Had a significant improvement in pathological complete response of 45.8% impaired with 16.8-29% for the other groups.

HER-2-overexerted in 20% of cases of biliary tract cancer.

HER2-neu overexressed in about 20% of patients with adenocarcinoma of the esophagus and gastric cancer.

HER2-neu overexressed in about one third of patients with adult B-cell ALL.

Leave a Reply

Your email address will not be published. Required fields are marked *