Human epidermal growth factor receptor 2 (ERBB2, formerly HER2/neu, c-erbB2), of a family of 4 membrane tyrosine kinases (TKs), was found to be amplified in a human breast cancer cell line in 1985, and this amplification was shown to be important in the pathogenesis and progression of human breast cancer shortly thereafter. Since that time, HER2 amplification and resultant HER2 protein over-expression have been linked to important tumor cell proliferation and survival pathways, several drugs have been developed to target the pathway, and the detection of HER2 has become a routine prognostic and predictive factor in breast carcinoma.
The estrogen receptor (ER) and the HER2 (c-erbB2, HER2/neu) signaling pathways are the dominant drivers of cell proliferation and survival in most (85%) breast cancers. Targeting these pathways provides the most effective therapy in appropriately selected patients. Endocrine therapy to target ER and trastuzumab to target HER2 provide striking disease-free and overall survival benefits in the adjuvant setting when micrometastatic disease is present (50% reduction in risk of recurrence).–6 In breast cancer, HER2 is the dominant TK receptor, being amplified in 20% of cases. Amongst the 4 Tyrosine Kinase receptors, HER1 – 4, HER2 has the strongest catalytic kinase activity and HER2-containing heterodimers have the strongest signaling activity. – 10 An aberrant form of HER2 missing the extracellular domain, so-called p95, is found in some breast cancers. p95 is constitutively active because the external domain of these receptors acts as an inhibitor until they are bound by ligand. p95 can cause resistance to trastuzumab, an antibody that works by binding to a domain in the external domain of HER2. This domain is missing in p95. p95 is not detected by antibodies that target the external domain of HER2 for the same reason. Normal tissues have a low complement of HER2 membrane protein. Over-expression of HER2 is seen in 20% of breast and in some ovarian and gastric cancers, and it confers worse biological behavior and clinical aggressiveness in breast cancer.,3 Breast cancers can have up to 25 to 50 copies of the HER2 gene and up to a 40- to 100-fold increase in HER2 protein resulting in 2 million receptors expressed at the tumor cell surface. The differential in HER2 expression between normal tissues and tumors helps to define HER2 as an ideal treatment target. Trastuzumab, the first treatment targeting HER2, is well tolerated in patients and has low toxicity because its effects are relatively specific for cancer cells over-expressing HER2. HER2-amplified breast cancers have unique biological and clinical characteristics. They have increased sensitivity to certain cytotoxic agents such as doxorubicin, relative resistance to hormonal agents, and propensity to metastasize to the brain and viscera., 16 These tumors have higher proliferation rates and more aneuploidy and are associated with poorer patient prognosis. The poor outcome is dramatically improved with appropriate chemotherapy combined with the HER2-targeting drug trastuzumab.
Gastric cancer is the fourth most common cancer worldwide with approximately 1 million cases/year, and remains the second most common cause of cancer-related death in the world. A recent clinical trial (ToGA) has shown the effectiveness of Trastuzumab in response rate, median progression-free survival, and prolonging overall survival in metastatic gastric carcinoma. This represents a new standard of therapy in the treatment of advanced gastric and GEJ carcinoma. Pathologic interpretation of HER2 testing in Gastric carcinoma via Immunohistochemistry involves different criteria than that in the case of breast carcinoma.
Human epidermal growth factor receptor 2 (ERBB2, formerly HER2/neu, c-erbB2), of a family of 4 membrane tyrosine kinases (TKs), was found to be amplified in a human breast cancer cell line in 1985, and this amplification was shown to be important in the pathogenesis and progression of human breast cancer shortly thereafter. Since that time, HER2 amplification and resultant HER2 protein over-expression have been linked to important tumor cell proliferation and survival pathways, several drugs have been developed to target the pathway, and the detection of HER2 has become a routine prognostic and predictive factor in breast carcinoma.
The estrogen receptor (ER) and the HER2 (c-erbB2, HER2/neu) signaling pathways are the dominant drivers of cell proliferation and survival in most (85%) breast cancers. Targeting these pathways provides the most effective therapy in appropriately selected patients. Endocrine therapy to target ER and trastuzumab to target HER2 provide striking disease-free and overall survival benefits in the adjuvant setting when micrometastatic disease is present (50% reduction in risk of recurrence).–6 In breast cancer, HER2 is the dominant TK receptor, being amplified in 20% of cases. Amongst the 4 Tyrosine Kinase receptors, HER1 – 4, HER2 has the strongest catalytic kinase activity and HER2-containing heterodimers have the strongest signaling activity. – 10 An aberrant form of HER2 missing the extracellular domain, so-called p95, is found in some breast cancers. p95 is constitutively active because the external domain of these receptors acts as an inhibitor until they are bound by ligand. p95 can cause resistance to trastuzumab, an antibody that works by binding to a domain in the external domain of HER2. This domain is missing in p95. p95 is not detected by antibodies that target the external domain of HER2 for the same reason. Normal tissues have a low complement of HER2 membrane protein. Over-expression of HER2 is seen in 20% of breast and in some ovarian and gastric cancers, and it confers worse biological behavior and clinical aggressiveness in breast cancer.,3 Breast cancers can have up to 25 to 50 copies of the HER2 gene and up to a 40- to 100-fold increase in HER2 protein resulting in 2 million receptors expressed at the tumor cell surface. The differential in HER2 expression between normal tissues and tumors helps to define HER2 as an ideal treatment target. Trastuzumab, the first treatment targeting HER2, is well tolerated in patients and has low toxicity because its effects are relatively specific for cancer cells over-expressing HER2. HER2-amplified breast cancers have unique biological and clinical characteristics. They have increased sensitivity to certain cytotoxic agents such as doxorubicin, relative resistance to hormonal agents, and propensity to metastasize to the brain and viscera., 16 These tumors have higher proliferation rates and more aneuploidy and are associated with poorer patient prognosis. The poor outcome is dramatically improved with appropriate chemotherapy combined with the HER2-targeting drug trastuzumab.
Gastric cancer is the fourth most common cancer worldwide with approximately 1 million cases/year, and remains the second most common cause of cancer-related death in the world. A recent clinical trial (ToGA) has shown the effectiveness of Trastuzumab in response rate, median progression-free survival, and prolonging overall survival in metastatic gastric carcinoma. This represents a new standard of therapy in the treatment of advanced gastric and GEJ carcinoma. Pathologic interpretation of HER2 testing in Gastric carcinoma via Immunohistochemistry involves different criteria than that in the case of breast carcinoma.
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Human epidermal growth factor receptor 2 (ERBB2, formerly HER2/neu, c-erbB2), of a family of 4 membrane tyrosine kinases (TKs), was found to be amplified in a human breast cancer cell line in 1985, and this amplification was shown to be important in the pathogenesis and progression of human breast cancer shortly thereafter. Since that time, HER2 amplification and resultant HER2 protein over-expression have been linked to important tumor cell proliferation and survival pathways, several drugs have been developed to target the pathway, and the detection of HER2 has become a routine prognostic and predictive factor in breast carcinoma.
The estrogen receptor (ER) and the HER2 (c-erbB2, HER2/neu) signaling pathways are the dominant drivers of cell proliferation and survival in most (85%) breast cancers. Targeting these pathways provides the most effective therapy in appropriately selected patients. Endocrine therapy to target ER and trastuzumab to target HER2 provide striking disease-free and overall survival benefits in the adjuvant setting when micrometastatic disease is present (50% reduction in risk of recurrence).–6 In breast cancer, HER2 is the dominant TK receptor, being amplified in 20% of cases. Amongst the 4 Tyrosine Kinase receptors, HER1 – 4, HER2 has the strongest catalytic kinase activity and HER2-containing heterodimers have the strongest signaling activity. – 10 An aberrant form of HER2 missing the extracellular domain, so-called p95, is found in some breast cancers. p95 is constitutively active because the external domain of these receptors acts as an inhibitor until they are bound by ligand. p95 can cause resistance to trastuzumab, an antibody that works by binding to a domain in the external domain of HER2. This domain is missing in p95. p95 is not detected by antibodies that target the external domain of HER2 for the same reason. Normal tissues have a low complement of HER2 membrane protein. Over-expression of HER2 is seen in 20% of breast and in some ovarian and gastric cancers, and it confers worse biological behavior and clinical aggressiveness in breast cancer.,3 Breast cancers can have up to 25 to 50 copies of the HER2 gene and up to a 40- to 100-fold increase in HER2 protein resulting in 2 million receptors expressed at the tumor cell surface. The differential in HER2 expression between normal tissues and tumors helps to define HER2 as an ideal treatment target. Trastuzumab, the first treatment targeting HER2, is well tolerated in patients and has low toxicity because its effects are relatively specific for cancer cells over-expressing HER2. HER2-amplified breast cancers have unique biological and clinical characteristics. They have increased sensitivity to certain cytotoxic agents such as doxorubicin, relative resistance to hormonal agents, and propensity to metastasize to the brain and viscera., 16 These tumors have higher proliferation rates and more aneuploidy and are associated with poorer patient prognosis. The poor outcome is dramatically improved with appropriate chemotherapy combined with the HER2-targeting drug trastuzumab.
Gastric cancer is the fourth most common cancer worldwide with approximately 1 million cases/year, and remains the second most common cause of cancer-related death in the world. A recent clinical trial (ToGA) has shown the effectiveness of Trastuzumab in response rate, median progression-free survival, and prolonging overall survival in metastatic gastric carcinoma. This represents a new standard of therapy in the treatment of advanced gastric and GEJ carcinoma. Pathologic interpretation of HER2 testing in Gastric carcinoma via Immunohistochemistry involves different criteria than that in the case of breast carcinoma.
