Breast Cancer, ERBB2 (HER2), Exon 20 Insertion

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Expand Collapse Breast Cancer  - General Description Breast cancer is a malignant tumor that usually forms in the glands that make milk (lobules) and the tubes (ducts) that carry milk to the nipple. This year about 231,8400 women (and 2,000 men) in the U.S. will be told by a doctor that they have breast cancer. Half of these people will be at least 61 years old. However, more than 10 times as many women, about 2.7 million, remain alive today after having been diagnosed with breast cancer.

Breast cancer is not one disease and is currently classified into 3 subtypes based on the receptors present on the surface of the cancer cell. If the tumor is positive for estrogen and/or progesterone receptors, it is called "hormone receptor breast cancer". In that case, drugs that block the hormones, such as tamoxifen or aromatase inhibitors, might work best initially. If the tumor is positive for another type of receptor, called HER2 (or ERBB2), it is called "HER2 positive breast cancer", and certain targeted therapies that block HER2, such as the medications trastuzumab (Herceptin), pertuzumab (perjeta), T-DM1 (Kadcyla), and lapatanib (Tykerb) might work best and are recommended by the FDA. If the tumor is negative for HER2, estrogen, and progesterone receptors, it is called "triple negative breast cancer".

Over time, breast cancer (and other tumors) can spread from the site where it started (the primary tumor) in 3 ways. First, breast cancer cells can invade the normal tissue surrounding the tumor. Second, breast cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the breast cancer cells can get into the blood stream and travel to other places in the body. In these distant places, the breast cancer cells cause secondary (metastatic) tumors to grow. The main sites where breast cancer spreads are the lungs, liver and bones. There is a lot of ongoing research to identify other receptors and mutations that are actionable through treatment using appropriate new targeted therapies that could be developed against the cancer.

Source: National Cancer Institute, 2015
Breast cancer is the most common non-cutaneous cancer among women in the United States. This year about 231,840 women (and 2,000 men) in the U.S. will be told by a doctor that they have breast cancer. Half of these people will be at least 61 years old. However, more than 10 times as many women, about 2.7 million, remain alive today after having been diagnosed with breast cancer.

Germline mutations in either the BRCA1 or BRCA2 gene confer an increased risk of breast and/or ovarian cancer. In addition, mutation carriers may be at increased risk of other primary cancers. Genetic testing is available to detect mutations in members of high-risk families. Such individuals should first be referred for counseling. Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy and hormone therapy.

Over the past years, significant major strides in understanding the biology of breast cancer have translated into actionable targeted therapies. For metastatic hormone receptor positive breast cancer, FDA approved therapies include tamoxifen, a selective estrogen modulator, aromatase inhibitors including exemestane, letrozole, and anastrozole, fulvestrant, a selective estrogen receptor blocker, and more recently everoliumus, a mTOR inhibitor, in combination with exemestane.

Despite significant improvements in the treatment of breast tumors, novel therapies and treatment strategies are needed. There are a number of novel therapies in development tailored to specific somatic mutations in the tumor.
Source: National Cancer Institute, 2014
Breast cancer is a malignant tumor that usually forms in the glands that make milk (lobules) and the tubes (ducts) that carry milk to the nipple. This year about 231,8400 women (and 2,000 men) in the U.S. will be told by a doctor that they have breast cancer. Half of these people will be at least 61 years old. However, more than 10 times as many women, about 2.7 million, remain alive today after having been diagnosed with breast cancer.

Breast cancer is not one disease and is currently classified into 3 subtypes based on the receptors present on the surface of the cancer cell. If the tumor is positive for estrogen and/or progesterone receptors, it is called "hormone receptor breast cancer". In that case, drugs that block the hormones, such as tamoxifen or aromatase inhibitors, might work best initially. If the tumor is positive for another type of receptor, called HER2 (or ERBB2), it is called "HER2 positive breast cancer", and certain targeted therapies that block HER2, such as the medications trastuzumab (Herceptin), pertuzumab (perjeta), T-DM1 (Kadcyla), and lapatanib (Tykerb) might work best and are recommended by the FDA. If the tumor is negative for HER2, estrogen, and progesterone receptors, it is called "triple negative breast cancer".

Over time, breast cancer (and other tumors) can spread from the site where it started (the primary tumor) in 3 ways. First, breast cancer cells can invade the normal tissue surrounding the tumor. Second, breast cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the breast cancer cells can get into the blood stream and travel to other places in the body. In these distant places, the breast cancer cells cause secondary (metastatic) tumors to grow. The main sites where breast cancer spreads are the lungs, liver and bones. There is a lot of ongoing research to identify other receptors and mutations that are actionable through treatment using appropriate new targeted therapies that could be developed against the cancer.

Source: National Cancer Institute, 2015
Breast cancer is the most common non-cutaneous cancer among women in the United States. This year about 231,840 women (and 2,000 men) in the U.S. will be told by a doctor that they have breast cancer. Half of these people will be at least 61 years old. However, more than 10 times as many women, about 2.7 million, remain alive today after having been diagnosed with breast cancer.

Germline mutations in either the BRCA1 or BRCA2 gene confer an increased risk of breast and/or ovarian cancer. In addition, mutation carriers may be at increased risk of other primary cancers. Genetic testing is available to detect mutations in members of high-risk families. Such individuals should first be referred for counseling. Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy and hormone therapy.

Over the past years, significant major strides in understanding the biology of breast cancer have translated into actionable targeted therapies. For metastatic hormone receptor positive breast cancer, FDA approved therapies include tamoxifen, a selective estrogen modulator, aromatase inhibitors including exemestane, letrozole, and anastrozole, fulvestrant, a selective estrogen receptor blocker, and more recently everoliumus, a mTOR inhibitor, in combination with exemestane.

Despite significant improvements in the treatment of breast tumors, novel therapies and treatment strategies are needed. There are a number of novel therapies in development tailored to specific somatic mutations in the tumor.
Source: National Cancer Institute, 2014
Expand Collapse ERBB2 (HER2)  - General Description
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ERBB2, often called HER2, is a gene that provides the code for making a cell surface protein called the ErbB2 (HER2) growth factor receptor. When certain growth factors (proteins that stimulate cell growth and division) bind to this receptor, they activate a signaling system inside the cell that ultimately promotes diverse functions such as growth, interaction and adhesion between cells, and ability of the cell to migrate within tissues. In some tumors, the activation of HER2 signaling is an important mechanism that drives the disease process. This can occur through HER2 gene amplification (the most common mechanism) or HER2 gene mutation in the cancer cells.

Extra copies of the HER2 gene (gene amplification) have been found in a number of different cancers. This causes the cancer cells to make excess HER2 (overexpression), which in turn, tells the cells to grow and divide in an uncontrolled manner. The presence of amplified HER2 has been reported in approximately 25% of breast tumors, 20% of esophageal tumors, 15% of gastric cancers and 20% of certain ovarian tumors. The FDA has approved the targeted therapies including trastuzumab (Herceptin), pertuzumab (Perjeta), lapatinib (Tykerb), and T-DM1 (Kadcyla) for the treatment of patients with certain kinds of breast cancer in which HER2 is overexpressed. Trastuzumab is also FDA approved to treat gastric cancer with amplification of this receptor.

Mutations in HER2 involving small duplications of the gene can promote resistance to some EGFR targeted therapies, but on the other hand, promote response to certain HER2 inhibitors. While very rare, these mutations are most often associated with non-small cell lung cancer, but have also been described in other malignancies including brain, gastric, breast and ovarian tumors. Tumor mutation profiling performed clinically at the MGH Cancer Center has identified HER2 mutations in a small subset of non-HER2 amplified breast cancer (1%) and non-small cell lung cancers (1%).

Source: Genetics Home Reference
The ERBB2 gene encodes for a cell surface protein that belongs to the ERBB family of receptor tyrosine kinases, known as ErbB2 (more commonly referred to as HER2). Four members of the ERBB family have been identified; EGFR (ERBB1, HER1), ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). Binding of a ligand induces ERBB receptor homo-/hetero-dimerization and triggers a signaling cascade that drives many cellular responses. These include the activation of PI3K/AKT/mTOR and MAP kinase/ERK pathways, which promote cell survival and proliferation. Although there is no known ligand for HER2, HER2 is the preferred dimerization partner for the other ERBB receptors. In some cancers, HER2 activity is increased through protein overexpression or gene mutation.

The overexpression of HER2 is tightly associated with amplification of the HER2 gene. HER2 amplification has been reported in multiple malignancies, including breast cancer (25% incidence), esophageal cancer (20% incidence), gastric cancer (15% incidence), and mucinous ovarian carcinomas (20% incidence).

Mutations in HER2 have also been identified as an important mechanism that could drive tumor growth and confer resistance to targeted therapies. In-frame duplication/insertions in a region of HER2 exon 20 that is conserved with EGFR have been demonstrated in ~2% of lung cancer patients. Mutations in HER2 receptor have also been described in a small subset of non-HER2 amplified breast cancer (1%).

Source: Genetics Home Reference
PubMed ID's
15864276, 9130710, 15457249, 16397024, 18772890, 16843263, 16988931, 22899400
Expand Collapse Exon 20 Insertion  in ERBB2 (HER2)
The ERBB2 exon 20 insertion consists of an in-frame addition of extra nucleotide bases within the portion of the gene that encodes the kinase domain, leading to a gain-of-function activity.

The ERBB2 exon 20 insertion is a mutation that consists of an in-frame addition of extra nucleotide bases within the portion of the gene that encodes the kinase domain, leading to a gain-of-function activity.

Novel HER2 mutations in the absence of HER2 gene amplification have been recently described in breast cancer. The activating mutations in HER2 occur in about 1% of breast carcinomas. Preclinical laboratory models have suggested that these mutations may promote sensitivity to the HER2 inhibitors lapatinib or neratinib. Clinical trials are currently underway to validate this hypothesis.

The ERBB2 exon 20 insertion is a mutation that consists of an in-frame addition of extra nucleotide bases within the portion of the gene that encodes the kinase domain, leading to a gain-of-function activity.

Novel HER2 mutations in the absence of HER2 gene amplification have been recently described in breast cancer. The activating mutations in HER2 occur in about 1% of breast carcinomas. Preclinical laboratory models have suggested that these mutations may promote sensitivity to the HER2 inhibitors lapatinib or neratinib. Clinical trials are currently underway to validate this hypothesis.

PubMed ID's
16843263
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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing Results: 1-10 of 41 Per Page:
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Protocol # Title Location Status Match
NCT01953926 An Open-label, Phase 2 Study of Neratinib in Patients With Solid Tumors With Somatic Human Epidermal Growth Factor Receptor (EGFR, HER2, HER3) Mutations or EGFR Gene Amplification An Open-label, Phase 2 Study of Neratinib in Patients With Solid Tumors With Somatic Human Epidermal Growth Factor Receptor (EGFR, HER2, HER3) Mutations or EGFR Gene Amplification MGH Open DGM
NCT02260531 Cabozantinib +/- Trastuzumab In Breast Cancer Patients w/ Brain Metastases Cabozantinib +/- Trastuzumab In Breast Cancer Patients w/ Brain Metastases MGH Open DG
NCT01971515 First-in-Human Dose Escalation Trial in Subjects With Advanced Malignancies First-in-Human Dose Escalation Trial in Subjects With Advanced Malignancies MGH Open DG
NCT02500199 Phase 1, Dose Escalation Study of Pyrotinib in Patients Who Progressed on Prior HER2 Targeted Therapy Phase 1, Dose Escalation Study of Pyrotinib in Patients Who Progressed on Prior HER2 Targeted Therapy MGH Open DG
NCT02326974 T-DM1+Pertuzumab in Pre-OP Early-Stage HER2+ BRCA T-DM1+Pertuzumab in Pre-OP Early-Stage HER2+ BRCA MGH Open DG
NCT01296555 A Dose Escalation Study Evaluating the Safety and Tolerability of GDC-0032 in Participants With Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma (NHL) and in Combination With Endocrine Therapy in Locally Advanced or Metastatic Hormone Receptor-Positive Breast Cancer A Dose Escalation Study Evaluating the Safety and Tolerability of GDC-0032 in Participants With Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma (NHL) and in Combination With Endocrine Therapy in Locally Advanced or Metastatic Hormone Receptor-Positive Breast Cancer MGH Open D
NCT02052778 A Dose Finding Study Followed by a Safety and Efficacy Study in Patients With Advanced Solid Tumors or Multiple Myeloma With FGF/FGFR-Related Abnormalities A Dose Finding Study Followed by a Safety and Efficacy Study in Patients With Advanced Solid Tumors or Multiple Myeloma With FGF/FGFR-Related Abnormalities MGH Open D
NCT02580448 A Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of VT-464 in Patients With Advanced Breast Cancer A Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of VT-464 in Patients With Advanced Breast Cancer MGH Open D
NCT02099058 A Phase 1/1b Study With ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Cancer Tumors A Phase 1/1b Study With ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Cancer Tumors MGH Open D
NCT02338349 A Phase I, Multicenter, Open-Label, Two-Part, Dose-escalation Study of RAD1901 in Postmenopausal Women With Advanced Estrogen Receptor Positive and HER2-Negative Breast Cancer A Phase I, Multicenter, Open-Label, Two-Part, Dose-escalation Study of RAD1901 in Postmenopausal Women With Advanced Estrogen Receptor Positive and HER2-Negative Breast Cancer MGH Open D
Trial Status: Showing Results: 1-10 of 41 Per Page:
12345Next »
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