Breast Cancer, ESR1

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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 ESR1  - General Description
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The ESR1 gene encodes an estrogen receptor, which is a ligand-activated transcription factor composed of hormone binding domain, DNA binding domain, and transcription activation domain. The protein localizes to the nucleus, where it forms homodimers, or heterodimerizes with ESR2. Transactivation in the nucleus involves either direct homodimer binding to an estrogen response element (ERE) sequence, or association with other DNA-binding transcription factors such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3 to mediate ERE-independent signaling. Mutual trans-repression occurs between the ESR and NF-kapa-B in a cell-type specific manner. Alternative promoter usage and alternative splicing result in dozens of transcript variants, but the full length nature of many of these variants has not been determined. Estrogen and its receptors are essential for sexual development and reproductive function, but also play a role in other tissues such as bone.

Sources: Ref Sequence Mar 2014; NCBI Gene; UniProt;
The ESR1 gene encodes an estrogen receptor, which is a ligand-activated transcription factor composed of hormone binding domain, DNA binding domain, and transcription activation domain. The protein localizes to the nucleus, where it forms homodimers, or heterodimerizes with ESR2. Transactivation in the nucleus involves either direct homodimer binding to an estrogen response element (ERE) sequence, or association with other DNA-binding transcription factors such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3 to mediate ERE-independent signaling. Mutual trans-repression occurs between the ESR and NF-kapa-B in a cell-type specific manner. Alternative promoter usage and alternative splicing result in dozens of transcript variants, but the full length nature of many of these variants has not been determined. Estrogen and its receptors are essential for sexual development and reproductive function, but also play a role in other tissues such as bone.

Sources: Ref Sequence Mar 2014; NCBI Gene; UniProt;
PubMed ID's
24217577, 12496244, 24398047, 24583794
Expand Collapse ESR1  in Breast Cancer
In addition to Estrogen Receptor’s normal role in sexual development, metabolism and bone development, ESR's are also involved in pathological processes including breast cancer. ESR1 is the gene that encodes the protein ESR alpha, which has been found to have a role in breast cancer. The following genetic alterations in the ESR1 gene have been found through the analysis of many indvidual breast tumors: Mutations in the Ligand-Binding Domain, or LBD (the part of the ESR alpha protein which binds to the hormone estrogen); a loss of ESR1 expression; Altered activity of Co-regulatory proteins of ESR1; Cross-talk between ER alpha and growth factor signal pathways in tumor cells; and ESR1 gene amplification. How each of these types of genetic alterations contributes to the development of breast cancer is currently under study.

Normally, ER alpha binds to its’ ligand, estrogen hormone, on part of the protein that is encoded by two segments of the genetic code in DNA, called codon 537 and codon 538. Together, these code the sequence for Ligand Binding Domain (LBD). When estrogen binds to ER alpha on the LBD, a conformational change in the protein takes place, which activates ER alpha to “turn on” specific genes in the nucleus of cells. Therefore, in ER-positive breast cancers, oncologists prescribe various anti-estrogen therapies, such as tamoxifen and fulvestrant, to inhibit cancer growth.

Some ER+ patients who have been treated with endocrine therapies eventually develop resistance, and their cancers progress. A subset of the patients who have developed resistance to endocrine therapies, mutations have been found in the LBD of ESR1, specifically in codons 537 and 538. In structural modeling studies of the LBD mutants, it has been shown that these mutations cause similar conformational changes to those induced by activated ligand-bound receptor. In other words, even in the absence of the ligand estrogen, because of the mutation in the LBD, the protein adopts the “active” conformation. Laboratory experiments have shown that these LBD mutant ESR1 proteins activate transcription and proliferation as if there were ligand present, and that they have reduced interaction with anti-estrogen therapies, such as tamoxifen and fulvestrant. LBD ESR1 mutations are found almost exclusively in patients who have been treated with hormone therapy, and they are found more frequently in patients who have had multiple rounds of hormone therapies.

In addition to Estrogen Receptor’s normal role in sexual development, metabolism and bone development, ESR's are also involved in pathological processes including breast cancer. ESR1 is the gene that encodes the protein ESR alpha, which has been found to have a role in breast cancer. The following genetic alterations in the ESR1 gene have been found through the analysis of many indvidual breast tumors: Mutations in the Ligand-Binding Domain, or LBD (the part of the ESR alpha protein which binds to the hormone estrogen); a loss of ESR1 expression; altered activity of Co-regulatory proteins of ESR1; Cross-talk between ER alpha and growth factor signal pathways in tumor cells; and ESR1 gene amplification. How each of these types of genetic alterations contributes to the development of breast cancer is currently under study.

Normally, ER alpha binds to its’ ligand, estrogen hormone, on part of the protein that is encoded by two segments of the genetic code in DNA, called codon 537 and codon 538. Together, these code the sequence for Ligand Binding Domain (LBD). When estrogen binds to ER alpha on the LBD, a conformational change in the protein takes place, which activates ER alpha to “turn on” specific genes in the nucleus of cells. Therefore, in ER-positive breast cancers, oncologists prescribe various anti-estrogen therapies, such as tamoxifen and fulvestrant, to inhibit cancer growth.

Some ER+ patients who have been treated with endocrine therapies eventually develop resistance, and their cancers progress. In a subset of the patients who have developed resistance to endocrine therapies, mutations have been found in the LBD of ESR1, specifically in codons 537 and 538. In structural modeling studies of the LBD mutants, it has been shown that these mutations cause similar conformational changes to those induced by activated ligand-bound receptor. In other words, even in the absence of the ligand estrogen, because of the mutation in the LBD, the protein adopts the “active” conformation. Laboratory experiments have shown that these LBD mutant ESR1 proteins activate transcription and proliferation as if there were ligand present, and that they have reduced interaction with anti-estrogen therapies, such as tamoxifen and fulvestrant. LBD ESR1 mutations are found almost exclusively in patients who have been treated with hormone therapy, and they are found more frequently in patients who have had multiple rounds of hormone therapies.

PubMed ID's
24398047
Expand Collapse No mutation selected
The mutation of a gene provides clinicians with a very detailed look at your cancer. Knowing this information could change the course of your care. To learn how you can find out more about genetic testing please visit http://www.massgeneral.org/cancer/news/faq.aspx or contact the Cancer Center.
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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene
Trial Status: Showing Results: 1-10 of 42 Per Page:
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Protocol # Title Location Status Match
NCT01857193 Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of Hormone Receptor Positive HER2 Negative Advanced Breast Cancer Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of Hormone Receptor Positive HER2 Negative Advanced Breast Cancer MGH Open DG
NCT01872260 Study of LEE011, BYL719 and Letrozole in Advanced ER+ Breast Cancer Study of LEE011, BYL719 and Letrozole in Advanced ER+ Breast Cancer 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
NCT01525589 A Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or Unselected Metastatic Breast Cancer A Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or Unselected Metastatic Breast Cancer MGH Open D
NCT02365662 A Study Evaluating Safety and Pharmacokinetics of ABBV-221 in Subjects With Advanced Solid Tumor Types Likely to Exhibit Elevated Levels of Epidermal Growth Factor Receptor A Study Evaluating Safety and Pharmacokinetics of ABBV-221 in Subjects With Advanced Solid Tumor Types Likely to Exhibit Elevated Levels of Epidermal Growth Factor Receptor MGH Open D
NCT02467361 A Study of BBI608 Administered in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Cancers A Study of BBI608 Administered in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Cancers MGH Open D
Trial Status: Showing Results: 1-10 of 42 Per Page:
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