Breast Cancer, ESR1

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Expand Collapse Breast Cancer  - General Description Breast cancer is the most common non-cutaneous cancer among women in the United States. This year about 252,710 women in the U.S. will be told by a doctor that they have breast cancer. Half of these people will be at least 62 years old. However, an estimated 3,327,552 women are living with female breast cancer in the United States following treatment.

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, 2017
Breast cancer is the most common non-cutaneous cancer among women in the United States. This year about 252,710 women in the U.S. will be told by a doctor that they have breast cancer. Half of these people will be at least 62 years old. However, an estimated 3,327,552 women are living with female breast cancer in the United States following treatment.

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, 2017
Breast cancer is the most common non-cutaneous cancer among women in the United States. This year about 252,710 women in the U.S. will be told by a doctor that they have breast cancer. Half of these people will be at least 62 years old. However, an estimated 3,327,552 women are living with female breast cancer in the United States following treatment.

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, 2017
Breast cancer is the most common non-cutaneous cancer among women in the United States. This year about 252,710 women in the U.S. will be told by a doctor that they have breast cancer. Half of these people will be at least 62 years old. However, an estimated 3,327,552 women are living with female breast cancer in the United States following treatment.

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, 2017
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
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 DG
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 DG
NCT02684032 A Study To Assess The Tolerability And Clinical Activity Of Gedatolisib In Combination With Palbociclib/Letrozole Or Palbociclib/Fulvestrant In Women With Metastatic Breast Cancer A Study To Assess The Tolerability And Clinical Activity Of Gedatolisib In Combination With Palbociclib/Letrozole Or Palbociclib/Fulvestrant In Women With Metastatic Breast Cancer 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
NCT02734615 Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers 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
NCT02732119 Study of Ribociclib With Everolimus + Exemestane in HR+ HER2- Locally Advanced/Metastatic Breast Cancer Post Progression on CDK 4/6 Inhibitor. Study of Ribociclib With Everolimus + Exemestane in HR+ HER2- Locally Advanced/Metastatic Breast Cancer Post Progression on CDK 4/6 Inhibitor. MGH Open DG
NCT02316509 Study of SRN-927 in Postmenopausal Women With Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer Study of SRN-927 in Postmenopausal Women With Locally Advanced or Metastatic Estrogen Receptor Positive 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
Trial Status: Showing Results: 1-10 of 42 Per Page:
12345Next »
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