Breast Cancer, PTEN, R233X (c.697C>T)

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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 PTEN  - General Description
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PTEN is a gene that provides the code for making a protein called phosphatase and tensin homolog (PTEN). Found in almost all tissues in the body, this protein acts as a tumor suppressor. That is, it keeps cells from growing and dividing too fast or in an uncontrolled way. The PTEN protein is part of a signaling pathway that tells cells to stop dividing and triggers their self-destruction (apoptosis). It also may help control how cells move (migration), stick to other cells (adhesion) and protect their genetic information.

Somatic mutations in PTEN are among the most common genetic changes found in human cancers. Instead of coming from a parent and being present in every cell (hereditary), somatic mutations are acquired during the course of a person's life and are found only in cells that become cancerous. PTEN may be the most frequently mutated gene in prostate cancer and endometrial cancer. These mutations usually result in a defective protein that has lost its ability to be a tumor suppressor. Such mutations also are found in certain brain tumors (glioblastomas and astrocytomas) and melanoma of the skin. Loss of PTEN expression is also a common way by which PTEN activity can be reduced and the PI3K pathway can be activated.

Several related conditions caused by inherited mutations in PTEN are grouped together as PTEN hamartoma tumor syndrome. One of these conditions is Cowden syndrome, which is characterized by the growth of many hamartomas and an increased risk of developing breast, thyroid or endometrial cancer. Mutations that cause Cowden syndrome lead to production of a defective PTEN protein that cannot stop cell division or trigger apoptosis, which contributes to the development of hamartomas and cancerous tumors.

Source: Genetics Home Reference
The PTEN gene encodes a lipid phosphatase that antagonizes oncogenic PI3K/AKT signaling via dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) at the cell membrane. Cancer-associated genomic alterations in PTEN result in PTEN inactivation and thus increased activity of the PI3K/AKT pathway. Somatic mutations of PTEN occur in multiple malignancies, including gliomas, melanoma, prostate, endometrial, breast, ovarian, renal and lung cancers. Germline PTEN mutations are associated with inherited hamartoma syndromes, including Cowden syndrome. Loss of PTEN expression is also a common way by which PTEN activity can be reduced and the PI3K pathway can be activated.

Source: Genetics Home Reference
Expand Collapse R233X (c.697C>T)  in PTEN
The PTEN R233X mutation arises from a single nucleotide change (c.697C>T) and results in an amino acid substitution of the arginine (R) at position 233 by a stop codon (X).
The PTEN R233X mutation arises from a single nucleotide change (c.697C>T) and results in an amino acid substitution of the arginine (R) at position 233 by a stop codon (X).

Mutations in the PTEN gene are relatively uncommon in breast cancer. However, PTEN loss of expression is found in 30% of the tumors, mainly in the triple-negative subtype.

Loss of PTEN protein expression in breast carcinoma is correlated with resistance to the HER2 targeted agent trastuzumab, as determined across multiple clinical trial studies. Conversely, in preclinical laboratory models, PTEN loss is associated with sensitivity to PI3K pathway inhibitors. Recent data suggest that the P110 beta catalytic subunit of PI3K drives cancer growth when PTEN function is lost. The role of PTEN mutations in predicting response to PI3K (including selective P110 beta inhibitors), AKT and/or mTOR inhibitors in breast cancer is actively being explored in clinical trials.

Mutations in the PTEN gene are relatively uncommon in breast cancer. However, PTEN loss of expression is found in 30% of the tumors, mainly in the triple-negative subtype.

Loss of PTEN protein expression in breast carcinoma is correlated with resistance to the HER2 targeted agent trastuzumab, as determined across multiple clinical trial studies. Conversely, in preclinical laboratory models, PTEN loss is associated with sensitivity to PI3K pathway inhibitors. Recent data suggest that the P110 beta catalytic subunit of PI3K drives cancer growth when PTEN function is lost. The role of PTEN mutations in predicting response to PI3K (including selective P110 beta inhibitors), AKT and/or mTOR inhibitors in breast cancer is actively being explored in clinical trials.

PubMed ID's
21135276, 18676830, 18755892
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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing Results: 1-10 of 38 Per Page:
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Protocol # Title Location Status Match
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
NCT01862081 A Dose-escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of GDC-0032 in Combination With Docetaxel or With Paclitaxel in Patients With HER2-negative Locally Recurrent or Metastatic Breast Cancer or Non-small Cell Lung Cancer A Dose-escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of GDC-0032 in Combination With Docetaxel or With Paclitaxel in Patients With HER2-negative Locally Recurrent or Metastatic Breast Cancer or Non-small Cell Lung 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
NCT02219724 A Phase I, Open-Label Study of MOXR0916 in Patients With Locally Advanced or Metastatic Solid Tumors A Phase I, Open-Label Study of MOXR0916 in Patients With Locally Advanced or Metastatic Solid Tumors 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
NCT01325441 A Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies A Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies MGH Open D
Trial Status: Showing Results: 1-10 of 38 Per Page:
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