Endometrial Cancer, TP53, All Mutations

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Expand Collapse Endometrial Cancer  - General Description Endometrial cancer begins in cells within the endometrium, the tissue that lines the inside of a woman's uterus. The uterus is the hollow muscular organ in which a baby (fetus) develops. The outer muscular layer of the uterus is called the myometrium. The lower end of the uterus is the cervix, which leads to the vagina. Cancer can develop in the cervix and vagina, but endometrial cancer is the most common cancer affecting a women's reproductive system. This year about 47,000 U.S. women will be diagnosed with endometrial cancer.

Most endometrial cancers are adenocarcinomas, which begin in gland-like cells that produce mucus and other fluids. Examination of the cancer tissue under a microscope can help differentiate the cancer type and roughly predict tumor behavior. When cancer cells are closer in appearance to normal endometrial tissue, it is classified as a well differentiated cancer and this usually indicates that the cancer will not spread. On the other hand, when the cancer cells are distinctly different from normal cells, they are considered poorly differentiated and are most likely to invade the myometrium. From the myometrium, the cancer can spread to lymph nodes in the pelvis and chest and to other parts of the body, such as the lungs, liver, bones, brain and vagina.

Endometrial cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the endometrial cancer cells cause secondary tumors to grow.

To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a lymph node near the primary tumor and a pathologist looks at it through a microscope to see if cancer cells are present. Several kinds of imaging can also be performed to determine if endometrial cancer has spread. These include chest x-rays, MRI and CT scans.

Despite significant improvements in the treatment of endometrial cancer, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2015
Estimated new cases and deaths from endometrial cancer in the United States in 2015:

New cases: 54,870
Deaths: 10,170

Cancer of the endometrium is the most common gynecologic malignancy and accounts for an estimated 47,000 newly diagnosed cases in the United States in 2012. Endometrial cancer encompasses a broad range of histologic subtypes, with the most common being the endometrioid endometrial adenocarcinoma. Marked differences in clinical behavior have been observed in patients with endometrial cancers depending on the histologic subtype, the tumor grade and the extent of cancer spread. A classification system that groups endometrial cancers into Type I and Type II has been proposed to account for the divide in clinical behavior.

Type I endometrial cancers account for approximately 75-85% of endometrial cancers and tend to be of endometrioid histology, are most commonly diagnosed at stage I/II or are confined to the uterus and cervix. These tumors can present with a precursor lesion known as atypical hyperplasia, and are associated with unopposed estrogen exposures such as obesity, hormone replacement or tamoxifen use. For these patients, surgery is likely to be a curative procedure and lymph node staging is generally not pursued unless risk factors are present. The addition of vaginal radiation has been shown to reduce recurrence of some early stage cancers if certain risk factors are present. Overall, the recurrence risk for these women is between 2-7%.

Type I cancers, type II endometrial cancers present with a spectrum of histologies including uterine papillary serous carcinoma (UPSC), carcinosarcoma, clear cell carcinoma and high-grade endometrioid carcinoma. These cancers are high-grade by definition, tend to present with disease outside of the uterus (stage III or IV) and have a high propensity to develop recurrence after primary therapy. Common sites of metastasis include pelvic/para-aortic lymph nodes, vagina, lungs, liver and peritoneum. The upfront therapeutic approach to type II cancers frequently involves individualized multi-modality combinations of aggressive cytoreductive surgery, followed by platinum containing chemotherapy and pelvic or abdominal radiation. While this subset of patients accounts for only 15-25% of patients with endometrial cancer, patients with these tumors account for 75% of the mortality observed.

In the recurrent setting, type I and II endometrial tumors tend to be managed in a similar fashion. When a localized recurrence occurs, surgery and focused radiation is commonly employed and is sometimes followed by platinum- and taxane-based cytotoxic chemotherapy. With widespread or surgically inaccessible recurrent disease, chemotherapies provide the mainstay of therapy. While low-grade advanced stage or recurrent tumors are commonly refractory to cytotoxic agents, they may (20-30%) respond to hormonal therapies that modulate the progesterone or estrogen receptor. As type II cancers are high-grade and commonly (40-50%) present with extra-uterine spread, the risk of recurrence is markedly elevated in this population and further therapeutic modalities in the upfront setting are often warranted.

Correlative scientific investigations have utilized the type I and II distinctions to describe molecular signatures specific to the individual tumors types that may be key drivers of the neoplasia. By targeting specific overactive pathways with novel small molecule tyrosine kinase inhibitors (TKI) or antibody therapies, investigators hope to improve the therapeutic options for patients with endometrial cancer. Type I cancers have been shown to have molecular alterations via gene mutation, gene amplification or protein expression in KRAS, CTNNB1 and PTEN. In contrast, type II cancers have been shown to have 20-30% gene amplification in the HER2 (ERBB2) gene and a close to 90% frequency of mutation in the TP53 gene. Alterations in the phosphoinositol 3-Kinase (PI3K) pathway appear to affect both type I and II endometrial cancers through alterations in PTEN (50-80%) and PIK3CA (25-40%). With many promising signatures, clinical trials are currently in development.

Source: National Cancer Institute, 2015
Endometrial cancer begins in cells within the endometrium, the tissue that lines the inside of a woman's uterus. The uterus is the hollow muscular organ in which a baby (fetus) develops. The outer muscular layer of the uterus is called the myometrium. The lower end of the uterus is the cervix, which leads to the vagina. Cancer can develop in the cervix and vagina, but endometrial cancer is the most common cancer affecting a women's reproductive system. This year about 47,000 U.S. women will be diagnosed with endometrial cancer.

Most endometrial cancers are adenocarcinomas, which begin in gland-like cells that produce mucus and other fluids. Examination of the cancer tissue under a microscope can help differentiate the cancer type and roughly predict tumor behavior. When cancer cells are closer in appearance to normal endometrial tissue, it is classified as a well differentiated cancer and this usually indicates that the cancer will not spread. On the other hand, when the cancer cells are distinctly different from normal cells, they are considered poorly differentiated and are most likely to invade the myometrium. From the myometrium, the cancer can spread to lymph nodes in the pelvis and chest and to other parts of the body, such as the lungs, liver, bones, brain and vagina.

Endometrial cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the endometrial cancer cells cause secondary tumors to grow.

To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a lymph node near the primary tumor and a pathologist looks at it through a microscope to see if cancer cells are present. Several kinds of imaging can also be performed to determine if endometrial cancer has spread. These include chest x-rays, MRI and CT scans.

Despite significant improvements in the treatment of endometrial cancer, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2015
Estimated new cases and deaths from endometrial cancer in the United States in 2015:

New cases: 54,870
Deaths: 10,170

Cancer of the endometrium is the most common gynecologic malignancy and accounts for an estimated 47,000 newly diagnosed cases in the United States in 2012. Endometrial cancer encompasses a broad range of histologic subtypes, with the most common being the endometrioid endometrial adenocarcinoma. Marked differences in clinical behavior have been observed in patients with endometrial cancers depending on the histologic subtype, the tumor grade and the extent of cancer spread. A classification system that groups endometrial cancers into Type I and Type II has been proposed to account for the divide in clinical behavior.

Type I endometrial cancers account for approximately 75-85% of endometrial cancers and tend to be of endometrioid histology, are most commonly diagnosed at stage I/II or are confined to the uterus and cervix. These tumors can present with a precursor lesion known as atypical hyperplasia, and are associated with unopposed estrogen exposures such as obesity, hormone replacement or tamoxifen use. For these patients, surgery is likely to be a curative procedure and lymph node staging is generally not pursued unless risk factors are present. The addition of vaginal radiation has been shown to reduce recurrence of some early stage cancers if certain risk factors are present. Overall, the recurrence risk for these women is between 2-7%.

Type I cancers, type II endometrial cancers present with a spectrum of histologies including uterine papillary serous carcinoma (UPSC), carcinosarcoma, clear cell carcinoma and high-grade endometrioid carcinoma. These cancers are high-grade by definition, tend to present with disease outside of the uterus (stage III or IV) and have a high propensity to develop recurrence after primary therapy. Common sites of metastasis include pelvic/para-aortic lymph nodes, vagina, lungs, liver and peritoneum. The upfront therapeutic approach to type II cancers frequently involves individualized multi-modality combinations of aggressive cytoreductive surgery, followed by platinum containing chemotherapy and pelvic or abdominal radiation. While this subset of patients accounts for only 15-25% of patients with endometrial cancer, patients with these tumors account for 75% of the mortality observed.

In the recurrent setting, type I and II endometrial tumors tend to be managed in a similar fashion. When a localized recurrence occurs, surgery and focused radiation is commonly employed and is sometimes followed by platinum- and taxane-based cytotoxic chemotherapy. With widespread or surgically inaccessible recurrent disease, chemotherapies provide the mainstay of therapy. While low-grade advanced stage or recurrent tumors are commonly refractory to cytotoxic agents, they may (20-30%) respond to hormonal therapies that modulate the progesterone or estrogen receptor. As type II cancers are high-grade and commonly (40-50%) present with extra-uterine spread, the risk of recurrence is markedly elevated in this population and further therapeutic modalities in the upfront setting are often warranted.

Correlative scientific investigations have utilized the type I and II distinctions to describe molecular signatures specific to the individual tumors types that may be key drivers of the neoplasia. By targeting specific overactive pathways with novel small molecule tyrosine kinase inhibitors (TKI) or antibody therapies, investigators hope to improve the therapeutic options for patients with endometrial cancer. Type I cancers have been shown to have molecular alterations via gene mutation, gene amplification or protein expression in KRAS, CTNNB1 and PTEN. In contrast, type II cancers have been shown to have 20-30% gene amplification in the HER2 (ERBB2) gene and a close to 90% frequency of mutation in the TP53 gene. Alterations in the phosphoinositol 3-Kinase (PI3K) pathway appear to affect both type I and II endometrial cancers through alterations in PTEN (50-80%) and PIK3CA (25-40%). With many promising signatures, clinical trials are currently in development.

Source: National Cancer Institute, 2015
Expand Collapse TP53  - General Description
CLICK IMAGE FOR MORE INFORMATION
The p53 (TP53) gene produces a protein, P53 which has many complex functions within the cell. It has been called the “guardian of the genome” for reasons that have to do with these complex functions. Normal, non-cancerous cells have tightly regulated pathways that control cell growth, mediating cessation of growth or even cell death when circumstances warrant it. P53 is at the center of these pathways, acting as a “tumor suppressor” in responding to circumstances in the cell that require a cessation of growth. Perhaps for this reason, P53 is one of the most commonly mutated genes across all cancer types.

P53 itself regulates the expression of several genes that are involved in growth arrest or “cell cycle arrest”. Growth arrest is important for stopping the cell from normal growth and cell division so that if, for instance, there has been damage to the DNA from UV irradiation or some other insult causing DNA damage, the cessation of the cell cycle allows DNA repair to take place before the cell resumes growth. If the damage to the DNA is too extensive to repair, or if other factors such as oncogenic stress impact the cell, P53 then has roles in other processes that are part of the cell’s repertoire of responses. These include processes such as apoptosis (programmed cell death), senescence (irreversible cell cycle arrest), autophagy (regulated destruction of selected proteins within the cell, leading to cell death), and some important metabolic changes in the cell (see graphic above, adapted with permission).

P53 is itself acted upon by proteins in the cell that detect DNA damage or oncogenic stress (see graphic depicting P53 at the center of a number of cellular responses). In the case of DNA damage to the cell, P53 is acted upon by a protein called ATM and another designated CHK2 (see glossary for more information). These proteins activate P53 to regulate the changes that will cause growth arrest. Interestingly, these two genes themselves are found to be mutated and have altered function in certain cancers. The fact that both P53 and the genes that trigger P53’s response and initiation of growth arrest are mutated in some cancers highlights the importance of P53 to normal cell growth. P53 is found to be mutated in over half of cancers studied, including ovarian cancer, colon and esophageal cancer, and many other types of cancer. Because p53 plays so many complex roles in the cell, we do not depict it in a simple graphic as we have with other proteins on this web site in which genetic alterations have been found in specific tumors that lead to dysregulation of these proteins. Rather, P53 as a negative regulator of cell growth under important circumstances plays this role at the center of a complex network of pathways within the cell. Many of the proteins involved in the pathways that regulate P53 and its responses are also found to be genetically altered in some cancers.

As we have seen, the P53 protein has many functions in the cell, and because of these many roles, its location in the nucleus or cytoplasm varies, depending on the function and when it exerts its effect during the cell cycle. One important protein that regulates P53 is called HDM2/MDM2, depicted in the graphic above. The HDM2/MDM2 protein contains a p53 binding domain, and once bound to p53, it inhibits the activation of the P53 protein, and thereby prevents P53 from regulating growth arrest, even when there is damage to the DNA. Some cancers have been found to overexpress HDM2/MDM2, meaning there is an excess of the protein which binds to P53, preventing it from exerting its important role in regulating growth arrest. Cell division that occurs despite damage to the DNA can lead to cancer. Interestingly, those cancers that have been found to over-express HDM2/MDM2 typically are not found to have p53 mutations. This provides scientists with evidence that by whatever means, either through increasing the amount of the P53 inhibitor HDM2/MDM2, or, through mutations in P53 that prevent the normal activities of the protein, the normal function of P53 is important in preventing cancer. MDM2 was named after its discovery in studies on laboratory mice. The human version of the gene is designated HumanDM2, or HDM2. Genetic alterations leading to over-expression of MDM2 are observed most commonly in sarcomas, but have also been observed in endometrial cancer, colon cancer, and stomach cancer.

Source: Molecular Genetics of Cancer, Second Edition
Chapter No. 2, Section No. 12
Leif W. Ellisen, MD, PhD
The p53 (TP53) gene produces a protein, P53 which has many complex functions within the cell. It has been called the “guardian of the genome” for reasons that have to do with these complex functions. Normal, non-cancerous cells have tightly regulated pathways that control cell growth, mediating cessation of growth or even cell death when circumstances warrant it. P53 is at the center of these pathways, acting as a “tumor suppressor” in responding to circumstances in the cell that require a cessation of growth. Perhaps for this reason, P53 is one of the most commonly mutated genes across all cancer types.

P53 itself regulates the expression of several genes that are involved in growth arrest or “cell cycle arrest”. Growth arrest is important for stopping the cell from normal growth and cell division so that if, for instance, there has been damage to the DNA from UV irradiation or some other insult causing DNA damage, the cessation of the cell cycle allows DNA repair to take place before the cell resumes growth. If the damage to the DNA is too extensive to repair, or if other factors such as oncogenic stress impact the cell, P53 then has roles in other processes that are part of the cell’s repertoire of responses. These include processes such as apoptosis (programmed cell death), senescence (irreversible cell cycle arrest), autophagy (regulated destruction of selected proteins within the cell, leading to cell death), and some important metabolic changes in the cell (see graphic above, adapted with permission).

P53 is itself acted upon by proteins in the cell that detect DNA damage or oncogenic stress (see graphic depicting P53 at the center of a number of cellular responses). In the case of DNA damage to the cell, P53 is acted upon by a protein called ATM and another designated CHK2 (see glossary for more information). These proteins activate P53 to regulate the changes that will cause growth arrest. Interestingly, these two genes themselves are found to be mutated and have altered function in certain cancers. The fact that both P53 and the genes that trigger P53’s response and initiation of growth arrest are mutated in some cancers highlights the importance of P53 to normal cell growth. P53 is found to be mutated in over half of cancers studied, including ovarian cancer, colon and esophageal cancer, and many other types of cancer. Because p53 plays so many complex roles in the cell, we do not depict it in a simple graphic as we have with other proteins on this web site in which genetic alterations have been found in specific tumors that lead to dysregulation of these proteins. Rather, P53 as a negative regulator of cell growth under important circumstances plays this role at the center of a complex network of pathways within the cell. Many of the proteins involved in the pathways that regulate P53 and its responses are also found to be genetically altered in some cancers.

As we have seen, the P53 protein has many functions in the cell, and because of these many roles, its location in the nucleus or cytoplasm varies, depending on the function and when it exerts its effect during the cell cycle. One important protein that regulates P53 is called HDM2/MDM2, depicted in the graphic above. The HDM2/MDM2 protein contains a p53 binding domain, and once bound to p53, it inhibits the activation of the P53 protein, and thereby prevents P53 from regulating growth arrest, even when there is damage to the DNA. Some cancers have been found to overexpress HDM2/MDM2, meaning there is an excess of the protein which binds to P53, preventing it from exerting its important role in regulating growth arrest. Cell division that occurs despite damage to the DNA can lead to cancer. Interestingly, those cancers that have been found to over-express HDM2/MDM2 typically are not found to have p53 mutations. This provides scientists with evidence that by whatever means, either through increasing the amount of the P53 inhibitor HDM2/MDM2, or, through mutations in P53 that prevent the normal activities of the protein, the normal function of P53 is important in preventing cancer. MDM2 was named after its discovery in studies on laboratory mice. The human version of the gene is designated HumanDM2, or HDM2. Genetic alterations leading to over-expression of MDM2 are observed most commonly in sarcomas, but have also been observed in endometrial cancer, colon cancer, and stomach cancer.

Source: Molecular Genetics of Cancer, Second Edition
Chapter No. 2, Section No. 12
Leif W. Ellisen, MD, PhD
Expand Collapse All Mutations  in TP53
TP53 Mutations that are associated with many cancer types result in the loss of function of the P53 proteins' tumor suppressor activity. Mutations in P53 that have been studied in tumors prevent P53 from acting to stop growth, or in other words, to cause cell cycle arrest. Cell cycle arrest mediated by P53 is necessary to give cells time to repair damaged DNA. P53 is also involved in other functions in the cellular repertoire to cause cells that have suffered too much damage to repair to undergo appoptosis or autophagy leading to deliberate cell death. When P53 normal function is debilitated through genetic mutations, the development of cancer is more likely than in cells that have intact and fully functional P53.
TP53 Mutations that are associated with many cancer types result in the loss of function of the P53 proteins' tumor suppressor activity. Mutations in P53 that have been studied in tumors prevent P53 from acting to stop growth, or in other words, to cause cell cycle arrest. Cell cycle arrest mediated by P53 is necessary to give cells time to repair damaged DNA. P53 is also involved in other functions in the cellular repertoire to cause cells that have suffered too much damage to repair to undergo appoptosis or autophagy leading to deliberate cell death. When P53 normal function is debilitated through genetic mutations, the development of cancer is more likely than in cells that have intact and fully functional P53.

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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing all 2 results Per Page:
Protocol # Title Location Status Match
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
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 D
MGH has many open clinical trials for other cancers not shown on the Targeted Cancer Care website. They can be found on the MassGeneral.org clinical trials search page.

Additional clinical trials may be applicable to your search criteria, but they may not be available at MGH. These clinical trials can typically be found by searching the clinicaltrials.gov website.
Trial Status: Showing all 2 results Per Page:
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