Endometrial Cancer, ATM

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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 ATM  - General Description
CLICK IMAGE FOR MORE INFORMATION
The ATM gene provides instructions for making a protein that is located primarily in the nucleus of cells, where it helps control the rate at which cells grow and divide. This protein also plays an important role in the normal development and activity of several body systems, including the nervous system and the immune system. Additionally, the ATM protein assists cells in recognizing damaged or broken DNA strands. The ATM protein coordinates DNA repair by activating enzymes that cause a delay in the cell cycle, enabling cells to repair broken strands. Efficient repair of damaged DNA strands helps maintain the stability of the cell's genetic information.

The maintenance of intact, correctly sequenced DNA is vital to the life of a cell. If there are mistakes made in replicating DNA before cell division, subsequent daughter cells will have inaccurate DNA, and may either die or carry mutations that can contribute to the development of cancer. For this reason, cells have evolved multiple pathways to repair mistakes in-or damage to- DNA. The specific repair pathway used by the cell depends on the type of DNA damage that has occurred. The types of DNA repair that we are focusing on relate directly to cancer. These involve a break in BOTH strands of DNA, which can be the result of ionizing radiation or other DNA damaging agents. This type of DNA damage is called Double Strand Breaks (DSB's). There are two main pathways used by cells to repair DSB's in their DNA, one is Homologous Recombination (HR), the other is Non-Homologous End Joining (NHEJ). This page of our website focuses on the HR pathway (there is a separate web page for NHEJ repair found if you select PKcs on the list of genes when you sign onto the web-page).

Many proteins are involved in the complex HR pathway to repair DSB's in DNA. There is a graphic above that depicts the HR pathway (if you click on the graphic, it will enlarge and become a bit easier to follow). While complicated, the DSB at the top right of the graphic is acted upon by a series of proteins in the circle of steps shown that ultimately lead to the complete and accurate repair of the DSB in the DNA.

Some of the proteins involved in the HR DSB repair pathway are MRE11, NBS1, RAD50. These three proteins make up the MRN complex. This complex detects DSB's in the DNA. Once the DSB is found by the MRN complex, the MRN complex functions with BRCA1 and CtIP to resect the DSB’s to form single stranded DNA “tails”. Meanwhile, DSB's also activate the ATM protein, which can act upon CHK2 to activate it, as well as directly activating the tumor suppressor TP53. TP53 can cause cell cycle delay, giving the cell time to repair DNA breaks or mistakes before the cell cycle leading to division resumes. In the next step, RPA binds to the single stranded DNA "tails" that have been created by BRCA1 and CtIP in conjunction with the MRN. The binding of RPA activates another protein called ATR. ATR has many important functions, including activating CHK1, which can cause cell cycle delay giving cells time to repair DNA. ATR also regulates BRCA1 which recruits a bound group of proteins including PALB2/BRCA2/RAD51. In the next step, RAD51 displaces the RPA that is on the single stranded DNA, with the involvement of BRCA2/PALB2 and RAD51c. BRCA1/BARD1 helps RAD51 coated single stranded DNA to invade double stranded DNA with homologous sequences to form a DNA repair loop. With the help of DNA polymerases, the repair loop creates the opportunity to use the intact homologous DNA as a template to correctly repair DSB’s. Enzymes called ligases reconnect the ends of the DNA, leading to complete and accurate repair of the DSB in DNA.

After studying familial cancer syndromes, BRCA1 and BRCA2 were identified a while ago as inherited genes that when altered by mutation, cause certain cancers. Some BRCA1 and BRCA2 genes become mutated somatically, meaning in a non-inherited way. When either gene is mutated, the resulting protein cannot perform its role in DNA repair correctly. This turns out to be true for other proteins in the HR pathway as well. Recently, scientists have found mutations in many of the other genes that encode the proteins involved in the HR pathway. Mutations in HR pathway members that have now been identified in certain cancers include MRE11, NBS1, RAD50, ATM, CHK2, BRCA1, PALB2, RAD51, BRCA2, BARD1, and RAD51c (these are depicted in red in the above graphic). This remarkable number of mutations highlights how important the HR DSB DNA repair pathway is in cells. The result of mutations in proteins involved in the HR pathway results in proteins that do not function properly in their role in DNA repair. Without proper function of all the proteins involved in DNA repair, DNA mistakes or breaks are not properly repaired, and the damaged DNA contributes to the development of cancer.

Many mutations in the ATM gene have been identified in different types of cancer. This leaves the cells totally reliant on the ATR pathway to delay the cell cycle so that DNA repair can be accomplished. Dependence on the ATR DNA repair pathway has therapeutic implications for patients whose tumors have mutations in ATM, or mutations in other proteins in the HR pathway.

Testing for mutations in the many genes (ATM and the other genes depicted in red in the graphic above) is available in the MGH genetics lab. Treatment as well as clinical trials studying new drugs that target defects in the DNA repair proteins-including strategies for cancers that have mutated ATM-are available at the MGH Cancer Center.
The ATM gene provides instructions for making a protein that is located primarily in the nucleus of cells, where it helps control the rate at which cells grow and divide. This protein also plays an important role in the normal development and activity of several body systems, including the nervous system and the immune system. Additionally, the ATM protein assists cells in recognizing damaged or broken DNA strands. The ATM protein coordinates DNA repair by activating enzymes that cause a delay in the cell cycle, enabling cells to repair broken strands. Efficient repair of damaged DNA strands helps maintain the stability of the cell's genetic information.

The maintenance of intact, correctly sequenced DNA is vital to the life of a cell. If there are mistakes made in replicating DNA before cell division, subsequent daughter cells will have inaccurate DNA, and may either die or carry mutations that can contribute to the development of cancer. For this reason, cells have evolved multiple pathways to repair mistakes in-or damage to- DNA. The specific repair pathway used by the cell depends on the type of DNA damage that has occurred. The types of DNA repair that we are focusing on relate directly to cancer. These involve a break in BOTH strands of DNA, which can be the result of ionizing radiation or other DNA damaging agents. This type of DNA damage is called Double Strand Breaks (DSB's). There are two main pathways used by cells to repair DSB's in their DNA, one is Homologous Recombination (HR), the other is Non-Homologous End Joining (NHEJ). This page of our website focuses on the HR pathway (there is a separate web page for NHEJ repair found if you select PKcs on the list of genes when you sign onto the web-page).

Many proteins are involved in the complex HR pathway to repair DSB's in DNA. There is a graphic above that depicts the HR pathway (if you click on the graphic, it will enlarge and become a bit easier to follow). While complicated, the DSB at the top right of the graphic is acted upon by a series of proteins in the circle of steps shown that ultimately lead to the complete and accurate repair of the DSB in the DNA.

Some of the proteins involved in the HR DSB repair pathway are MRE11, NBS1, RAD50. These three proteins make up the MRN complex. This complex detects DSB's in the DNA. Once the DSB is found by the MRN complex, the MRN complex functions with BRCA1 and CtIP to resect the DSB’s to form single stranded DNA “tails”. Meanwhile, DSB's also activate the ATM protein, which can act upon CHK2 to activate it, as well as directly activating the tumor suppressor TP53. TP53 can cause cell cycle delay, giving the cell time to repair DNA breaks or mistakes before the cell cycle leading to division resumes. In the next step, RPA binds to the single stranded DNA "tails" that have been created by BRCA1 and CtIP in conjunction with the MRN. The binding of RPA activates another protein called ATR. ATR has many important functions, including activating CHK1, which can cause cell cycle delay giving cells time to repair DNA. ATR also regulates BRCA1 which recruits a bound group of proteins including PALB2/BRCA2/RAD51. In the next step, RAD51 displaces the RPA that is on the single stranded DNA, with the involvement of BRCA2/PALB2 and RAD51c. BRCA1/BARD1 helps RAD51 coated single stranded DNA to invade double stranded DNA with homologous sequences to form a DNA repair loop. With the help of DNA polymerases, the repair loop creates the opportunity to use the intact homologous DNA as a template to correctly repair DSB’s. Enzymes called ligases reconnect the ends of the DNA, leading to complete and accurate repair of the DSB in DNA.

After studying familial cancer syndromes, BRCA1 and BRCA2 were identified a while ago as inherited genes that when altered by mutation, cause certain cancers. Some BRCA1 and BRCA2 genes become mutated somatically, meaning in a non-inherited way. When either gene is mutated, the resulting protein cannot perform its role in DNA repair correctly. This turns out to be true for other proteins in the HR pathway as well. Recently, scientists have found mutations in many of the other genes that encode the proteins involved in the HR pathway. Mutations in HR pathway members that have now been identified in certain cancers include MRE11, NBS1, RAD50, ATM, CHK2, BRCA1, PALB2, RAD51, BRCA2, BARD1, and RAD51c (these are depicted in red in the above graphic). This remarkable number of mutations highlights how important the HR DSB DNA repair pathway is in cells. The result of mutations in proteins involved in the HR pathway results in proteins that do not function properly in their role in DNA repair. Without proper function of all the proteins involved in DNA repair, DNA mistakes or breaks are not properly repaired, and the damaged DNA contributes to the development of cancer.

Many mutations in the ATM gene have been identified in different types of cancer. This leaves the cells totally reliant on the ATR pathway to delay the cell cycle so that DNA repair can be accomplished. Dependence on the ATR DNA repair pathway has therapeutic implications for patients whose tumors have mutations in ATM, or mutations in other proteins in the HR pathway.

Testing for mutations in the many genes (ATM and the other genes depicted in red in the graphic above) is available in the MGH genetics lab. Treatment as well as clinical trials studying new drugs that target defects in the DNA repair proteins-including strategies for cancers that have mutated ATM-are available at the MGH Cancer Center.

PubMed ID's
27617969, 24003211, PMC2988877
Expand Collapse ATM  in Endometrial Cancer
Genetic alterations in DNA repair genes such as ATM have been found in endometrial cancers. Mutations in the ATM gene result in an altered ATM protein, that does not function normally. If ATM can no longer activate CHK2 or TP53 (see graphic above), then there is no Cell cycle arrest. Cell cycle arrest is a pause in the cell cycle that allows cells to repair damaged DNA. An accumulation of damaged DNA can lead to the development of cancer.

Genetic alterations in DNA repair genes such as ATM have been found in endometrial cancers. Mutations in the ATM gene result in an altered ATM protein, that does not function normally. If ATM can no longer activate CHK2 or TP53 (see graphic above), then there is no Cell cycle arrest. Cell cycle arrest is a pause in the cell cycle that allows cells to repair damaged DNA. An accumulation of damaged DNA can lead to the development of cancer.

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 all 7 results Per Page:
Protocol # Title Location Status Match
NCT02715284 A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors MGH Open D
NCT02052778 A Study of TAS-120 in Patients With Advanced Solid Tumors A Study of TAS-120 in Patients With Advanced Solid Tumors MGH Open D
NCT02454972 Clinical Trial of Lurbinectedin (PM01183) in Selected Advanced Solid Tumors Clinical Trial of Lurbinectedin (PM01183) in Selected Advanced Solid Tumors MGH Open D
NCT02465060 NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma MGH Open D
NCT01953926 Neratinib HER Mutation Basket Study (SUMMIT) Neratinib HER Mutation Basket Study (SUMMIT) MGH Open D
NCT02725268 Phase 2 Study of MLN0128, Combination of MLN0128 With MLN1117, Paclitaxel and Combination of MLN0128 With Paclitaxel in Women With Endometrial Cancer Phase 2 Study of MLN0128, Combination of MLN0128 With MLN1117, Paclitaxel and Combination of MLN0128 With Paclitaxel in Women With Endometrial Cancer MGH Open D
NCT02912572 Study of Avelumab in Patients With MSS, MSI-H and POLE-mutated Recurrent or Persistent Endometrial Cancer Study of Avelumab in Patients With MSS, MSI-H and POLE-mutated Recurrent or Persistent Endometrial Cancer 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 7 results Per Page:
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