Endometrial Cancer, FGFR 1, 2, 3 and 4, All Genetic Alterations

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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 FGFR 1, 2, 3 and 4  - General Description
CLICK IMAGE FOR MORE INFORMATION
Fibroblast growth factors (FGF’s) are ligands that bind to FGF cell surface receptors (FGFR’s) and activate them. Once activated, FGFR’s on normal cells transmit a growth signal inside the cell. This growth signal is transmitted via two important pathways inside cells; the RAS-dependent MAP kinase pathway, and a second signal pathway that involves PI3K and AKT. There are four different FGFR’s that make up a family of FGFR tyrosine kinase cell surface receptors, each having an extracellular domain that binds FGF ligands, a second domain that goes through the cell outer membrane, and a third domain that is inside the cell cytoplasm (see diagram above). FGFR signaling in normal cells stimulates proliferation, differentiation, embryonic development, cell migration, survival, angiogenesis (vascularization), and organogenesis (organ development).

Recently, FGFR genetic abnormalities have been found in several types of cancer. There are four FGFR family members, FGFR1, FGFR2, FGFR3, and FGFR4. Alterations in FGFR genes result in dysregulated FGF receptors and can promote cancer growth and metastasis. In a recent study of almost 5000 tumors, alterations in FGFR were found in 7% of of tumors. Among these tumors, alterations were identified in all 4 FGFR’s including FGFR1 (49%), FGFR2 (19%), FGFR3 (23%), and FGFR4 (7%). A small number of the tumors had genetic alterations in more than one type of FGFR. Clearly cancers have found a way to take advantage of FGF/FGFR signaling pathway in cells to cause uncontrolled growth leading to tumors.

While the FGFR genetic abnormalities may vary in frequency depending on the group of tumor types tested, there are clearly some patterns emerging in terms of which tumor types are likely to have specific kinds of genetic alterations in FGFR 1, 2, 3 or 4. Genetic alterations in the FGFR receptors can include point mutations, insertions/deletions, gene amplification, or translocations. The sensitivity of various gene alterations to FGFR inhibition is currently under investigation. Drugs targeting the FGF/FGFR pathway include small molecule tyrosine kinases inhibitors and ligand traps.

Several pharmaceutical companies have developed drugs that target and inhibit FGFR in tumors. Some of these are designed to target multiple members of the FGFR family. At MGH and other major cancer centers, clinical trials are available to patients whose tumors have been tested and found to have genetically altered FGFR. Treatment for these patients can be available on clinical studies testing these FGFR inhibitors, including FGFR inhibitors called TAS120 and Debio 1347. Other agents such as FGF401 and BLU554 are specific for inhibiting FGFR4 and are being tested in liver cancer. Contact the MGH Cancer Center to find out more about having genetic testing performed on a tumor, or for more information about these clinical trials.

Fibroblast growth factors (FGF’s) are ligands that bind to FGF cell surface receptors (FGFR’s) and activate them. Once activated, FGFR’s on normal cells transmit a growth signal inside the cell. This growth signal is transmitted via two important pathways inside cells; the RAS-dependent MAP kinase pathway, and a second signal pathway that involves PI3K and AKT. There are four different FGFR’s that make up a family of FGFR tyrosine kinase cell surface receptors, each having an extracellular domain that binds FGF ligands, a second domain that goes through the cell outer membrane, and a third domain that is inside the cell cytoplasm (see diagram above). FGFR signaling in normal cells stimulates proliferation, differentiation, embryonic development, cell migration, survival, angiogenesis (vascularization), and organogenesis (organ development).

Recently, FGFR genetic abnormalities have been found in several types of cancer. There are four FGFR family members, FGFR1, FGFR2, FGFR3, and FGFR4. Alterations in FGFR genes result in dysregulated FGF receptors and can promote cancer growth and metastasis. In a recent study of almost 5000 tumors, alterations in FGFR were found in 7% of of tumors. Among these tumors, alterations were identified in all 4 FGFR’s including FGFR1 (49%), FGFR2 (19%), FGFR3 (23%), and FGFR4 (7%). A small number of the tumors had genetic alterations in more than one type of FGFR. Clearly cancers have found a way to take advantage of FGF/FGFR signaling pathway in cells to cause uncontrolled growth leading to tumors.

While the FGFR genetic abnormalities may vary in frequency depending on the group of tumor types tested, there are clearly some patterns emerging in terms of which tumor types are likely to have specific kinds of genetic alterations in FGFR 1, 2, 3 or 4. Genetic alterations in the FGFR receptors can include point mutations, insertions/deletions, gene amplification, or translocations. The sensitivity of various gene alterations to FGFR inhibition is currently under investigation. Drugs targeting the FGF/FGFR pathway include small molecule tyrosine kinases inhibitors and ligand traps.

Several pharmaceutical companies have developed drugs that target and inhibit FGFR in tumors. Some of these are designed to target multiple members of the FGFR family. At MGH and other major cancer centers, clinical trials are available to patients whose tumors have been tested and found to have genetically altered FGFR. Treatment for these patients can be available on clinical studies testing these FGFR inhibitors, including FGFR inhibitors called TAS120 and Debio 1347. Other agents such as FGF401 and BLU554 are specific for inhibiting FGFR4 and are being tested in liver cancer. Contact the MGH Cancer Center to find out more about having genetic testing performed on a tumor, or for more information about these clinical trials.

PubMed ID's
9212826, 24265351
Expand Collapse All Genetic Alterations  in FGFR 1, 2, 3 and 4
As explained above, specific types of tumors are associated with different genetic alterations. These include mutations, where a single nucleotide change in the gene can confer an altered FGFR protein that cannot be regulated normally. A second type of genetic alteration in FGFR family members involves insertions or deletions. In this case, a portion of the FGFR is missing, or, a portion of some other gene has been inserted in the FGFR gene, altering its normal function and regulation. A third type of genetic alteration in FGFR is translocation, where a whole portion of the FGFR gene has broken away from the rest of the gene, and attached iteself to another gene. These fusion proteins have part of FGFR, and part of another protein, and do not behave normally. Genetic testing of tumors identifies each of these genetic changes in a tumor, indicating specific treatment options.
As explained above, specific types of tumors are associated with different genetic alterations. These include mutations, where a single nucleotide change in the gene can confer an altered FGFR protein that cannot be regulated normally. A second type of genetic alteration in FGFR family members involves insertions or deletions. In this case, a portion of the FGFR is missing, or, a portion of some other gene has been inserted in the FGFR gene, altering its normal function and regulation. A third type of genetic alteration in FGFR is translocation, where a whole portion of the FGFR gene has broken away from the rest of the gene, and attached iteself to another gene. These fusion proteins have part of FGFR, and part of another protein, and do not behave normally. Genetic testing of tumors identifies each of these genetic changes in a tumor, indicating specific treatment options.

FGFR genetic alterations have been found in endometrial cancers, leading to abnormally activated FGFR receptors. Mutation in the gene for FGFR2 has been found to contain mutations in some endometrial cancers. Rarely, mutations have also been found in the FGFR4 gene.

Testing for genetic alterations in FGFR can be performed at the MGH Cancer Center. Clinical trials for treatment with FGFR inhibitors are also underway at the MGH Cancer Center.

Source N. Hallinan et al., Cancer Treatment Reviews 46 (2016) 51-62.

FGFR genetic alterations have been found in endometrial cancers, leading to abnormally activated FGFR receptors. Mutation in the gene for FGFR2 has been found to contain mutations in some endometrial cancers. Rarely, mutations have also been found in the FGFR4 gene.

Testing for genetic alterations in FGFR can be performed at the MGH Cancer Center. Clinical trials for treatment with FGFR inhibitors are also underway at the MGH Cancer Center.

Source N. Hallinan et al., Cancer Treatment Reviews 46 (2016) 51-62.

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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing all 5 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 DG
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
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
NCT02318329 Open-Label, Dose-Finding Study Evaluating Safety and PK of FPA144 in Patients With Advanced Solid Tumors Open-Label, Dose-Finding Study Evaluating Safety and PK of FPA144 in Patients With Advanced Solid Tumors 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
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 5 results Per Page:
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