Endometrial Cancer, ERBB2 (HER2)

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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 ERBB2 (HER2)  - General Description
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ERBB2, often called HER2, is a gene that provides the code for making a cell surface protein called the ErbB2 (HER2) growth factor receptor. When certain growth factors (proteins that stimulate cell growth and division) bind to this receptor, they activate a signaling system inside the cell that ultimately promotes diverse functions such as growth, interaction and adhesion between cells, and ability of the cell to migrate within tissues. In some tumors, the activation of HER2 signaling is an important mechanism that drives the disease process. This can occur through HER2 gene amplification (the most common mechanism) or HER2 gene mutation in the cancer cells.

Extra copies of the HER2 gene (gene amplification) have been found in a number of different cancers. This causes the cancer cells to make excess HER2 (overexpression), which in turn, tells the cells to grow and divide in an uncontrolled manner. The presence of amplified HER2 has been reported in approximately 25% of breast tumors, 20% of esophageal tumors, 15% of gastric cancers and 20% of certain ovarian tumors. The FDA has approved the targeted therapies including trastuzumab (Herceptin), pertuzumab (Perjeta), lapatinib (Tykerb), and T-DM1 (Kadcyla) for the treatment of patients with certain kinds of breast cancer in which HER2 is overexpressed. Trastuzumab is also FDA approved to treat gastric cancer with amplification of this receptor.

Mutations in HER2 involving small duplications of the gene can promote resistance to some EGFR targeted therapies, but on the other hand, promote response to certain HER2 inhibitors. While very rare, these mutations are most often associated with non-small cell lung cancer, but have also been described in other malignancies including brain, gastric, breast and ovarian tumors. Tumor mutation profiling performed clinically at the MGH Cancer Center has identified HER2 mutations in a small subset of non-HER2 amplified breast cancer (1%) and non-small cell lung cancers (1%).

Source: Genetics Home Reference
The ERBB2 gene encodes for a cell surface protein that belongs to the ERBB family of receptor tyrosine kinases, known as ErbB2 (more commonly referred to as HER2). Four members of the ERBB family have been identified; EGFR (ERBB1, HER1), ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). Binding of a ligand induces ERBB receptor homo-/hetero-dimerization and triggers a signaling cascade that drives many cellular responses. These include the activation of PI3K/AKT/mTOR and MAP kinase/ERK pathways, which promote cell survival and proliferation. Although there is no known ligand for HER2, HER2 is the preferred dimerization partner for the other ERBB receptors. In some cancers, HER2 activity is increased through protein overexpression or gene mutation.

The overexpression of HER2 is tightly associated with amplification of the HER2 gene. HER2 amplification has been reported in multiple malignancies, including breast cancer (25% incidence), esophageal cancer (20% incidence), gastric cancer (15% incidence), and mucinous ovarian carcinomas (20% incidence).

Mutations in HER2 have also been identified as an important mechanism that could drive tumor growth and confer resistance to targeted therapies. In-frame duplication/insertions in a region of HER2 exon 20 that is conserved with EGFR have been demonstrated in ~2% of lung cancer patients. Mutations in HER2 receptor have also been described in a small subset of non-HER2 amplified breast cancer (1%).

Source: Genetics Home Reference
PubMed ID's
15864276, 9130710, 15457249, 16397024, 18772890, 16843263, 16988931, 22899400
Expand Collapse ERBB2 (HER2)  in Endometrial Cancer
Gene amplification is the primary genetic abnormality of the ERBB2 (HER2) gene in endometrial cancer, while HER2 mutations are exceedingly rare in this malignancy (~2%). Currently, HER2 gene amplification (or protein overexpression) does not direct endometrial cancer patients towards specific therapies. Preclinical studies utilizing cell lines with amplification of the HER2 gene have demonstrated sensitivity to trastuzumab, pertuzumab and lapatinib, and clinical trials are evaluating the potential for use of these agents in the clinic. So far, only one trial has tested trastuzumab as a single-drug therapy for HER2-positive (gene amplified or protein over-expressed) recurrent endometrial cancer, but found no responses across 33 patients.

Amplification of the HER2 gene has been identified in 10-20% of endometrioid and serous endometrial cancers and has been associated with a decrease in overall survival.

Gene amplification is the primary genetic abnormality of the ERBB2 (HER2) gene in endometrial cancer, while HER2 mutations are exceedingly rare in this malignancy (~2%). Currently, HER2 gene amplification (or protein overexpression) does not direct endometrial cancer patients towards specific therapies. Preclinical studies utilizing cell lines with amplification of the HER2 gene have demonstrated sensitivity to trastuzumab, pertuzumab and lapatinib, and clinical trials are evaluating the potential for use of these agents in the clinic. So far, only one trial has tested trastuzumab as a single-drug therapy for HER2-positive (gene amplified or protein over-expressed) recurrent endometrial cancer, but found no responses across 33 patients.

Amplification of the HER2 gene has been identified in 10-20% of endometrioid and serous endometrial cancers and has been associated with a decrease in overall survival.

PubMed ID's
17945336
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 5 results Per Page:
Protocol # Title Location Status Match
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 DG
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
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
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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