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Gastric/Esophageal, FGFR 1, 2, 3 and 4, All Genetic Alterations

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Expand Collapse Gastric/Esophageal  - General Description Cancers of the stomach (gastric) and esophagus are a major public health concern. Other terms for these cancers include gastroesophageal cancer or esophagogastric cancer. About 13,000 men and 8,000 women will be diagnosed with gastric or esophageal cancer yearly in the United States. Though the incidence of certain types of gastric cancers has decreased, cancers of the gastroesophageal (GE) junction and lower esophagus are increasing in frequency.

The innermost layers of the esophagus and stomach are the site where esophageal and gastric cancers most often begin. Cancers affecting the esophagus are usually either “squamous cell carcinoma" (SCC) or “adenocarcinoma”, which differ in a number of ways. Most SCCs develop in the upper or middle esophageal region and smoking and alcohol use are the major risk factors. Adenocarcinomas of the esophagus tend to start in the distal esophagus or GE junction. For esophageal or GE junction adenocarcinomas, the predominant risk factors are obesity, smoking, having a disorder called “Barrett’s esophagus”, or gastroesophageal reflux disease (GERD). Cancer arising in the stomach is mainly adenocarcinoma. Infection in the stomach by a certain bacteria called Helicobacter pylori is a primary risk factor for developing this disease.

Stomach and esophageal cancers tend to develop slowly over many years. Precancerous changes that occur in the inner mucosal layer of the stomach or esophagus rarely cause symptoms, and therefore frequently go undetected. Once symptoms develop and the cancer has been identified, esophagogastric cancers can be removed using surgery as the primary method of treatment. However, when these cancers spread from the area where they initially develop (the “primary” tumor), the major focus of treatment becomes chemotherapy with or without radiation therapy. There are three different ways tumors can spread. First, the primary tumor can grow and invade the other layers of the stomach or esophagus and invade normal tissue surrounding the tumor. Second, cancer cells from the tumor can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, cancer cells from the tumor can get into the bloodstream, and travel to other places in the body. In these distant places, the esophagogastric cancer cells can cause secondary tumors (metastases) to grow. To find out whether the cancer is limited to the primary site or whether the cancer has begun to spread, the lymph nodes near the primary tumor are often evaluated through biopsy. Several kinds of imaging may also be performed in diagnosing gastric and esophageal cancers to “stage” the disease. These include chest x-ray, MRI, CT scan, and PET scan techniques.

Testing for the presence of a specific cancer-related protein called HER2 (ERBB2) in the tumor specimen is an additional evaluation that is performed in esophagogastric cancer. The presence of HER2-expression in esophagogastric cancer has important therapeutic implications. There are also trials being conducted for patients with MET-amplified or EGFR-amplified tumors.

Sources: National Cancer Institute, 2013; The American Cancer Society, 2013; Partners Clinical Handbook, 2013
Cancers of the stomach and esophagus, also collectively referred to as gastroesophageal or esophagogastric cancer, represent a major public health concern. Gastric cancer is the fourth most commonly diagnosed cancer and the second most common cause of cancer death worldwide. Gastric cancer incidence varies throughout the world, with Japan and Korea having the highest incidences. According to the American Cancer Society (ACS), 21,600 new cases and 10,990 deaths are estimated for 2013 in the United States. For esophageal cancers, the ACS estimates 17,990 new esophageal cancers diagnosed in the United States during 2013, resulting in about 15,210 deaths (12,220 men and 2,990 women).

Most cancers involving the esophagus or stomach are either squamous cell (SCC) or adenocarcinoma. Squamous cell cancers were formerly the predominant histology for esophageal cancers. However, since the 1970s, the frequency of adenocarcinomas of the esophagus, gastroesophageal junction (GEJ), and gastric cardia has increased dramatically. Esophageal SCCs and adenocarcinomas of the distal esophagus, GEJ, or gastric cardia differ in a number of ways. Most SCCs develop in the “middle esophageal” region, and smoking and alcohol use are the major risk factors. For adenocarcinomas, the predominant risk factors are obesity, smoking, and “Barrett’s esophagus” with associated intestinal metaplasia, or gastroesophageal reflux disease (GERD). Meanwhile, risk factors associated with more distal gastric adenocarcinomas include 1) Helicobacter pylori infection, 2) a diet low in fruits and vegetables, 3) a diet high in salted, smoked, or preserved foods, 3) chronic atrophic gastritis, and 4) pernicious anemia, among other risk factors.

Gastric and esophageal cancers tend to develop slowly over many years in the inner mucosal layer of the stomach or esophagus. These early changes rarely cause symptoms, and therefore frequently go undetected. As esophageal and gastric cancers become more advanced, symptoms can include discomfort or pain in the stomach area, difficulty swallowing, nausea and vomiting, weight loss, feeling full or bloated after a small meal, vomiting blood, or having blood in the stool. Once symptoms bring a patient to medical attention, endoscopic biopsy is routinely used to diagnose the cancer. Staging workup should include radiographic imaging, such as CT with intravenous contrast, with or without accompanying PET scan. In the case of esophageal cancer, endoscopic ultrasound (EUS) with fine-needle biopsy of suspicious lymph nodes may be used to more accurately stage locoregional disease. The staging workup of gastric cancers may involve diagnostic laparoscopy to rule out occult metastatic disease.

Treatment options for esophageal and gastric cancers depend on the size and location of the tumor, the stage of disease, and overall health of the patient. In the absence of distant spread of disease, a multi-disciplinary approach involving surgery, radiation and chemotherapy is required. Except in cases of very early-stage disease, neoadjuvant and peri-operative approaches involving chemotherapy with or without radiation should be considered in order to optimize the chances of curative resection. In cases of gastric or GEJ cancers where surgery is pursued first, adjuvant therapy may be appropriate.

Metastatic esophageal and gastric adenocarcinomas are treated similarly with systemic chemotherapy. Despite a variety of chemotherapeutic regimens that are available, the median survival for metastatic esophagogastric cancer patients is less than 1 year. Therefore, there has been a growing interest in the molecular features of these diseases, with the expectation that activating molecular lesions may be targets for novel therapeutic agents. For patients with HER2-positive tumors, targeted therapy is now an option. There are also trials being conducted for patients with MET-amplified or EGFR-amplified tumors.

Source: National Cancer Institute, 2013; The American Cancer Society, 2013; Up-To-Date, 2013
Cancers of the stomach (gastric) and esophagus are a major public health concern. Other terms for these cancers include gastroesophageal cancer or esophagogastric cancer. About 13,000 men and 8,000 women will be diagnosed with gastric or esophageal cancer yearly in the United States. Though the incidence of certain types of gastric cancers has decreased, cancers of the gastroesophageal (GE) junction and lower esophagus are increasing in frequency.

The innermost layers of the esophagus and stomach are the site where esophageal and gastric cancers most often begin. Cancers affecting the esophagus are usually either “squamous cell carcinoma" (SCC) or “adenocarcinoma”, which differ in a number of ways. Most SCCs develop in the upper or middle esophageal region and smoking and alcohol use are the major risk factors. Adenocarcinomas of the esophagus tend to start in the distal esophagus or GE junction. For esophageal or GE junction adenocarcinomas, the predominant risk factors are obesity, smoking, having a disorder called “Barrett’s esophagus”, or gastroesophageal reflux disease (GERD). Cancer arising in the stomach is mainly adenocarcinoma. Infection in the stomach by a certain bacteria called Helicobacter pylori is a primary risk factor for developing this disease.

Stomach and esophageal cancers tend to develop slowly over many years. Precancerous changes that occur in the inner mucosal layer of the stomach or esophagus rarely cause symptoms, and therefore frequently go undetected. Once symptoms develop and the cancer has been identified, esophagogastric cancers can be removed using surgery as the primary method of treatment. However, when these cancers spread from the area where they initially develop (the “primary” tumor), the major focus of treatment becomes chemotherapy with or without radiation therapy. There are three different ways tumors can spread. First, the primary tumor can grow and invade the other layers of the stomach or esophagus and invade normal tissue surrounding the tumor. Second, cancer cells from the tumor can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, cancer cells from the tumor can get into the bloodstream, and travel to other places in the body. In these distant places, the esophagogastric cancer cells can cause secondary tumors (metastases) to grow. To find out whether the cancer is limited to the primary site or whether the cancer has begun to spread, the lymph nodes near the primary tumor are often evaluated through biopsy. Several kinds of imaging may also be performed in diagnosing gastric and esophageal cancers to “stage” the disease. These include chest x-ray, MRI, CT scan, and PET scan techniques.

Testing for the presence of a specific cancer-related protein called HER2 (ERBB2) in the tumor specimen is an additional evaluation that is performed in esophagogastric cancer. The presence of HER2-expression in esophagogastric cancer has important therapeutic implications. There are also trials being conducted for patients with MET-amplified or EGFR-amplified tumors.

Sources: National Cancer Institute, 2013; The American Cancer Society, 2013; Partners Clinical Handbook, 2013
Cancers of the stomach and esophagus, also collectively referred to as gastroesophageal or esophagogastric cancer, represent a major public health concern. Gastric cancer is the fourth most commonly diagnosed cancer and the second most common cause of cancer death worldwide. Gastric cancer incidence varies throughout the world, with Japan and Korea having the highest incidences. According to the American Cancer Society (ACS), 21,600 new cases and 10,990 deaths are estimated for 2013 in the United States. For esophageal cancers, the ACS estimates 17,990 new esophageal cancers diagnosed in the United States during 2013, resulting in about 15,210 deaths (12,220 men and 2,990 women).

Most cancers involving the esophagus or stomach are either squamous cell (SCC) or adenocarcinoma. Squamous cell cancers were formerly the predominant histology for esophageal cancers. However, since the 1970s, the frequency of adenocarcinomas of the esophagus, gastroesophageal junction (GEJ), and gastric cardia has increased dramatically. Esophageal SCCs and adenocarcinomas of the distal esophagus, GEJ, or gastric cardia differ in a number of ways. Most SCCs develop in the “middle esophageal” region, and smoking and alcohol use are the major risk factors. For adenocarcinomas, the predominant risk factors are obesity, smoking, and “Barrett’s esophagus” with associated intestinal metaplasia, or gastroesophageal reflux disease (GERD). Meanwhile, risk factors associated with more distal gastric adenocarcinomas include 1) Helicobacter pylori infection, 2) a diet low in fruits and vegetables, 3) a diet high in salted, smoked, or preserved foods, 3) chronic atrophic gastritis, and 4) pernicious anemia, among other risk factors.

Gastric and esophageal cancers tend to develop slowly over many years in the inner mucosal layer of the stomach or esophagus. These early changes rarely cause symptoms, and therefore frequently go undetected. As esophageal and gastric cancers become more advanced, symptoms can include discomfort or pain in the stomach area, difficulty swallowing, nausea and vomiting, weight loss, feeling full or bloated after a small meal, vomiting blood, or having blood in the stool. Once symptoms bring a patient to medical attention, endoscopic biopsy is routinely used to diagnose the cancer. Staging workup should include radiographic imaging, such as CT with intravenous contrast, with or without accompanying PET scan. In the case of esophageal cancer, endoscopic ultrasound (EUS) with fine-needle biopsy of suspicious lymph nodes may be used to more accurately stage locoregional disease. The staging workup of gastric cancers may involve diagnostic laparoscopy to rule out occult metastatic disease.

Treatment options for esophageal and gastric cancers depend on the size and location of the tumor, the stage of disease, and overall health of the patient. In the absence of distant spread of disease, a multi-disciplinary approach involving surgery, radiation and chemotherapy is required. Except in cases of very early-stage disease, neoadjuvant and peri-operative approaches involving chemotherapy with or without radiation should be considered in order to optimize the chances of curative resection. In cases of gastric or GEJ cancers where surgery is pursued first, adjuvant therapy may be appropriate.

Metastatic esophageal and gastric adenocarcinomas are treated similarly with systemic chemotherapy. Despite a variety of chemotherapeutic regimens that are available, the median survival for metastatic esophagogastric cancer patients is less than 1 year. Therefore, there has been a growing interest in the molecular features of these diseases, with the expectation that activating molecular lesions may be targets for novel therapeutic agents. For patients with HER2-positive tumors, targeted therapy is now an option. There are also trials being conducted for patients with MET-amplified or EGFR-amplified tumors.

Source: National Cancer Institute, 2013; The American Cancer Society, 2013; Up-To-Date, 2013
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.

Genetic alterations in FGFR family members have been found in gastric and esophageal cancers. Amplification of FGFR1 has been found in some esophageal tumors. Either mutation or amplification of FGFR2 have been found in different gastric tumors.

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.

Genetic alterations in FGFR family members have been found in gastric and esophageal cancers. Amplification of FGFR1 has been found in some esophageal tumors. Either mutation or amplification of FGFR2 have also been found in different gastric tumors.

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.

PubMed ID's
27109926

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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing Results: 1-10 of 17 Per Page:
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Trial Status: Showing Results: 1-10 of 17 Per Page:
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