Breast cancer is the most common non-cutaneous cancer among women in the United States. This year about 252,710 women in the U.S. will be told by a doctor that they have breast cancer. Half of these people will be at least 62 years old. However, an estimated 3,327,552 women are living with female breast cancer in the United States following treatment.
Germline (inherited) mutations in either the BRCA1 or BRCA2 gene confer an increased risk of breast and/or ovarian cancer to women. In addition, women and men carrying BRCA1 or BRCA2 mutations are at increased risk of developing other primary cancers. Genetic testing is available at the MGH genetics lab to detect mutations in members of high-risk families. Such individuals should also be referred for genetic counseling to obtain more information about the implications of inherited BRCA1 and BRCA2 mutations. Innovative treatments are available for patients with inherited BRCA1 or BRCA2 mutations at the MGH Cancer Center. There is also a large portfolio of clinical trials testing the newest treatments at the MGH Cancer Center.
Despite significant improvements in the treatment of breast tumors, new therapies and treatment strategies are needed to improve outcomes for breast cancer patients. There are a number of novel targeted therapies as well as new immuno-therapies being used that are tailored to individual patient mutations at the MGH Cancer Center.
Source: National Cancer Institute, 2017
Breast cancer is the most common non-cutaneous cancer among women in the United States. This year about 252,710 women in the U.S. will be told by a doctor that they have breast cancer. Half of these people will be at least 62 years old. However, an estimated 3,327,552 women are living with female breast cancer in the United States following treatment.
Germline (inherited) mutations in either the BRCA1 or BRCA2 gene confer an increased risk of breast and/or ovarian cancer to women. In addition, women and men carrying BRCA1 or BRCA2 mutations are at increased risk of developing other primary cancers. Genetic testing is available at the MGH genetics lab to detect mutations in members of high-risk families. Such individuals should also be referred for genetic counseling to obtain more information about the implications of inherited BRCA1 and BRCA2 mutations. Innovative treatments are available for patients with inherited BRCA1 or BRCA2 mutations at the MGH Cancer Center. There is also a large portfolio of clinical trials testing the newest treatments at the MGH Cancer Center.
Despite significant improvements in the treatment of breast tumors, new therapies and treatment strategies are needed to improve outcomes for breast cancer patients. There are a number of novel targeted therapies as well as new immuno-therapies being used that are tailored to individual patient mutations at the MGH Cancer Center.
Source: National Cancer Institute, 2017
CLICK IMAGE FOR MORE INFORMATIONFibroblast 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,
24265351As 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 with varying frequency in breast cancers. FGFR1 gene amplification, or alteration by genetic mutation have been identified in some breast cancers. FGFR2 gene amplifications and translocations have been found in some types of breast cancer.
There is also a germline (inheritied) genetic alteration in FGFR2 that leads to an increased incidence of breast cancer.
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 with varying frequency in breast cancers. FGFR1 gene amplification, or alteration by genetic mutation have been identified in some breast cancers. FGFR2 gene amplifications and translocations have been found in some types of breast cancer.
There is also a germline (inheritied) genetic alteration in FGFR2 that leads to an increased incidence of breast cancer.
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
24265351