Prostate Cancer, BRCA1 and BRCA2

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Expand Collapse Prostate Cancer  - General Description This year about 220,800 men in the U.S. will be told by a doctor that they have prostate cancer. About half will be at least 67 years old. However, 10 times as many men (2.5 million) are alive today after having been diagnosed with prostate cancer.

The prostate is a walnut-sized gland located behind the rectum and under the bladder. It is the part of a man's reproductive system that produces some of the fluids that make up semen, which carries sperm out of the body. Nearly all primary prostate cancers are adenocarcinomas, which begin in cells that line certain internal organs and produce mucus or other fluids.

Prostate 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 cancer cells cause secondary tumors to grow. The main sites to which prostate cancer spreads are the bones, lungs and liver. Some patients live a long time even after prostate cancer has spread to distant sites.

To find out whether prostate cancer has entered the lymph system, a surgeon may perform a pelvic lymphadenectomy to remove the lymph nodes in the pelvis. A pathologist looks at these lymph node tissues through a microscope to see if cancer cells are present. Several kinds of imaging technologies can also be performed to determine if prostate cancer has spread. These include bone scans, MRI and CT scans.

Despite significant improvements in the treatment of prostate cancers, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2015
Carcinoma of the prostate is predominantly a tumor of older men, which frequently responds to treatment when widespread and may be cured when localized. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone. Because the median age at diagnosis is 72 years, many patients, especially those with localized tumors, may die of other illnesses without ever having suffered significant disability from the cancer. The approach to treatment is influenced by age and coexisting medical problems. Side effects of various forms of treatment should be considered in selecting appropriate management. Controversy exists in regard to the value of screening, the most appropriate staging evaluation and the optimal treatment of each stage of the disease.

A complicating feature when evaluating survival after treatment, or when comparing the various treatment strategies, is that improved diagnostic methods can increasingly identify non-lethal tumors. Non-randomized comparisons of treatments may be confounded not only by patient-selection factors, but also by time trends. For example, a population-based study in Sweden showed that from 1960 to the late 1980s, before the use of prostate-specific antigen (PSA) for screening purposes, long-term relative survival rates after the diagnosis of prostate cancer improved substantially as more sensitive methods of diagnosis were introduced. This occurred despite the use of watchful waiting or palliative hormonal treatment as the most common treatment strategies for localized prostate cancer during the entire era (<150 radical prostatectomies per year were performed in Sweden during the late 1980s). The investigators estimated that if all cancers diagnosed between 1960 and 1964 were of the lethal variety, then at least 33% of cancers diagnosed between 1980 and 1984 were of the non-lethal variety. With the advent of PSA screening, the ability to diagnose non-lethal prostate cancers may increase further.

Another issue complicating comparisons of outcomes among non-concurrent series of patients is the possibility of changes in criteria for histologic diagnosis of prostate cancer. This phenomenon creates a statistical artifact that can produce a false sense of therapeutic accomplishment and may also lead to more aggressive therapy. For example, prostate biopsies from a population-based cohort of 1,858 men diagnosed with prostate cancer from 1990 through 1992 were re-read in 2002 to 2004. The contemporary Gleason score readings were an average of 0.85 points higher (95% confidence interval [CI], 0.79 0.91; P<0.001) than the same slides read in 1990 to 1992. As a result, Gleason score-standardized prostate cancer mortality for these men was artifactually improved from 2.08 to 1.50 deaths per 100 person years. This resulted in a 28% decrease, even though overall outcomes were unchanged.

Source: National Cancer Institute, 2012
This year about 220,800 men in the U.S. will be told by a doctor that they have prostate cancer. About half will be at least 67 years old. However, 10 times as many men (2.5 million) are alive today after having been diagnosed with prostate cancer.

The prostate is a walnut-sized gland located behind the rectum and under the bladder. It is the part of a man's reproductive system that produces some of the fluids that make up semen, which carries sperm out of the body. Nearly all primary prostate cancers are adenocarcinomas, which begin in cells that line certain internal organs and produce mucus or other fluids.

Prostate 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 cancer cells cause secondary tumors to grow. The main sites to which prostate cancer spreads are the bones, lungs and liver. Some patients live a long time even after prostate cancer has spread to distant sites.

To find out whether prostate cancer has entered the lymph system, a surgeon may perform a pelvic lymphadenectomy to remove the lymph nodes in the pelvis. A pathologist looks at these lymph node tissues through a microscope to see if cancer cells are present. Several kinds of imaging technologies can also be performed to determine if prostate cancer has spread. These include bone scans, MRI and CT scans.

Despite significant improvements in the treatment of prostate cancers, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2015
Carcinoma of the prostate is predominantly a tumor of older men, which frequently responds to treatment when widespread and may be cured when localized. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone. Because the median age at diagnosis is 72 years, many patients, especially those with localized tumors, may die of other illnesses without ever having suffered significant disability from the cancer. The approach to treatment is influenced by age and coexisting medical problems. Side effects of various forms of treatment should be considered in selecting appropriate management. Controversy exists in regard to the value of screening, the most appropriate staging evaluation and the optimal treatment of each stage of the disease.

A complicating feature when evaluating survival after treatment, or when comparing the various treatment strategies, is that improved diagnostic methods can increasingly identify non-lethal tumors. Non-randomized comparisons of treatments may be confounded not only by patient-selection factors, but also by time trends. For example, a population-based study in Sweden showed that from 1960 to the late 1980s, before the use of prostate-specific antigen (PSA) for screening purposes, long-term relative survival rates after the diagnosis of prostate cancer improved substantially as more sensitive methods of diagnosis were introduced. This occurred despite the use of watchful waiting or palliative hormonal treatment as the most common treatment strategies for localized prostate cancer during the entire era (<150 radical prostatectomies per year were performed in Sweden during the late 1980s). The investigators estimated that if all cancers diagnosed between 1960 and 1964 were of the lethal variety, then at least 33% of cancers diagnosed between 1980 and 1984 were of the non-lethal variety. With the advent of PSA screening, the ability to diagnose non-lethal prostate cancers may increase further.

Another issue complicating comparisons of outcomes among non-concurrent series of patients is the possibility of changes in criteria for histologic diagnosis of prostate cancer. This phenomenon creates a statistical artifact that can produce a false sense of therapeutic accomplishment and may also lead to more aggressive therapy. For example, prostate biopsies from a population-based cohort of 1,858 men diagnosed with prostate cancer from 1990 through 1992 were re-read in 2002 to 2004. The contemporary Gleason score readings were an average of 0.85 points higher (95% confidence interval [CI], 0.79 0.91; P<0.001) than the same slides read in 1990 to 1992. As a result, Gleason score-standardized prostate cancer mortality for these men was artifactually improved from 2.08 to 1.50 deaths per 100 person years. This resulted in a 28% decrease, even though overall outcomes were unchanged.

Source: National Cancer Institute, 2012
Expand Collapse BRCA1 and BRCA2  - General Description
BRCA1 and BRCA2 are genes that encode proteins that play an important role in DNA repair. DNA is damaged in organisms through various means-UV from the sunlight, and exposure to other substances that cause breaks or cross-links in the DNA. DNA breaks also occur when cells are dividing and chromosomes need to separate, especially in cells that will eventually have half the number of chromosomes-the egg and sperm-during a process called meiosis. When the proteins that are involved in DNA repair are mutated or missing, breaks in the DNA do not get repaired, resulting in an accumulation of DNA that is incorrectly arranged, which leads to cancer. For this reason, BRCA1 and BRCA2 are called tumor suppressor genes, because when they function correctly, they participate in repairing DNA and preventing cancers.

When both strands of the DNA helix are disrupted, a process called Double Stranded DNA Repair takes place through a process called Homologous Recombination. This process involves a complex-or group-of many different proteins, some that attach onto the broken ends of DNA and then recruit other proteins to the site that are able to repair double strand breaks (DSB's) in the DNA so that the genes they encode are correctly sequenced when the repair is complete. Along with the BRCA proteins, proteins called RAD50 and RAD51 are part of the complex of proteins involved in DNA repair. During the DNA repair process, BRCA2 recruits RAD51 into the complex that is responsible for DNA repair. (See DNA repair details if you select ATR from the drop down of genes on this site).

BRCA1 and BRCA2 are genes that were discovered in families that had a high incidence of breast cancer. In these families, the genetic alterations in BRCA1 or BRCA2 are present in the germ-line, which means they are inherited. Inherited germ-line mutations in BRCA1 or BRCA2 greatly increase the likelihood of developing cancer of the breast or ovary, as well as prostate cancer in men. BRCA1 has many functions in the cell. It is involved in transcription of genes, targeting proteins for degradation in the cell, cell cycle regulation, and homologous recombination to repair DNA. BRCA2 is also involved in homologous recombination to repair DNA. When either BRCA gene is missing or inactivated, the result is hereditary breast and ovarian cancer (HBOC). BRCA2 mutations confer a 50-60% lifetime risk of breast cancer, a 30% lifetime risk of ovarian cancer, a 20 fold risk of prostate cancer, a tenfold risk of pancreatic cancer, and potentially increased frequency of other cancers as well.

Patients can also develop somatic mutations or deletions of the BRCA1 or BRCA2 gene during their lifetime, instead of inheriting these mutations. Spontaneous mutations in BRCA1 or BRCA2 in an individual are called sporadic mutations. As more patients with different tumor types are tested for BRCA1 and BRCA2, it is becoming evident that multiple tumor types can harbor BRCA1 or BRCA2 mutations or deletions of the gene. Mutations in other genes involved in DNA repair can also contribute to the development of tumors. (See DNA repair proteins that have been found to be mutated in cancers in the graphic after selecting ATR on the drop down menu on this site).

Testing is available for BRCA1 and BRCA2 mutations (as well as the genes encoding many other proteins involved in DNA repair) at MGH, where there are established treatments such as PARP inhibitors in use, as well as clinical trials testing the newest therapies for improved treatment of patients carrying these mutations.

Sources:
The DNA Damage Response: Ten Years After, J. Wade Harper, Stephen J. Elledge, Molecular Cell, Vol.28, Issue 5, 2007, pages 739-745.

DNA repair targeted therapy: The past or future of cancer treatment? 2017
Science Direct article pii/S0163725816000322
BRCA1 and BRCA2 are genes that encode proteins that play an important role in DNA repair. DNA is damaged in organisms through various means-UV from the sunlight, and exposure to other substances that cause breaks or cross-links in the DNA. DNA breaks also occur when cells are dividing and chromosomes need to separate, especially in cells that will eventually have half the number of chromosomes-the egg and sperm-during a process called meiosis. When the proteins that are involved in DNA repair are mutated or missing, breaks in the DNA do not get repaired, resulting in an accumulation of DNA that is incorrectly arranged, which leads to cancer. For this reason, BRCA1 and BRCA2 are called tumor suppressor genes, because when they function correctly, they participate in repairing DNA and preventing cancers.

When both strands of the DNA helix are disrupted, a process called Double Stranded DNA Repair takes place through a process called Homologous Recombination. This process involves a complex-or group-of many different proteins, some that attach onto the broken ends of DNA and then recruit other proteins to the site that are able to repair double strand breaks (DSB's) in the DNA so that the genes they encode are correctly sequenced when the repair is complete. Along with the BRCA proteins, proteins called RAD50 and RAD51 are part of the complex of proteins involved in DNA repair. During the DNA repair process, BRCA2 recruits RAD51 into the complex that is responsible for DNA repair. (See DNA repair details if you select ATR from the drop down of genes on this site).

BRCA1 and BRCA2 are genes that were discovered in families that had a high incidence of breast cancer. In these families, the genetic alterations in BRCA1 or BRCA2 are present in the germ-line, which means they are inherited. Inherited germ-line mutations in BRCA1 or BRCA2 greatly increase the likelihood of developing cancer of the breast or ovary, as well as prostate cancer in men. BRCA1 has many functions in the cell. It is involved in transcription of genes, targeting proteins for degradation in the cell, cell cycle regulation, and homologous recombination to repair DNA. BRCA2 is also involved in homologous recombination to repair DNA. When either BRCA gene is missing or inactivated, the result is hereditary breast and ovarian cancer (HBOC). BRCA2 mutations confer a 50-60% lifetime risk of breast cancer, a 30% lifetime risk of ovarian cancer, a 20 fold risk of prostate cancer, a tenfold risk of pancreatic cancer, and potentially increased frequency of other cancers as well.

Patients can also develop somatic mutations or deletions of the BRCA1 or BRCA2 gene during their lifetime, instead of inheriting these mutations. Spontaneous mutations in BRCA1 or BRCA2 in an individual are called sporadic mutations. As more patients with different tumor types are tested for BRCA1 and BRCA2, it is becoming evident that multiple tumor types can harbor BRCA1 or BRCA2 mutations or deletions of the gene. Mutations in other genes involved in DNA repair can also contribute to the development of tumors. (See DNA repair proteins that have been found to be mutated in cancers in the graphic after selecting ATR on the drop down menu on this site).

Testing is available for BRCA1 and BRCA2 mutations (as well as the genes encoding many other proteins involved in DNA repair) at MGH, where there are established treatments such as PARP inhibitors in use, as well as clinical trials testing the newest therapies for improved treatment of patients carrying these mutations.

Sources:
The DNA Damage Response: Ten Years After, J. Wade Harper, Stephen J. Elledge, Molecular Cell, Vol.28, Issue 5, 2007, pages 739-745.

DNA repair targeted therapy: The past or future of cancer treatment? 2017
Science Direct article pii/S0163725816000322
PubMed ID's
19553641,
Expand Collapse BRCA1 and BRCA2  in Prostate Cancer


In prostate cancer, there is much ongoing research examining the use of targeted systemic therapies (such as drugs that are inhibitors of a protein called PARP) for patients who have either germline (inherited) or somatic (newly altered) mutations that affect DNA repair. When damage to DNA occurs, repair involves a number of proteins. At MGH, testing is available for mutations in a panel of genes that encode proteins involved in DNA repair. These include not only BRCA1 and BRCA2, but also other genes that encode proteins involved in DNA repair including PALB2, ATM, Fanconi's anemia genes, CHK 2, as well as others. Mutations in any of these genes are what we call predictive biomarkers, meaning patients who have a mutation in any of these DNA repair genes can be treated with targeted therapies.

Research involving biomarker testing described above can be performed on germline DNA (inherited), tumor tissue DNA, and circulating tumor DNA (tumors shed cells and DNA into the blood, which can be isolated). The use of blood is a way to avoid tumor biopsies and still accurately test for mutations in the above DNA repair genes. These exciting tests are being developed at MGH and treatment and clinical trials are available to prostate cancer patients who have one of these mutations.

In prostate cancer, there is much ongoing research examining the use of targeted systemic therapies (such as drugs that are inhibitors of a protein called PARP) for patients who have either germline (inherited) or somatic (newly altered) mutations that affect DNA repair. When damage to DNA occurs, repair involves a number of proteins. At MGH, testing is available for mutations in a panel of genes that encode proteins involved in DNA repair. These include not only BRCA1 and BRCA2, but also other genes that encode proteins involved in DNA repair including PALB2, ATM, Fanconi's anemia genes, CHK 2, as well as others. Mutations in any of these genes are what we call predictive biomarkers, meaning patients who have a mutation in any of these DNA repair genes can be treated with targeted therapies.

Research involving biomarker testing described above can be performed on germline DNA (inherited), tumor tissue DNA, and circulating tumor DNA (tumors shed cells and DNA into the blood, which can be isolated). The use of blood is a way to avoid tumor biopsies and still accurately test for mutations in the above DNA repair genes. These exciting tests are being developed at MGH and treatment and clinical trials are available to prostate cancer patients who have one of these mutations.

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 Results: 1-10 of 16 Per Page:
12Next »
Protocol # Title Location Status Match
NCT03016312 A Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Enzalutamide in Participants With Metastatic Castration-Resistant Prostrate Cancer (mCRPC) After Failure of an Androgen Synthesis Inhibitor And Failure of, Ineligibility For, or Refusal of a Taxane Regimen A Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Enzalutamide in Participants With Metastatic Castration-Resistant Prostrate Cancer (mCRPC) After Failure of an Androgen Synthesis Inhibitor And Failure of, Ineligibility For, or Refusal of a Taxane Regimen MGH Open D
NCT02467361 A Study of BBI608 Administered in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Cancers A Study of BBI608 Administered in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Cancers MGH Open D
NCT02950064 A Study to Determine the Safety of BTP-114 for Treatment in Patients With Advanced Solid Tumors With BRCA Mutations A Study to Determine the Safety of BTP-114 for Treatment in Patients With Advanced Solid Tumors With BRCA Mutations MGH Open D
NCT02531516 An Efficacy and Safety Study of JNJ-56021927 (Apalutamide) in High-risk Prostate Cancer Subjects Receiving Primary Radiation Therapy: ATLAS An Efficacy and Safety Study of JNJ-56021927 (Apalutamide) in High-risk Prostate Cancer Subjects Receiving Primary Radiation Therapy: ATLAS MGH Open D
NCT02854436 An Efficacy and Safety Study of Niraparib in Men With Metastatic Castration-Resistant Prostate Cancer and DNA-Repair Anomalies An Efficacy and Safety Study of Niraparib in Men With Metastatic Castration-Resistant Prostate Cancer and DNA-Repair Anomalies MGH Open D
NCT01961713 Circulating Tumor Cell Analysis in Patients With Localized Prostate Cancer Undergoing Prostatectomy Circulating Tumor Cell Analysis in Patients With Localized Prostate Cancer Undergoing Prostatectomy MGH Open D
NCT01949337 Enzalutamide With or Without Abiraterone and Prednisone in Treating Patients With Castration-Resistant Metastatic Prostate Cancer Enzalutamide With or Without Abiraterone and Prednisone in Treating Patients With Castration-Resistant Metastatic Prostate Cancer MGH Closed 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
NCT02799602 ODM-201 in Addition to Standard ADT and Docetaxel in Metastatic Castration Sensitive Prostate Cancer ODM-201 in Addition to Standard ADT and Docetaxel in Metastatic Castration Sensitive Prostate Cancer MGH Open D
NCT02219711 Phase 1/1b Study of MGCD516 in Patients With Advanced Cancer Phase 1/1b Study of MGCD516 in Patients With Advanced Cancer MGH Open D
Trial Status: Showing Results: 1-10 of 16 Per Page:
12Next »
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