Prostate Cancer, PTEN, R233X (c.697C>T)

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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 PTEN  - General Description
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PTEN is a gene that provides the code for making a protein called phosphatase and tensin homolog (PTEN). Found in almost all tissues in the body, this protein acts as a tumor suppressor. That is, it keeps cells from growing and dividing too fast or in an uncontrolled way. The PTEN protein is part of a signaling pathway that tells cells to stop dividing and triggers their self-destruction (apoptosis). It also may help control how cells move (migration), stick to other cells (adhesion) and protect their genetic information.

Somatic mutations in PTEN are among the most common genetic changes found in human cancers. Instead of coming from a parent and being present in every cell (hereditary), somatic mutations are acquired during the course of a person's life and are found only in cells that become cancerous. PTEN may be the most frequently mutated gene in prostate cancer and endometrial cancer. These mutations usually result in a defective protein that has lost its ability to be a tumor suppressor. Such mutations also are found in certain brain tumors (glioblastomas and astrocytomas) and melanoma of the skin. Loss of PTEN expression is also a common way by which PTEN activity can be reduced and the PI3K pathway can be activated.

Several related conditions caused by inherited mutations in PTEN are grouped together as PTEN hamartoma tumor syndrome. One of these conditions is Cowden syndrome, which is characterized by the growth of many hamartomas and an increased risk of developing breast, thyroid or endometrial cancer. Mutations that cause Cowden syndrome lead to production of a defective PTEN protein that cannot stop cell division or trigger apoptosis, which contributes to the development of hamartomas and cancerous tumors.

Source: Genetics Home Reference
The PTEN gene encodes a lipid phosphatase that antagonizes oncogenic PI3K/AKT signaling via dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) at the cell membrane. Cancer-associated genomic alterations in PTEN result in PTEN inactivation and thus increased activity of the PI3K/AKT pathway. Somatic mutations of PTEN occur in multiple malignancies, including gliomas, melanoma, prostate, endometrial, breast, ovarian, renal and lung cancers. Germline PTEN mutations are associated with inherited hamartoma syndromes, including Cowden syndrome. Loss of PTEN expression is also a common way by which PTEN activity can be reduced and the PI3K pathway can be activated.

Source: Genetics Home Reference
Expand Collapse R233X (c.697C>T)  in PTEN
The PTEN R233X mutation arises from a single nucleotide change (c.697C>T) and results in an amino acid substitution of the arginine (R) at position 233 by a stop codon (X).
The PTEN R233X mutation arises from a single nucleotide change (c.697C>T) and results in an amino acid substitution of the arginine (R) at position 233 by a stop codon (X).

Loss of PTEN function through gene deletion or mutation is one of the most common genetic events in prostate cancer and is frequently associated with advanced disease, disease progression and increased risk of recurrence. However, there is some discrepancy as to whether PTEN loss is independently associated with worse survival.

PTEN mutations in prostate cancer have been associated with resistance to hormonal therapy. Preclinical models have indicated that hormone treatment may in fact be more effective when combined with PI3K pathway inhibitors in patients with PTEN-mutant prostate tumors.

Recent data suggest that the P110 beta catalytic subunit of PI3K drives the growth of tumors when PTEN function is lost, but evidence in prostate cancer specifically is lacking. Therefore, the role of PTEN mutations in predicting response to PI3K (including selective P110 beta), AKT and mTOR inhibitors is currently being explored in multiple clinical trials across a number of different cancer types.

Loss of PTEN function through gene deletion or mutation is one of the most common genetic events in prostate cancer and is frequently associated with advanced disease, disease progression and increased risk of recurrence. However, there is some discrepancy as to whether PTEN loss is independently associated with worse survival.

PTEN mutations in prostate cancer have been associated with resistance to hormonal therapy. Preclinical models have indicated that hormone treatment may in fact be more effective when combined with PI3K pathway inhibitors in patients with PTEN-mutant prostate tumors.

Recent data suggest that the P110 beta catalytic subunit of PI3K drives the growth of tumors when PTEN function is lost, but evidence in prostate cancer specifically is lacking. Therefore, the role of PTEN mutations in predicting response to PI3K (including selective P110 beta), AKT and mTOR inhibitors is currently being explored in multiple clinical trials across a number of different cancer types.

PubMed ID's
20104229, 19402094, 18854827, 22684219, 17616663, 17700571, 21878536, 21620777, 21575859, 17638861
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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing all 10 results Per Page:
Protocol # Title Location Status Match
NCT01999972 A Phase 1b Study Of Axitinib In Combination With Crizotinib In Patients With Advanced Solid Tumors A Phase 1b Study Of Axitinib In Combination With Crizotinib In Patients With Advanced Solid Tumors 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
NCT02082210 A Study of LY2875358 in Combination With Ramucirumab (LY3009806) in Participants With Advanced Cancer A Study of LY2875358 in Combination With Ramucirumab (LY3009806) in Participants With Advanced Cancer MGH Open D
NCT02200614 Efficacy and Safety Study of BAY1841788 (ODM-201) in Men With High-risk Non-metastatic Castration-resistant Prostate Cancer (ARAMIS) Efficacy and Safety Study of BAY1841788 (ODM-201) in Men With High-risk Non-metastatic Castration-resistant Prostate Cancer (ARAMIS) 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
NCT02655822 Phase 1/1b Study to Evaluate the Safety and Tolerability of CPI-444 Alone and in Combination With Atezolizumab in Advanced Cancers Phase 1/1b Study to Evaluate the Safety and Tolerability of CPI-444 Alone and in Combination With Atezolizumab in Advanced Cancers MGH Open D
NCT01631552 Phase I/II Study of IMMU-132 in Patients With Epithelial Cancers Phase I/II Study of IMMU-132 in Patients With Epithelial Cancers MGH Open D
NCT02709889 Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors MGH Open D
NCT01391143 Safety Study of MGA271 in Refractory Cancer Safety Study of MGA271 in Refractory Cancer MGH Open D
NCT02607228 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GS-5829 as a Single Agent and In Combination With Enzalutamide in Participants With Metastatic Castrate-Resistant Prostate Cancer Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GS-5829 as a Single Agent and In Combination With Enzalutamide in Participants With Metastatic Castrate-Resistant Prostate 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 10 results Per Page:
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