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Brca Gene And Prostate Cancer

Inheritance Of Prostate Cancer Risk

BRCA Gene Testing and Prostate Cancer

Many types of epidemiologic studies strongly suggest that prostate cancer susceptibility genes exist in the population. Analysis of longer follow-up of the monozygotic and dizygotic twin pairs in Scandinavia concluded that 58% of prostate cancer risk may be accounted for by heritable factors. Additionally, among affected MZ and DZ pairs, the time to diagnosis in the second twin was shortest in MZ twins . This is in agreement with a previous U.S. study that showed a concordance of 7.1% between DZ twin pairs and a 27% concordance between MZ twin pairs. A Swedish study also found concordance with disease aggressiveness defined as Gleason score greater than 6, clinical stage greater than T2, N1, M1, and PSA greater than 10 .

The first segregation analysis was performed in 1992 using families from 740 consecutive probands who had radical prostatectomies between 1982 and 1989. The study results suggested that familial clustering of disease among men with early-onset prostate cancer was best explained by the presence of a rare autosomal dominant, highly penetrant allele. Hereditary prostate cancer susceptibility genes were predicted to account for almost half of early-onset disease . In addition, early-onset disease has been further supported to have a strong genetic component from the study of common variants associated with disease onset before age 55 years.

References
  • Stanford JL, Ostrander EA: Familial prostate cancer. Epidemiol Rev 23 : 19-23, 2001.
  • Treatment Implications Of Germline Testing

    Advanced disease

    PARPi. Patients with DNA repair mutations have higher response rates to PARPi and platinum chemotherapy.31,32 In 2020, two PARPi received FDA approval for treatment of mCRPC with germline or somatic DNA damage repair gene mutations. Rucaparib was approved based on the phase 2 TRITON2 study it reported a 51% radiographic response rate among men with mCRPC and BRCA1/2 alterations.33 The benefit for men with non-BRCA DNA repair mutations was less clear, and rucaparib is currently approved only for carriers of BRCA1/2 mutations. 33-35 The olaparib label includes a larger number of mutated genes eligible for treatment , based on results of the phase 3 ProFOUND study . ProFOUND compared olaparib with enzalutamide or abiraterone and showed improved radiographic progression-free survival with olaparib. 36 Several other ongoing studies are evaluating the efficiency of PARPi monotherapy and combined therapies in mCRPC. Table 3 summarizes study results reporting response rates to PARPi in prostate cancer. 37

    Brcaness’ In Prostate Cancer

    Several studies in breast and ovarian cancer have identified sporadic cancers with molecular and clinical characteristics similar to BRCA-related tumours, defining a group of tumours with BRCAness characteristics that benefits from the same therapeutic strategies as those for BRCA mutant tumours., , ,

    The aggressive phenotype and poor prognosis associated with PCa in patients with germline BRCA mutations is very likely to be associated with a different cancer biology from BRCA wild-type PCa. The identification of these differential molecular characteristics could be essential in tailoring treatment for this population, but it may also be of great importance for the management of some sporadic PCa cases which may have similar clinical characteristics and aggressive behaviour.

    Gene promoter hypermethylation is a mechanism of BRCA function loss in sporadic breast and ovarian cancer that triggers tumours with similar characteristics to those with germline mutations in these genes, although this has still not been analysed in PCa. At this time, the study by Bednarz et al. is the only one that has analysed a series of sporadic PCas, finding that those with BRCA1 somatic loss presented more frequently with node involvement and shorter disease-free survival than those with functional BRCA1.

    Recommended Reading: Preparation For Prostate Mri Scan

    Lowering Risk Of Death

    There are two different management approaches for people with BRCA2 mutations, both of which are designed to reduce the chance that a person will die from one of the cancers of risk:

    • Early detection: Early detection is the process of trying to find a cancer which has formed at the earliest stage possible. With many cancers, we know that survival is higher when it’s found at an early stage than if it is discovered at a later stage . With early detection, the goal is to find cancer before it would otherwise cause the symptoms that would lead to its discovery. We don’t have methods to detect all cancers at these early stages, and the tests we do have are not perfect. For example, despite having had a normal mammogram, some women are diagnosed with breast cancer shortly thereafter.
    • Risk reduction: Risk reduction strategies work to reduce the risk that a cancer will develop in the first place. They are designed to prevent cancer from occurring. Methods of reduction may include surgery or medications .

    Most approaches to a genetic predisposition to cancer include either screening or risk reduction, but there is one test that can do both. Colonoscopy can be used to detect colon cancer in the earliest stages. It can also be used to reduce the risk of a person getting cancer if a pre-cancerous polyp is found and removed before it becomes malignant.

    What Are The Benefits Of Genetic Testing For Brca1 And Brca2 Variants

    BRCA Gene and Prostate Cancer

    There can be benefits to genetic testing, regardless of whether a person receives a positive or a negative result.

    The potential benefits of a true negative result include a sense of relief regarding the future risk of cancer, learning that one’s children are not at risk of inheriting the family’s cancer susceptibility, and the possibility that special check-ups, tests, or risk-reducing surgeries may not be needed.

    A positive test result may allow people to make informed decisions about their future health care, including taking steps to reduce their cancer risk.

    Prevalence Of Brca Mutations In Prostate Cancers

    The incidence of germline mutation in DDR genes among men with metastatic PCa varies between 11% and 33%, and it is significantly higher compared to the incidence in men with localized PCa . In a landmark study, Pritchard and colleagues showed that 11% of 692 patients with metastatic PCa harbored inherited mutations in 16 DDR genes . The most frequent aberration was BRCA2 followed by ATM , CHEK2 , BRCA1 , and RAD51 . Mutation frequency did not differ based on PCa family history or age at diagnosis . In a multi-institutional integrative clinical sequencing analysis, 23% of 150 mCRPC biopsies were found to be positive for DDR aberrations. BRCA2 was mutated in 13% of samples followed by ATM , MSH2 , BRCA1, FANCA, MLH1, and RAD51 .

    Several studies showed a different genomic landscape in mCRPC compared to localized PCa . In a large retrospective study, Robinson et al. analyzed 680 primary tumors and 333 mCRPC biopsies . The authors identified germline and/or somatic DDR defects in 10% of primary tumors and 27% of metastatic samples. The different molecular profile between localized PCa and metastatic lesions might be a direct consequence of tumor evolution under the selective pressure of ARSi or chemotherapy. However, small subpopulations of variant clones might be already present in primary tumors and might expand during the development of metastatic disease.

    What The Studies Showed

    Clinical trial results showed the drugs were well-tolerated, with side effects similar to mild chemotherapy. Rucaparib was tested in a single-arm clinical trial , enrolling nearly 400 men with BRCA-positive metastatic prostate cancer who were no longer responding to other treatments. Results showed that tumors shrank in 44% of the enrolled subjects, in some cases for up to two years. Olaparib was tested in a similar population and delayed disease progression by an average of 7.4 months, which was just over two times longer than a type of hormonal therapy used in the control arm of that study.

    Both drugs have their shortcomings. As personalized therapies, they work only for men with BRCA-positive prostate cancer, and just half the treated men will benefit. Furthermore, the experience with PARP-inhibitors so far is that tumors become resistant to therapy within six to 12 months. Whether PARP-inhibitors actually lengthen survival for men with metastatic prostate cancer is still being investigated. And many other questions remain about how to use the drugs most effectively to maximize their benefits.

    What This Means For You

    The researchers believe that this is the largest study done so far on men with a BRCA1 or BRCA2 mutation. The results show that the characteristics of cancers diagnosed in men with a BRCA2 mutation are different from the characteristics of cancers diagnosed in men with a BRCA1 mutation.

    If youre a man, youre much more likely to have a BRCA1 or BRCA2 mutation if:

    • You have female relatives on either your mother’s or father’s side of the family who had breast cancer diagnosed before age 50.
    • There is both breast and ovarian cancer on the same side of the family or in a single individual.
    • There are other cancers in your family in addition to breast, such as prostate, melanoma, pancreatic, stomach, uterine, thyroid, colon, and/or sarcoma.
    • Women in your family have had cancer in both breasts.
    • You are of Ashkenazi Jewish heritage.
    • A man in your family has had breast cancer.

    If you are a man and know that you have a BRCA1 or BRCA2 mutation or have a strong family history of breast or prostate cancer, its recommended that you have a breast exam by your doctor every year and do a monthly breast self-exam.

    Its also very important that you be aware of any signs that might indicate breast cancer.

    Talk to your doctor right away about any changes in your breasts, including:

    • nipple pain

    What Other Cancers Are Linked To Harmful Variants In Brca1 And Brca2

    BRCA Testing and Prostate Cancer Treatment Decisions | Ask a Prostate Expert, Mark Scholz, MD

    Harmful variants in BRCA1 and BRCA2 increase the risk of several additional cancers. In women, these include fallopian tube cancer and primary peritoneal cancer , both of which start in the same cells as the most common type of ovarian cancer. Men with BRCA2 variants, and to a lesser extent BRCA1 variants, are also at increased risk of breast cancer and prostate cancer . Both men and women with harmful BRCA1 or BRCA2 variants are at increased risk of pancreatic cancer, although the risk increase is low .

    In addition, certain variants in BRCA1 and BRCA2 can cause subtypes of Fanconi anemia, a rare syndrome that is associated with childhood solid tumors and development of acute myeloid leukemia . The mutations that cause these Fanconi anemia subtypes have a milder effect on protein function than the mutations that cause breast and ovarian cancer. Children who inherit one of these variants from each parent will develop Fanconi anemia.

    Ethics Approval And Consent To Participate

    Ethical clearance and approval of the study was sought from the institution review board of the School of Biomedical Science of Makerere College of Health Sciences . A reference number HDR-IRB-605 for the study was provided. Written consent to use the specimens of the patients included in this study was obtained from the chairperson of the IRB. The consent requires maintaining maximum confidentiality for the information of the patients whose specimens were used for the research as per guidelines for research stipulated by the institution which conform with the international guidelines for research including those of the Helsinki Declaration.

    What Are Brca1 And Brca2

    BRCA1 and BRCA2 are genes that produce proteins that help repair damaged DNA. Everyone has two copies of each of these genesone copy inherited from each parent. BRCA1 and BRCA2 are sometimes called tumor suppressor genes because when they have certain changes, called harmful variants , cancer can develop.

    People who inherit harmful variants in one of these genes have increased risks of several cancersmost notably breast and ovarian cancer, but also several additional types of cancer. People who have inherited a harmful variant in BRCA1 and BRCA2 also tend to develop cancer at younger ages than people who do not have such a variant.

    A harmful variant in BRCA1 or BRCA2 can be inherited from either parent. Each child of a parent who carries any mutation in one of these genes has a 50% chance of inheriting the mutation. Inherited mutationsalso called germline mutations or variantsare present from birth in all cells in the body.

    Even if someone has inherited a harmful variant in BRCA1 or BRCA2 from one parent, they would have inherited a normal copy of that gene from the other parent . But the normal copy can be lost or change in some cells in the body during that persons lifetime. Such a change is called a somatic alteration. Cells that dont have any functioning BRCA1 or BRCA2 proteins can grow out of control and become cancer.

    What To Do If You’re Worried

    Speak to a GP if cancer runs in your family and you’re worried you may get it too. They may refer you to a local genetics service for an NHS genetic test, which will tell you if you have inherited one of the cancer risk genes.

    This type of testing is known as predictive genetic testing. It’s “predictive” because a positive result means you have a greatly increased risk of developing cancer. It does not mean you have cancer or are definitely going to develop it.

    You may be eligible for this NHS test if the faulty gene has already been identified in one of your relatives, or if there is a strong family history of cancer in your family.

    Increased Risk Of Prostate Cancer In Men With Brca2 Gene Fault

    (PDF) Somatic aberrations of BRCA1 gene are associated ...

    by Cancer Research UK

    Men with the BRCA2 gene fault have an increased risk of prostate cancer and could benefit from PSA testing to help detect the disease earlier, according to researchers funded by Cancer Research UK.

    Previous studies have shown that PSA is not a suitable test for screening for prostate cancer in the general population, and this remains the case. There are limitations to the PSA testincluding false positives, false negatives and overdiagnosis.

    But new research found that PSA tests were more likely to pick out more serious forms of prostate cancer in men who carry the BRCA2 gene fault than in non-carrierssuggesting these men could benefit from regular PSA testing.

    In the study published today in European Urology, researchers at The Institute of Cancer Research, London, looked at around 1400 men and compared those who don’t carry the BRCA2 gene fault with those who do.

    Men were offered a yearly PSA test and depending on the result, they were either offered a biopsy to confirm their disease and treated if needed or asked to come back the following year.

    The researchers found that men who carry the BRCA2 gene fault were almost twice as likely to be diagnosed with prostate cancer than non-carriers.

    They also found that carriers were diagnosed at a younger agean average of 61 compared with 64 in non-carriers.

    And receiving a false positive result can lead to unnecessary worry and unnecessary biopsies.

    Explore further

    Brca Mutations In Prostate Cancer: Prognostic And Predictive Implications

    Elisa Zanardi

    1Department of Medical Oncology, Santa Chiara Hospital, 38122 Trento, Italy

    2Department of Internal Medicine and Medical Specialties , University of Genoa, 16132 Genoa, Italy

    3Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre , Madrid 28029, Spain

    4Academic Unit of Medical Oncology, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy

    5Genitourinary Tumors Traslational Research Group, Biomedical Research Institute of Malaga and Hospital Universitario Virgen de la Victoria, 29010 Malaga, Spain

    Abstract

    1. Introduction

    1.1. Prevalence of BRCA Mutations in Prostate Cancers

    The incidence of germline mutation in DDR genes among men with metastatic PCa varies between 11% and 33%, and it is significantly higher compared to the incidence in men with localized PCa . In a landmark study, Pritchard and colleagues showed that 11% of 692 patients with metastatic PCa harbored inherited mutations in 16 DDR genes . The most frequent aberration was BRCA2 followed by ATM , CHEK2 , BRCA1 , and RAD51 . Mutation frequency did not differ based on PCa family history or age at diagnosis . In a multi-institutional integrative clinical sequencing analysis, 23% of 150 mCRPC biopsies were found to be positive for DDR aberrations. BRCA2 was mutated in 13% of samples followed by ATM , MSH2 , BRCA1, FANCA, MLH1, and RAD51 .

    1.2. Clinical Implications of BRCA Mutations in Prostate Cancers
    1.3. Targeting BRCA Mutations in Prostate Cancer

    Clinical Implications Of Brca Mutations In Prostate Cancers

    PCa is a clinically heterogeneous disease. Patients commonly show variable responses to treatments that result in different clinical outcomes. This clinical variability may reflect molecular heterogeneity. Therefore, molecular profiling could have a meaningful translational relevance, allowing to distinguish PCa with indolent behaviour from those with a lethal course. Several studies explored the prognostic role of BRCA mutations in localized PCa and in mCRPC patients treated with standard therapies . In a large retrospective study, BRCA1/2 mutations correlated with higher Gleason score, nodal involvement, metastatic disease at diagnosis, and T3/4 stage . Moreover, BRCA2 was an independent prognostic factor that was associated with poorer outcomes. In localized PCa, the 5-year CSS and MFS were significantly shorter in BRCA2 carriers than in noncarriers . Given conflicting results reported in retrospective studies, it is currently uncertain whether BRCA2 mutation may affect the clinical outcome of mCRPC patients treated with standard treatments . Annala and colleagues retrospectively analyzed 319 charts of mCRPC patients, including 22 germline DDR carriers . Interestingly, gDDR carriers had a significant shorter progression-free survival than noncarriers when treated with first-line ARSi .

    New Drugs Approved For Advanced Brca

    • By Charlie Schmidt, Editor, Harvard Medical School Annual Report on Prostate Diseases

    Defective BRCA genes are well known for their ability to cause breast and ovarian cancers in women. But these same gene defects are also strong risk factors for aggressive prostate cancer in men. About 10% of men with metastatic prostate cancer meaning cancer that is spreading away from the prostate test positive for genetic mutations in BRCA genes. Fortunately, these cancers can be treated with new types of personalized therapies.

    In May, the FDA approved two new drugs specifically for men with BRCA-positive metastatic prostate cancer that has stopped responding to other treatments. One of the drugs, called rucaparib, was approved on May 15. The other one, olaparib, was approved on May 19.

    Both drugs work by shutting down the cancer cells ability to fix its DNA. Like all cells in the body, cancer cells are bombarded every day by free radicals, low-level radiation, and other stressors that cause DNA damage. BRCA genes ordinarily fix that damage so that cells can function normally and survive. But if the genes are defective, then the damage piles up. BRCA-positive tumors get around that problem by deploying an alternate DNA repair gene called PARP. Rucaparib and olaparib both inhibit PARP, leaving cancer cells without any way to fix their increasingly mangled DNA eventually the cells die.

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