Wednesday, December 7, 2022

Brca Testing For Prostate Cancer

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Resistance Mechanisms To Parp Inhibitors

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

There are a few mechanisms that cause PARP inhibitors resistance. Firstly, tumor cells can perform mutational reversion of BRCA1/2, which causes restoration of the HR DNA repair pathway . Secondly, the stabilization of stalled forks in the cells also leads to resistance this is achieved through the loss of fork degradation pathways . A third mechanism is through the mutation of PARP1 in tumor cells preventing trapping and cytotoxicity to these cells . Lastly, tumor cells can upregulate the permeability glycoprotein efflux pumps, causing reduction of PARP inhibitors concentration intracellularly and decreased efficacy . The summary of the mechanisms of resistance to PARP inhibitors is presented in Figure 2.

Mechanisms of resistance to PARP inhibitors. Cancer cells develop different resistance mechanisms that pose a significant obstacle to the prolonged use of PARPi. Several proposed molecular mechanisms of PARPi resistance, including restoration of HR capacity, stabilization of replication forks, diminished trapping of PARP-1, and P-gp-mediated drug efflux, are highlighted in four sections.

What The Results Show

In all 357 men were biopsied, and 112 of them were diagnosed prostate with cancer. The BRCA2 mutation carriers had the greatest cancer risk: 5.2% of them were diagnosed with the disease, and most of their tumors had intermediate- or high-risk features. BRCA1 mutation carriers had a lower risk: 3.4% of them were diagnosed with prostate cancer. And the men who tested negative for BRCA1 and BRCA2 mutations had the lowest risk overall, with diagnosis rates of 3.0% and 2.7% respectively.

Based on the results, Ros Eeles from the Institute of Cancer Research in London, who led the research, issued a statement calling on regulatory bodies to update guidance so that men with BRCA2 defects can get regular PSA screening after age 40.

Most expert groups in the United States recommend that doctors start talking about the pros and cons of PSA testing with patients who are 55 or older. However, guidelines are being rewritten to focus screening on high-risk groups at younger ages, and BRCA2 mutation carriers are widely considered to be in the highest-risk category.

Men should consider being tested for BRCA mutations under the following conditions:

  • If theres a history of prostate, breast, or ovarian cancer in the immediate family, particularly among younger members
  • if other family members test positive for BRCA1 or BRCA2 mutations
  • if they are of Ashkenazi Jewish descent, since BRCA mutations occur frequently in this ethnic population.

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What You Can Do

  • Maintaining a healthy body mass index
  • Eating more fruits and vegetables
  • Cutting down on red meat, sugary drinks, and ultra-processed foods

If you smoke, quit. Current smokers are more likely than nonsmokers to have aggressive tumors or cancer that comes back after treatment. Smoking also raises your odds of dying from prostate cancer.

Scientists continue to study how gene changes are linked to prostate cancer. If you have a BRCA gene mutation, ask your doctor if a chemoprevention clinical trial might be right for you. These are studies that test new drugs designed to prevent people from getting cancer.

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Genetic Testing For Prostate Cancer: What You Should Know

Doctors have known for decades that genetics can play a vital role in breast and ovarian cancer. Lately, scientists have begun to realize that many of these same genetic changes may lead to a man’s risk of developing prostate cancer. These findings are leading to earlier identification of men at risk for prostate cancer.

They are also leading to more targeted care options for some men with advanced prostate cancer, says Todd Morgan, M.D., Associate Professor of Urology at the University of Michigan.

This year nearly 165,000 men in the United States will be diagnosed with prostate cancer. More than 29,000 will die from the disease. The risk of prostate cancer is 74 percent higher in blacks than in whites. The reasons for this are still unclear.

Overall, men have a 1 in 9 chance of being diagnosed with prostate cancer. That rises to a 1 in 6 chance for African-American men. Men with a family history of the disease have a 1 in 5 chance of getting the disease themselves.

A man is two to three times more likely to get prostate cancer if his father, brother or son had it. This risk rises with the number of family members who have prostate cancer, breast cancer, and ovarian cancer. The age when a close family member was diagnosed is also a vital factor.

Some genes linked to prostate cancer also can cause breast, ovarian and other cancers. These genes have a 50 percent chance of being passed on to children. The most well-known of these genes are BRCA1 and BRCA2.

Understanding Brca1 And Brca2

ESMO Virtual Congress 2020: Imaging Based Prostate Cancer Screening ...

The BRCA genes were once again in the news this week, following results of a new drug, olaparib, which has been shown to work as an effective treatment for men with mutations in BRCA1 and 2, as well as other genes. Headlines on BRCA are familiar sight in the news by now, from their role in mens risk of prostate cancer to using them in prostate cancer spit tests.

The BRCA genes were once again in the news this week, following results of a new drug, olaparib, which has been shown to work as an effective treatment for men with mutations in BRCA1 and 2, as well as other genes. Headlines on BRCA are familiar sight in the news by now, from their role in mens risk of prostate cancer to using them in prostate cancer spit tests.

But what are the BRCA genes? Why is it such a problem when they change or ‘mutate’? And, what does a BRCA gene mutation mean for men?

What are the BRCA genes?

The cells in our body undergo a daily cycle of DNA damage and repair. In a normal day, the DNA in each cell can be damaged between 1,000 and 1,000,000 times. Luckily, we’ve evolved very efficient ways to either repair the DNA or destroy the ‘broken’ cells. One of these repair mechanisms are controlled by the BRCA1 and BRCA2 genes.

Because the BRCA genes are an important part of the repair process for the daily onslaught of DNA damage, any faults can mean mistakes start to build up in the DNA, which increases the chances of the cell becoming cancerous.

How can I be tested for BRCA 1 and 2 mutations?

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What Is A Mammogram

A mammogram is a low-dose X-ray procedure that produces images of the inside of the breasts. Mammography can detect some suspicious breast changes that are too small or too deep to be felt on breast examination.

A newer technology, called 3-dimensional mammography, or breast tomosynthesis, can be done as part of mammography screening. Although some studies have suggested that breast tomosynthesis may find more breast cancers and have fewer false positives than standard mammography, it remains unclear whether this is a better approach. All men should discuss this screening option in more detail with their doctor.

Typically beginning at 35 to 40, male BRCA mutation carriers should begin yearly clinical breast exams with a physician.

Predictive Genetic Tests For Cancer Risk Genes

Cancer is not usually inherited, but some types mainly breast, ovarian, colorectal and prostate cancer can be strongly influenced by genes and can run in families.

We all carry certain genes that are normally protective against cancer. These genes correct any DNA damage that naturally happens when cells divide.

Inheriting faulty versions or “variants” of these genes significantly raises your risk of developing cancer, because the altered genes cannot repair the damaged cells, which can build up and form a tumour.

BRCA1 and BRCA2 are examples of genes that raise your cancer risk if they become altered. Having a variant BRCA gene greatly increases a woman’s chance of developing breast cancer and ovarian cancer. They also increase a man’s chance of developing male breast cancer and prostate cancer.

BRCA genes are not the only cancer risk genes. Researchers recently identified more than 100 new gene variants associated with an increased risk of breast, prostate and ovarian cancer. Individually, these new gene variants only slightly increase the risk of cancer, but a combination could mean a high risk overall.

If you or your partner have a high-risk cancer gene, such as an altered version of BRCA1, it can be passed on to any children you have.

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Prostate Cancer Risk Assessment And Consideration Of Genetic Testing

Prostate cancer has long been recognised to have a familial component. Of all human cancers, prostate cancer is the most common familial cancer.

Most clusters of prostate cancer in families are multifactorial with no clear genetic cause that can be identified through genetic testing. The exception to this is when there is a co-ocurring family history of breast and / or ovarian cancer, or multiple young cancers in close relatives or where limited family history information is known to assess familial risk accurately.

Patients with a family history of breast and / or ovarian cancer, or close relatives with young prostate cancer may want to discuss if there is a role for genetic testing about their risk for prostate and other cancers. All men with metastatic or hormone resistant prostate cancer are now encouraged to speak with their Doctor about determining whether they carry an inherited cancer risk mutation.

What is the incidence of an inherited predisposition

The incidence of men with prostate cancer with an inherited predisposition to cancer is not high, probably in the order of 1-2% if you look at ALL men with prostate cancer.

Implications for the family

Implications of finding a faulty gene

New Zealand Guidelines

In 2018 the National Comprehensive Cancer Network in the USA recommended that all men, with advanced prostate cancer, should have genetic counselling and be offered genetic testing to determine if they have an inherited predisposition to cancer .

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Unique Aspects Of Genetic Counselling For Men With Prostate Cancer

Metastatic Prostate Cancer: Testing for BRCA Mutations

With the expansion of genetic testing criteria for prostate cancer,, improved insight is needed in to how men process the pre-test counselling discussion, understand their genetic results and handle the anxiety or guilt of having an inherited genetic mutation. Many men might have high satisfaction with their genetic evaluation experience, but some men may have difficulty with the process. Patients might need additional resources or support to understand their genetic results. For example, results are emerging that report that some men who undergo prostate cancer genetic testing might have limited understanding of VUS. Given that ~30% of men undergoing prostate cancer germline testing will have VUS reported,, this proportion represents a substantial number of men in need of reinforcement of information to enhance understanding of results and to limit propagation of misinformation in families.

Overall, identifying and addressing the clinical, genetic and psychosocial issues for men is important for facilitating decision-making on genetic testing and for supporting men in their cancer treatment and genetic evaluation experience.

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Results Could Lead To Earlier Cancer Screening

Finding out you have a genetic mutation linked to prostate cancer benefits the whole family. Other family members also may want to think about testing. This will tell them if they have inherited the same gene.

This is called “cascade testing” and is often offered to family members after a discussion with a genetic counselor. Men who are found to have a genetic mutation should start being screened for prostate cancer at a younger age than men without a family history of the disease.

The first step in screening is a prostate-specific antigen blood test. In general, the higher a man’s PSA level, the more likely he has prostate cancer. If prostate cancer is suspected, the doctor may suggest more tests. This could include a prostate biopsy . In a man with a genetic mutation, the doctor may use a lower PSA score to decide whether a biopsy is needed.

If you have an inherited risk of prostate cancer, your doctor may talk to you about certain lifestyle changes. These can include adding exercise, quitting smoking and keeping a healthy weight, which may lower your risk of cancer.

“Many men are surprised to hear inherited genes can play a major role in prostate cancer,” Dr. Morgan said. “But when I talk with men who may benefit from testing about why they should consider it, they often decide to get tested in order to receive more health information that can help them and their family make vital health decisions.”

Heritable Risks Of Prostate Cancer

Germline testing in men with prostate cancer is being performed more often since an important number of prostate cancer cases have a heritable component.1,2 Germline mutations in DNA repair genes, such as BRCA1/2, contribute to hereditary prostate cancer risk and are present in up to 11.8% of men with metastatic prostate cancer,3 compared with 4.6% among men with localized prostate cancer and 2.7% in persons without a known cancer diagnosis.3,4

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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.

Management Of Prostate Cancer Based On Germline Mutations

BRCA1/BRCA2 Cancer Risk DNA Test (Selected Variants Only)  DNA Access Lab

Historically, germline testing for cancer predisposition syndromes was performed to inform cancer risk, screening and cancer risk-reduction measures. However, advances in precision medicine have heralded a new era of expanded therapeutic utility of germline testing, which is now highly relevant to prostate cancer,,,,,, . Hereditary cancer management for syndrome-associated cancers including and beyond prostate cancer is also crucial,.

Genetically based management of men with early-stage prostate cancer is also evolving regarding active surveillance discussions. In one study, 6 of 11 men with BRCA2 mutations on active surveillance had significant upgrading of biopsy samples, either scheduled or prompted by serum PSA levels, compared with 283 of 1,200 non-BRCA2 carriers . Surveillance biopsies were performed at 12 years after prostate cancer diagnosis based on the cohorts included in the analysis. These early results point to the potential need to include germline test results, particularly for BRCA2 mutations, in active surveillance discussions further data are needed for definitive recommendations and current practice is evolving based on expert consensus,.

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What Do Brca1 And Brca2 Genetic Test Results Mean

BRCA1 and BRCA2 mutation testing can give several possible results: a positive result, a negative result, or a variant of uncertain significance result.

Positive result. A positive test result indicates that a person has inherited a known harmful variant in BRCA1 or BRCA2 and has an increased risk of developing certain cancers. However, a positive test result cannot tell whether or when the tested individual will develop cancer. Some people who inherit a harmful BRCA1 or BRCA2 variant never develop cancer.

A positive test result may also have important implications for family members, including future generations.

  • Both men and women who inherit a harmful BRCA1 or BRCA2 variant, whether or not they develop cancer themselves, may pass the variant to their children. Each child has a 50% chance of inheriting a parents variant.
  • All blood relatives of a person who has inherited a harmful BRCA1 or BRCA2 variant are at some increased risk of having the variant themselves. For example, each of that persons full siblings has a 50% chance of having inherited the variant as well.
  • Very rarely, an individual may test positive for a harmful variant not inherited from either parent. This is called a de novo variant. Such a variant is one that arose in a germ cell of one of the parents and is present in all the cells of the person who grew from that cell. The children of someone with a de novo variant are at risk of inheriting the variant.

What Can Genetic Testing Tell Men About Prostate Cancer

Genetic counseling and testing can be powerful tools in understanding the risk you and your family members face for developing cancer, as well as how to potentially treat it.

Test results may influence your:

  • Screening frequency: If you do not have prostate cancer but have a genetic mutation that increases your risk of developing it, your doctor may recommend more active surveillance from a younger age. This could include prostate-specific antigen testing or digital rectal exams .
  • Diagnosis: Men who have prostate cancer caused by a genetic mutation may be more likely to develop an aggressive form of the disease. Knowing this might impact your initial treatment options.
  • Treatment options: Men with specific genetic mutations may respond better to certain drugs and treatments. For example, men with metastatic prostate cancer who also have BRCA mutations may benefit from a targeted therapy known as a PARP inhibitor. Having certain genetic mutations also may affect eligibility for some clinical trials.
  • Relatives’ health decisions: Genetic testing doesnt just affect you. It also can benefit family members by helping them understand and manage their risk for cancer. Depending on your results, other family members may want to get tested. If the same mutation is discovered, they can begin screening for the disease from an earlier age, if recommended.

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