Germlines 'Rich Source' of Prostate Cancer Info

Kate O'Rourke

July 21, 2020

Germline testing is an increasingly crucial component of the assessment, management, and treatment of prostate cancer. Once identified, relevant gene mutations can alert physicians when patients are at an elevated risk of disease or, when metastatic disease is already present, steer patients toward the precision therapies most likely to benefit them. But taking full advantage of germline testing requires staying up to date on the latest data, which is no small challenge for clinicians given how quickly the field is developing.

Veda Giri, MD

It was therefore welcome news when the Philadelphia Prostate Cancer Consensus Conference was convened in 2019 to take stock of these developments in germline testing and provide clinicians with guidelines on its use. With those guidelines now made available in the Journal of Clinical Oncology, Medscape reached out to lead author Veda Giri, MD, associate professor of medical oncology, cancer biology and urology, and director of cancer risk assessment and clinical cancer genetics at the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, to highlight what clinicians most need to know. This interview has been edited for length and clarity.

Medscape: Why did you decide to formulate these recommendations now?

Dr Giri: Germline testing for prostate cancer, which is basically testing for hereditary cancer gene mutations, is rapidly increasing. There are growing indications for testing in men with metastatic prostate cancer. For example, two poly (ADP-ribose) polymerase (PARP) inhibitors, rucaparib and olaparib, have recently been approved by the US Food and Drug Administration for men with metastatic prostate cancer after progressing through the initial lines of therapy. There is also an increasing potential role of genetic information in discussions of active surveillance for men with early-stage disease, as well as in the early detection setting.

These are exciting times in terms of the role of genetic testing for men with prostate cancer, but there are some key considerations or challenges that have been arising as these testing indications have expanded.

Some of these challenges are the rising volume of men meeting testing criteria who need to be evaluated and need genetic counseling. There is also variability in genetic testing indications from different guidelines that can be difficult to implement, which may lead to confusion for doctors in deciding who to test.

Furthermore, there is also expansion of laboratories and panel testing options for men, so thinking about which panels might be the optimal ones to use for testing of men with prostate cancer is another challenge. There is also an increasing demand for genetic counseling and concurrently, many nongenetic providers, such as urologists and oncologists, are ordering their own genetic testing.

All of these challenges led us to come together for an expert review of the data and to pull together a framework for responsible implementation of germline testing for prostate cancer.

What percentage of men harbor germline mutations for prostate cancer?

There is a range of prevalence of mutations that have been reported from various studies. They have ranged anywhere from 12% to 17%, particularly in men with metastatic disease.

Which men should be considered for germline prostate cancer genetic testing?

We tiered our recommendations when considering which men should undergo germline testing. "Recommend" indicated 75% or more agreement by consensus panel participants. "Consider" indicated that 50% to 74% of the panel agreed on a particular criteria.

The strongest recommendations for thinking about which men should be considered for germline testing were for all men with metastatic prostate cancer, whether they were castration-resistant or castration-sensitive, or family history suspicious for hereditary prostate cancer. That family history includes having a brother, father, or two or more male relatives diagnosed with prostate cancer at a young age (<60 years), or any men who had a relative who died of prostate cancer or a relative with metastatic prostate cancer.

Considerations for testing also would include men with advanced disease such as T3a disease or higher, men with intraductal or ductal pathology, or men who had grade group 4 or Gleason 8 disease or hi gher. Men of Ashkenazi Jewish ancestry could be considered for genetic testing, recognizing that there are higher rates of BRCA mutations in this population.

Additional suggestions for testing included a broader family history, such as having two or more cancers associated with syndromes related to hereditary cancers, such as hereditary breast or ovarian cancer and Lynch syndrome. A cancer diagnosis at a young age (<50 years) in a family member significantly raises the suspicion for considering that man for germline testing.   

Identifying men for genetic testing might inform treatment or management. For men with metastatic prostate cancer, the purpose of genetic testing might be to help inform their therapeutic decision-making. For example, would they be eligible for a PARP inhibitor or a clinical trial? In the nonmetastatic setting or the early-stage setting, perhaps the clinical role would be if a genetic mutation would help with active surveillance discussions. In men without a diagnosis of prostate cancer, the genetic result may inform prostate cancer screening discussions.

Which panels should be considered and which genes should be prioritized for testing?

We recognize that there are panels available for genetic testing for prostate cancer that range in size from focused panels, including 5 or 6 genes, for which there are guidelines available for management or screening. There are also prostate cancer-specific panels, which include approximately 15 genes, and broad cancer panels that include 80 plus genes.

In the metastatic setting, the priority genes that we recommend be tested are BRCA2, BRCA1, and the DNA mismatch repair genes. We endorsed broad germline panel testing that includes these genes and many other genes to identify men for treatment or clinical trials. Individuals should be tested for additional genes on the basis of personal or family history.

In the nonmetastatic setting, BRCA2 received a high consensus recommendation. Again, it is important to test additional genes on the basis of personal or family history. In the nonmetastatic setting, there was moderate consensus panel agreement to think about using reflex panels. Reflex panels are where you can start with a smaller set of genes for testing and then leave the option open for broader testing based on family or personal history.

In unaffected males, priority genes were BRCA2 and HOXB13, with a consideration for BRCA1, DNA mismatch repair genes, and ATM. For unaffected males, there was a moderate consensus to think about using reflex panels. Also, in unaffected males, test additional genes on the basis of personal or family history.

What prostate cancer-specific recommendations should be considered on the basis of genetic results?

In the metastatic setting, there was a strong recommendation for genetic testing to inform enrollment of men with prostate cancer in precision medicine trials. If men had BRCA2 mutations and BRCA1 mutations, that could help to open the door for PARP inhibitor therapy. I think this is especially important now with the two PARP inhibitor approvals of rucaparib and olaparib for men with metastatic prostate cancer. Germline mutations in the DNA mismatch repair genes may also inform response to anti-programmed death 1 (anti-PD-1) therapy, particularly through clinical trials.

For the early-stage setting, BRCA2 was recommended to include in active surveillance discussions regarding definitive treatment vs a surveillance approach to prostate cancer management.

For men without a prostate cancer diagnosis who are mutation carriers, referral to a specialty prostate cancer high-risk clinic and/or early detection trials was recommended. There was a strong recommendation that men who are BRCA2 carriers should start prostate cancer screening at age 40 or 10 years before the youngest prostate cancer diagnosis in a family. The same suggestion was made for BRCA1, HOXB13, ATM, and DNA mismatch repair genes, particularly MSH2 .

What barriers should be addressed to enhance prostate cancer genetic testing?

One of them is to raise providers' level of working knowledge about genetic testing for prostate cancer. We laid out some of the resources, courses, and tutorials that are available online or at in-person events to gain more information and knowledge about genetic testing.

Other barriers that need to be overcome include the need for increased advocacy and public awareness of prostate cancer genetic testing. Reimbursement for telehealth and telephone counseling is also needed to help expand access to genetic counseling. There is a growing need for virtual tumor boards or virtual genetic boards to help get that expertise out into the community regarding genetic testing and interpretation of results.

Redefining "actionability" in terms of insurance coverage for genetic testing is also important. Often, that actionability is for familial impact but is met with challenges for insurance coverage. Furthermore, engaging with primary care providers is important to enhance the population impact of germline testing for prostate cancer.

Dr Giri disclosed stock ownership in Novopyxis and speaker agreements with Janssen and Invitae.

Kate O'Rourke is a freelance writer in Portland, Maine. She has covered the field of oncology for over 10 years. 

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