Oncologist’s View: Germline Testing in Prostate Cancer

Germline testing has become increasingly common for men with prostate cancer since the discovery that many men with advanced disease carry germline alterations in DNA repair genes.  The results of testing can direct treatment as well, as eligibility for clinical trials and may be important for family members.

Current National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer recommends offering germline testing to all patients deemed likely to have germline DNA repair mutations, i.e., men with metastatic, regional (node-positive), high-risk or very high-risk localized prostate cancer, or men meeting certain family or personal history criteria.1 Post genetic testing counseling is strongly recommended for patients who test positive for a gene mutation. Germline testing also has implications for patients’ family members (cascade testing). Urologists, oncologists, and other healthcare providers are all encouraged to take an active role in delivery and follow-up of germline testing.

Catherine H. Marshall, MD, MPH, Assistant Professor of Oncology at The Johns Hopkins School of Medicine, Baltimore, whose special interests include prostate cancer, spoke with David Ambinder, MD, for GU Oncology Now, about how she uses germline testing in her own clinical practice and how it impacts the management of patients she sees.

GU Oncology Now: How do you identify the patients with prostate cancer who are most appropriate for germline testing?

Dr Marshall: There are two things I think about when deciding whether or not somebody needs to be tested for germline genetic alterations. One is family history, and the other is their disease state. The patients I see are predominantly those with metastatic cancer, all of whom should undergo germline genetic testing. There are also data from retrospective studies suggesting that people who have certain pathologies like intraductal carcinoma detected on biopsy or radical prostatectomy may benefit from germline genetic testing, and I usually offer it to those patients as well. In the setting of localized disease without apparent metastasis, I usually recommend testing for those with high-risk or very high-risk disease.

With respect to family history, there are data in prostate cancer showing that it doesn’t necessarily correlate well with testing positive. However, men with a close family history of BRCA-related cancers not limited to prostate cancer, but also cancers such as breast, ovarian, and pancreatic cancer, should be considered for germline testing. A detailed family history is important, because some of our patients are not necessarily thinking about cancers that predominantly impact the women in their family, including cousins and aunts. So, it is important to ask about prostate and other cancers.

GU Oncology Now: Do you always test family members of prostate cancer patients?

Dr Marshall: I don’t test family members. I always test the person who has the disease, who is the patient I am seeing in clinic. Patients who test positive for a germline pathogenic alteration I refer for genetic counseling. In addition, I recommend that the family members go for genetic counseling to help them decide whether or not to be tested.

GU Oncology Now: If a patient tests positive for a mutation such as BRCA1/2, how would that impact their management?

Dr Marshall: In the metastatic castration-resistant setting, we have poly (ADP-ribose) polymerase (PARP) inhibitors approved for treatment, so the biggest change in management in that case would be their eligibility for PARP inhibitors. That could come from the results of germline genetic or somatic tumor testing. If they had alterations in BRCA1/2 or some other genes, they may benefit from a PARP inhibitor such as Rucaparib or Olaparib. There are many clinical trials looking at targeted therapy for other germline mutations such as ATM. So, if I’m considering a patient for a clinical trial, then I’ll also ensure that they have germline and somatic tumor testing, because many clinical trials now are targeted for a range of mutations.

GU Oncology Now:  Which clinical trials are you particularly interested in at this time?

Dr Marshall:  I’m involved in phase 1 and phase 2 studies of drugs that are targeting patients with ATM mutations. The ATM mutation is the most prevalent mutation in prostate cancer after BRCA1/2, and cancers with the ATM mutation don’t respond to PARP inhibitors as well as those with BRCA1/2. So developing drugs for that subpopulation will be important and it’s exciting that there is a lot of work in that area currently.

GU Oncology Now: What resources do you provide to patients who have positive germline genetic tests?

Dr Marshall:  We have genetic counselors within our cancer center, and when patients see our genetic counselors, they can also sign up for an internal registry we have and/or the PROMISE registry. This allows them to receive updates and learn more about the various gene alterations. Many companies that do germline genetic testing also offer genetic counseling for patients who test positive, so I let patients know about that resource. Other resources that I direct patients towards include the American Society of Clinical Oncology (ASCO) patient website (CancerNet) and the website of the Prostate Cancer Foundation. There is a lot of useful information available about genetic testing.

GU Oncology Now: How does genetic testing impact patients financially?

Dr Marshall: For most patients with metastatic disease who are receiving germline and somatic tumor testing, there tends to be minimal to no-cost. Sometimes, if the testing is done outside of the NCCN guideline recommended states, then there will be an associated cost. I usually counsel patients accordingly, and if there is a consideration of cost or if I get a notification from the person’s insurance company that the test isn’t going to be covered, I will reach out to the company to work with them on the available options and how to get it covered or get the fees reduced.

GU Oncology Now: How do you find genetic testing impacts a patient’s psychological wellbeing? Does it increase patient anxiety?

Dr Marshall: It’s variable. Most people, especially those with metastatic disease, want to have more information, especially if it could potentially broaden their treatment options. Then there is also the knowledge that the risk for the disease could be passed on to family members. For example, if a patient found out that he had a BRCA2 mutation and he had a daughter who was thinking about her risk for breast cancer, finding out that she had a BRCA2 mutation might affect her decision based on different recommendations for prevention and screening. So, most patients I come across want to know that information so that they can share it with family members. Of course, not everybody reacts that way, and I have had patients say, “I don’t want to know this information,” in which case we don’t do the testing.

GU Oncology Now: How important is germline testing in non-metastatic prostate cancer?

Dr Marshall: There are some patients who could benefit from germline genetic testing around the time of diagnosis, especially those at high and very high risk with localized disease. These are patients who are usually coming in to see the urologist well before they see medical oncology. These patients may benefit from genetic testing and, if available, genetic counseling.

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology. 

Reference

  1. NCCN Clinical Practice Guidelines in Oncology. Prostate cancer, version 1.2022. January 10, 2022; National Comprehensive Cancer Network. Accessed March 23, 2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459