Brian T. Helfand MD PhD - Renal and Urology News

Ask the Experts – Brian T. Helfand, MD, PhD

Expert Perspective
Germline Testing for Prostate Cancer Active Surveillance
Brian Helfand, MD, PhD

Brian T. Helfand, MD, PhD

Practice Community: Evanston, Illinois

Hospital and Institutional Affiliations: Clinical Associate Professor, Richard Melman Family Chair of Prostate Cancer, and Clinical Lead for the Program for Personalized Cancer Care at NorthShore University HealthSystem.

Practice Niche: Urologic Oncology, Prostate Cancer

Dr Helfand gave a presentation on germline testing for prostate cancer prognosis and its implications for active surveillance at the recent 2019 Philadelphia Prostate Cancer Consensus Conference: Implementation of Genetic Testing for Inherited Prostate Cancer, which was sponsored by the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia.

Question 1. You have proposed germline testing for all patients at the time of prostate cancer diagnosis, even those with low-risk disease. Why?
Answer
As clinicians, we do a relatively bad job at identifying who is at high risk of prostate cancer. When you look at prostate cancer in general from the time of diagnosis to the time of biopsy and treatment, there’s so many inherent errors that are built into the most common tests that we utilize. This starts with taking a family history—which is currently the recommended standard for obtaining germline genetic testing. A large proportion of men do not know their family history. Therefore, it is not surprising that when you look at published studies, 60% of men who actually report no risk factors like family history of prostate cancer will harbor a mutation. These studies have included prostate cancer patients with advanced and localized prostate cancer. That’s why I believe universal testing should be recommended for all men diagnosed with cancer of any grade or stage. Genetic testing has become inexpensive, and the stakes are so high, that I believe genetic testing is worthwhile for all men with high- and low-risk disease.
Question 2. Is there a prostate cancer genetic testing protocol at your institution?
Answer
We offer every man diagnosed with prostate cancer the opportunity for genetic testing. Usually, as a urologist, I initially discuss that testing with my patients. We talk about the risk and benefits of genetic testing and its relevance to prostate cancer decision-making. And ultimately, I order the test and if they test positive for mutations or have a variant of unknown significance, I continue to counsel them regarding the implications for prostate cancer management and also coordinate care with genetic counselors. The genetic counselors discuss implications and screening strategies for other cancers. In addition, they initiate discussions with the family members for cascade testing. In addition, if our genetic counselors identify male family members with germline mutations associated with prostate cancer risk and aggressiveness (for example, BRCA2 or ATM mutations), they will refer them to our clinic for patients who are at high genetic risk for prostate cancer for screening discussions. Interim results from the IMPACT trial (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in men at higher genetic risk and controls) have shown that earlier screening of men with mutated BRCA2 genes identifies more men with higher-grade disease.1
Question 3. How could genetic testing results be incorporated in active surveillance decision-making?
Answer
One of the big issues in prostate cancer is overall risk assessment and distinguishing who has high-grade disease and who doesn’t. There are really no perfect tests by which we can currently ascertain that information. For active surveillance, I foresee that we would focus on a relatively small panel of genes that have been associated reproducibly with aggressiveness. Genes like BRCA2, ATM, and probably MSH2 that pretty reproducibly have an association with aggressive, metastatic and lethal prostate cancer. The findings could inform decisions about whether to recommend a patient for active surveillance. As such, genetic testing has already been included as part of our assessment in our active surveillance program.
Question 4. What would you advise a patient with Grade Group 1 disease who might otherwise be a candidate for AS, but has a BRCA2 mutation?
Answer
If you take all men with Grade Group 1 cancer, over 30% to 40% of them will progress or be reclassified over time while on active surveillance. Just by having that BRCA2 mutation, a patient will have an almost 5-fold higher risk of being reclassified as Grade Group 3 or higher during AS compared with men who have the same initial biopsy pathology. I tend to steer these patients towards earlier treatments because of the data demonstrating that these mutations are significantly associated with higher frequencies of higher grade tumors, metastatic and lethal cancers.
Question 5. Should genetic testing results be used in guiding AS follow-up protocol?
Answer
I believe genetic testing should be used routinely as part of AS surveillance protocols. Specific mutations such as BRCA2 and ATM have reproducibly been associated with worse clinical outcomes. As such, I have an informed conversation that discusses the risks of these mutations with my AS patients. However, despite the increasing evidence, I recognize that not all men and clinicians are accepting of upfront treatment in the AS setting among mutation carriers. Therefore, at a minimum I would recommend closer surveillance (eg, more frequent biopsies) for relevant germline mutation carriers who desire to continue AS.

Reference

  1. Page EC, Bancroft EK, Brook MN, et al. Interim results from the IMPACT study: Evidence for prostate-specific antigen screening in BRCA2 mutation carriers [published online September 16, 2019]. Eur Urol. doi:10.1016/j.eururo.2019.08.019