How prostate cancer genetics will change front-line care

Leonard G. Gomella, MDOngoing genetic discoveries continue to enhance our knowledge of conditions such as prostate cancer. In this interview, Leonard G. Gomella, MD, provides an update on prostate cancer genetics, discusses the recent Prostate Cancer International Consensus Conference, and outlines why urologists should conduct more extensive family histories of their prostate cancer patients. Dr. Gomella is chairman of the department of urology and senior director for clinical affairs, Jefferson Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia. Dr. Gomella was interviewed by Urology Times Editorial Council member Stacy Loeb, MD, MSc, assistant professor of urology and population health at New York University Langone and the Manhattan VA, New York.

What percentage of prostate cancer cases are caused by genetics?

Most cases of prostate cancer are caused by genetic alterations. The problem is that when you break it down to very specific, identifiable, inherited prostate cancer risk genes, we have very few at the present time. All tumors are driven by genetics, but when you look at specific inherited risk, our current level of understanding is that about 10% to 15% of patients can have a clearly identifiable inherited component to their prostate cancer.

This is a very active area of research. Please talk about what’s new and exciting in the world of prostate cancer genetics.

The completion of the Human Genome Project in 2003 opened the door for not only basic science advances but drove the clinical applications of genomic and genetics. Urologists have recently become very familiar with the genomics of prostate tumors studying somatic mutations to help guide treatment decisions. The area we are now becoming interested in is known as germline testing or the study of inherited genetics. We’ve been able to identify more and more inherited genetic alterations in medicine. The traditional ones that we have the most familiarity with are the BRCA1 and BRCA2 abnormalities associated with hereditary breast and ovarian cancer. But it turns out that a significant number of men can also have BRCA1 or BRCA2 genetic alterations that can confer an increased risk of prostate cancer.

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Several newer genes such as HOXB13 and ATM have also been identified as being associated with prostate cancer. Importantly, we’re recognizing that not only can prostate cancer run in families but it also can be related to breast cancer, ovarian cancer, pancreatic cancer, melanoma, and Lynch syndrome in other family members. This area of research is giving us some direction on how urologists can think about approaching our patients concerning the need for more detailed family histories.

Lastly, genetic panels are now being offered by commercial laboratories specifically for prostate cancer. Urologists need to be aware that these panels are out there, and the best way to utilize these genetic testing panels is something we’re all going to have to learn in the coming years.

Next: What was discussed at the Prostate Cancer International Consensus Conference

You recently served as co-chair for the Prostate Cancer International Consensus Conference on the role of genetic testing for inherited prostate cancer risk. Could you talk about the rationale for this meeting and what was discussed?

With all the recent advances in genomics and genetic testing, we realized that there was an information void when it comes to urologists and other prostate cancer experts in providing guidance to patients concerning the possibility of inherited prostate cancer risk. At the Sidney Kimmel Cancer Center at Thomas Jefferson University, in collaboration with the Foundation for Breast and Prostate Health, we brought together approximately 70 stakeholders in the field of prostate cancer and genetics including urologists, radiation oncologists, medical oncologists, genetic counselors, basic science researchers, ethicists, and patient advocates. This was the first centralized, comprehensive, and multidisciplinary consensus to address a working framework for genetic evaluation of inherited prostate cancer in the multigene testing era.

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At this 2-day meeting held this past March, we presented the latest information on inherited prostate cancer risk and the role of genetic testing and developed a series of consensus questions to answer. Topics addressed concerned the influence of family history, which genes confer the most risk for inherited prostate cancer, and what is the best approach for patients and providers in deciding on whom to perform genetic germline testing. When you look at the literature, we do have some general guidelines about genetic testing for inherited prostate cancer risk and these often focus on male relatives of women with inherited breast and ovarian cancer syndromes. At the present time, we are lacking on consistent and specific recommendations for men. This area should be of significant interest to urologists since we’re usually on the front line of diagnosing prostate cancer. We felt it was important to gather a group and come up with some reasonable guidelines to inform patients and providers on how to best approach genetic counseling and genetic testing for inherited prostate cancer. The consensus preliminary findings were first presented at the Society of Urologic Oncology session at the AUA annual meeting in Boston by Dr. Veda Giri and the consensus paper is currently under journal review.

What were some of the recommendations that were made?

Shared decision-making about undergoing genetic testing was considered very important. We recognize that discussions about potentially inherited diseases are not easy ones to have. We also recognize that a lot of us, urologists in particular, are not very familiar with how to approach genetic counseling.

We agreed that urologists need to conduct a more extensive family history than we are used to doing. Family history of prostate, breast, and ovarian cancer are important but so are other cancers that you don’t normally think about being related to prostate cancer like pancreatic cancer, melanoma, and Lynch syndrome. For example, if a review of family history reveals hereditary ovarian breast cancer syndrome, in which multiple female relatives are afflicted, a man with newly diagnosed prostate cancer might consider genetic testing for prostate cancer risk.

A more established concept is that if multiple young male members of a family under the age of 55 are afflicted with prostate cancer, you should probably consider genetic testing and counseling. Conditions such as Lynch syndrome, also called hereditary non-polyposis colorectal cancer, can have an association with upper tract urothelial carcinoma as well. It has been discovered that the mismatch genes that may be involved with Lynch syndrome may also be a component of prostate cancer. Having urologists do a more extensive family history is something that we should start considering and when they identify these hereditary conditions, strongly consider referral to a genetic counselor.

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The consensus panel members did have a little bit of a disagreement on how much individual genetic testing and counseling a urologist, medical oncologist, or radiation oncologist should offer patients. Most consensus participants agreed that if genetic the testing is being considered, the patient would probably be best served by a professional genetic counselor. While many genes are now available on commercial testing panels, the genes that the group felt had the most potential contribution to inherited prostate cancer risk assessment included BRCA1/2, HOXB13, TP53, ATM, and Lynch syndrome DNA repair mismatch genes.

Next: What is the future?

What is the future? Do you think clinical trials will be stratified based on genetic factors or that genetic information will be used for entry into clinical trials? Will screening and treatment in the future all be based on genetics?

All of the trends you mentioned are going to come true. We are already starting to see germline mutations direct new experimental treatments. For example, clinical trials are now in place to determine if a patient has a germline BRCA1/2 abnormality and metastatic castrate-resistant prostate cancer has a better response to PARP inhibitors as opposed to other standard therapies.

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The role of prostate cancer genetic panel testing-how many different genes and which genes to check as part of a patient’s screening-is going to evolve. We don’t have directionality yet on how to best use these panels for screening or treatment. There are major trials ongoing in England, such as the PROFILE study, examining the question on how germline testing correlates with targeted prostate cancer screening efforts. Hopefully in the next 3 to 5 years, we will see how screening patients for germline mutations may direct how aggressively-or perhaps less aggressively-we might screen them for prostate cancer.

What are some final take-home messages for urologists? Should we be taking much more detailed family history than we had previously, and do we need to consider genetic referral for patients who have high-risk disease and a strong family history?

Yes, those are both items that we need to start thinking about as urologists because we’re central in the diagnosis and management of these patients. It’s important to understand that this area will become part of our so-called “precision medicine” portfolio in the coming years where we no longer rely simply on family history, physical exam, and laboratory parameters but do a deep dive into germline genetics and tumor genomics to determine the best way to not only screen patients but also to treat both localized  and metastatic disease.

Urologists are very familiar with concept of studying somatic mutations in the primary tumor. We now need to keep our eyes open to germline genetic testing and how this will direct screening and treatment of localized and advanced disease. With the increase in the numbers and types of genetic panel testing for prostate cancer being brought to the marketplace, we need to work with our colleagues in the areas of genetic counseling to determine the best way to use this information in clinical care.

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