Genetic testing’s role centers on advanced prostate cancer

Some 15% of men with metastatic castrate-resistant prostate cancer have a clearly identified germline genetic inherited component to their disease, and these patients may soon benefit from new treatment options. In this interview, Leonard G. Gomella, MD, discusses the increasingly important role genetic testing plays in prostate cancer, current obstacles to testing, and when and how it will be carried out.

Dr. Gomella is professor and chair of urology at Thomas Jefferson University and senior director for clinical affairs at the Sidney Kimmel Cancer Center, Philadelphia. He was interviewed by Richard R. Kerr, content channel director of Urology Times.

Currently about what percentage of patients with prostate cancer have an identifiable inherited component to their disease?

While the majority of prostate cancers are sporadic, approximately 30% of prostate cancers can be identified as being inherited or familial in nature. Prostate cancer is connected genetically to mutated genes that also increase the risk of melanoma, pancreatic, breast, and ovarian cancer not only in the individual but within the family as well.

When you get down to specific clinical situations in prostate cancer, about 15% of patients with metastatic castrate-resistant prostate cancer have an identified germline genetic inherited component. In localized prostate cancer, about 5% of patients have an identifiable genetic component. These numbers in localized disease may not seem big, but these are the patients who are likely to progress to life-threatening prostate cancer and this group is now receiving increased research attention.

There are new therapeutics being developed for advanced prostate cancer that are based on genetic testing. One such example is the poly (ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors stop the PARP from repairing cancer cells and cause the cells in the presence of a mutated DNA repair gene to die. When the PARP inhibitors get approved for the treatment of advanced prostate cancer they will require a companion diagnostic test that will have to show that the patient with metastatic castrate-resistant prostate cancer has a specific germline mutation to be eligible for treatment.

What have been the major developments in prostate cancer genomics and germline testing in particular over the last year or two?

What we’re seeing is that patients with advanced and aggressive prostate cancer are increasingly undergoing germline genetic testing for inherited prostate cancer risk, not only in the individual but also in their family members. Testing other family members for an inherited cancer risk is known as “cascade testing.” More medical organizations are advocating that men who have BRCA1, BRCA2, and related abnormalities should be aggressively screened for prostate cancer. This is a big take-home message over the last few years.

Our colleagues in Europe, particularly in England, who have done extensive population studies, are promoting this. They’ve shown that if a man has one of these inherited abnormalities in the DNA repair pathway-BRCA1 and BRCA2 are the highlights right now but there are others-he should undergo more focused screening for prostate cancer than a man who does not have such abnormalities.

Today, how does a man without a diagnosis of prostate cancer come to be identified with one of these mutated genes? Most likely he has a relative who has had aggressive prostate cancer and has undergone genetic testing or he’s had a female first-degree relative-mother or sister-who had hereditary breast or ovarian cancer, and it’s been recommended based on a family pedigree that he undergo germline genetic testing.

Next:Discussing the second International Prostate Cancer Consensus Conference

The second International Prostate Cancer Consensus Conference was held in Philadelphia in October 2019. The meeting emphasized implementation of genetic testing for inherited prostate cancer. What have been the major developments in how genetic testing is implemented?

The second International Prostate Cancer Consensus Conference focused on the practical aspects of testing for these genetic alterations in men with prostate cancer. The consensus sought to optimize testing strategies integrating evolving genetic data and growth of panel options, recommend consistency in testing indications and genetically based management, and identify alternate evaluation models addressing a shortage of genetic services.

How should men with prostate cancer be evaluated for the need to undergo genetic testing? Ideally, a provider identifies a patient as having a potential genetically inherited mutation that predisposes to prostate cancer or the patient has an advanced or aggressive cancer. A prostate cancer genetic panel can be ordered, or the patient can be referred to a genetic counselor.

The reality is that not all men with prostate cancer need to undergo genetic testing. In the ideal setting, a genetic counselor would go over the characteristics of the individual’s tumor, the family pedigree, and what other cancers may be in the family and come up with a reasonable approach to testing. There would be a recommendation for the individual to undergo genetic testing or for genetic testing in family members.

How should we handle genetic testing when there is currently limited access to genetic counselors in the United States who have expertise in prostate cancer? The fact is that we have a nationwide shortage of genetic counselors. What alternative evaluation models are needed was a central theme of our second consensus conference. Many genetic testing reference labs have helped to deal with this limitation by providing basic initial genetic consultation by phone.

What are some of the current best practices in the use of these tests?

Right now, the best practices are genetic testing in men with advanced metastatic castrate-resistant prostate cancer, metastatic prostate cancer, and newly diagnosed prostate cancer with adverse features. Organizations supporting genetic testing for this group of high-risk men include the National Comprehensive Cancer Network (NCCN). As noted, the PARP inhibitors, which are already available and FDA approved for ovarian and breast cancer, are a significant driver of this. We’re now looking for PARP inhibitors to be approved, probably sometime in the first half of 2020, for metastatic castrate-resistant prostate cancer.

The PARP inhibitors are found to be most effective in cases where the patient has an inherited mutated gene in the BRCA1/BRCA2 and other DNA repair pathway. The approval for the PARP inhibitors will include pharmacogenomic testing to e determine eligibility for these drugs. From a best practice standpoint, using genetic testing in men with advanced castrate-resistant prostate cancer is a good approach because it will give men with difficult-to-manage prostate cancer more options, including participation in clinical trials.

Next: Does genomic testing have a role beyond metastatic disease?Does genomic testing have a role beyond metastatic disease?

We’re really just beginning to explore that. If a patient has high-risk prostate cancer-a very high Gleason score, high PSA, advanced clinical stage, adverse features, or intraductal carcinoma-while his cancer might not yet be metastatic or castrate resistant, NCCN guidelines indicate he should undergo genetic testing. What’s happening, as with everything in medicine, is that you start with the most advanced clinical scenarios and then begin to investigate earlier stages of a disease.

I believe one of the most exciting areas for genomic testing is the area of active surveillance. One paper in particular by Dr. Ballentine Carter from Johns Hopkins looked at doing genetic profiling on men who are in active surveillance (Eur Urol 2019; 75:743–9). It showed that if you have an altered inherited DNA repair pathway gene like BRCA1 or BRCA2, you are more likely to fall off the active surveillance pathway because of grade progression on subsequent biopsy.

Did the consensus conference address gaps in prostate cancer guidelines?

We identified a series of priority genes that should be used to direct precision treatment of prostate cancer such as BRCA1, BRCA2, MSH2/MSH6, ATM, and other mismatch repair (MMR) genes. In non-metastatic PCA, consensus testing recommendations emerged encompassing personal, pathologic, and family history criteria. Priority genes for active surveillance discussions primarily focused on BRCA2 and ATM. Our 2019 consensus paper is currently in press in the Journal of Clinical Oncology, and we are hopeful that the recommendations of our interdisciplinary group will help address issues in prostate cancer guidelines. The NCCN has been very good at rapidly responding to new developments and updating their recommendations in this area over the last 2 years.

What other issues were discussed at the consensus conference?

There was a great deal of discussion about the best way to share the information from genetic testing with the patient and the best way to counsel them. The federal GINA (Genetic Information Nondiscrimination Act of 2008) laws protect individuals from health insurance and employment discrimination who have undergone genetic testing. Providers who are ordering genetic testing should be aware that these laws may not apply to patients who are interested in long-term health care, disability insurance, and related issues.

An area of group discussion centered on whether genetic testing should be done reflexively. Or should you actually have informed consent before the test is ordered? A focus of this discussion was the fact that we have such a significant shortage of genetic counselors in the United States, and we need to look at genetic testing alternatives until we build up an adequate pool of genetic counselors.

How are practicing urologists being educated about genetic testing for prostate cancer?

I recommend keeping up with the latest NCCN guidelines. I don’t think urologists are as engaged in this area as other medical specialists because genetic testing came into our clinical practices very quickly. The department of urology at the Sidney Kimmel Cancer Center conducted the first international consensus on genetic testing for inherited prostate cancer risk in 2017 because we realized that scientific information was coming at a very rapid rate, but it was not being acted upon in general urology practice. I believe we need to improve training of our residents, in particular, in this area.

Providers who are trained in medical oncology tend to have more background in this area, simply because breast and ovarian cancer are so far ahead of prostate cancer in the genetic testing world. Most fellows who are completing medical oncology training have had some formal genetic counseling and testing experience because of the well-established world of breast cancer genetic testing.

We are very interested in having urologists get up to speed and include genetic testing in our training programs. The Society of Urologic Oncology and the AUA have partnered in educational programs in advanced prostate cancer for residents, fellows, advanced practice providers, and practicing urologists. We have incorporated educational modules that address genetic testing and what are the best practices today. We need to do more to have urologists engaged considering the PARP inhibitors are oral agents that many urologists who treat advanced prostate cancer will begin to prescribe.

Next: Who should be conducting genetic testing for prostate cancer?Who should be conducting genetic testing for prostate cancer?

Most urologists outside of major medical centers don’t have easy access to prostate cancer-trained genetic counselors and can easily order genetic panel testing from a variety of commercial labs. Urologists are used to asking male patients if their father or grandfather or brothers had prostate cancer. We can’t just ask those family history questions anymore. We’ve got to expand our questioning and ask about pancreatic, breast, and ovarian cancer, melanoma, as well as Lynch syndrome and colorectal cancer. The urologist needs to start asking these questions and identify that a patient may have a familial hereditary or potentially inherited form of prostate cancer. (Also see, “Hereditary vs. inherited prostate cancer")

Do we know yet precisely which genetic mutations to look for in prostate cancer, or is that a work in progress?

There are a lot of candidate genes; the list includes at least 20 or 30 genes. We have what I would call the “top” mutated genes, most of which are DNA repair pathway abnormalities: BRCA1, BRCA2, ATM, CHEK, and EPCAM, among others.

We certainly don’t have all the genes identified yet. If you look at the commercial prostate cancer panels, most will have a core of those 10 to 12 most common genes, but many of the genetic testing companies test for many more genes than that. Unfortunately, we still don’t know how to interpret a lot of those other genes, specifically when it comes to prostate cancer. (See table on page 20 that summarizes some of the most common mutated genes that increase prostate cancer risk.)

Are there genetic tests for prostate cancer that are in development and might become commercially available?

There is considerable work being done with single nucleotide polymorphism (SNP or “snip”) tests. These tests look not necessarily at identified genes that are mutated but at identified variable DNA sequences-SNPs associated with prostate cancer. Some researchers feel that looking at a few short sequences of DNA as opposed to a whole known gene may be more useful in some patients. Those tests are just becoming available.

Is there anything else you would like to add?

This is an area that is exploding in urology, and urologists need to keep abreast of what’s happening. We are working on alternatives to identify ways to address a shortage of genetic services. At the Sidney Kimmel Cancer Center, our team members are involved in graduate training programs and are developing an app to help medical oncologists and urologists potentially screen patients for appropriate prostate cancer genetic testing.

Next: Hereditary vs. inherited prostate cancerHereditary vs. inherited prostate cancer

It’s important to draw a distinction between hereditary and inherited prostate cancer, according to Leonard G. Gomella, MD.

“Hereditary prostate cancer is a much broader umbrella that suggests there may be genetic alterations that are passed down from generation to generation that may increase the risk of developing an aggressive prostate cancer or other cancers known to cluster in families,” Dr. Gomella said. “Inherited prostate cancer, by comparison, involves genes such as the HOXB13 gene, a gene in family members where multiple younger men develop aggressive prostate cancer. Most of the mutated genes we’re talking about in prostate cancer are DNA damage response genes-BRCA1, BRCA2, ATM, and others. They can result in increased heredity prostate cancer risk or may simply suggest that there may be something going on in the family that increases the risk of other associated cancers in multiple family members.

“It’s also important to point out that these mutated genes do not cause prostate cancer,” he pointed out. “This is a common misconception. They don’t cause the cancer, but it turns out if you have one or more of these of these mutated genes, it does something to make prostate cancer a more aggressive, more lethal form.”