Testing Picture Is Coming Into Sharper Focus for Familial and Hereditary Prostate Cancer

Raoul S. Concepcion, MD

Research into the biology of prostate cancer has resulted in a growing understanding of the molecular drivers of the malignancy, resulting in a rapid evolution of genetic testing that is poised to revolutionize the diagnosis and care of at-risk men as well as those who have the disease.

During a recent OncLive^® Peer Exchange^®, a group of prostate cancer experts provided insights into heritable cancers and the current state of genetic and genomic testing. The discussion made clear that much progress is being made but that numerous challenges have yet to be overcome.

“Treatment of castration-resistant prostate cancer has become increasingly complex, not only because of the number of novel therapies available with distinct mechanisms of action but also because of the lack of comparative data or validated predictive markers to help guide choice of therapy,” said Raoul S. Concepcion, MD, who served as moderator of the panel discussion. “However, there is light at the end of the tunnel. As new platforms for molecular testing continue to emerge, we are entering an era of more personalized therapy.”

Changing Role for PSA

Panelist Neal D. Shore, MD, commented on the need to translate advancements into clinical practice. “We’re just at the beginning of the beginning,” he said.Currently, prostate-specific antigen (PSA) testing remains the gold-standard screening tool for prostate cancer, but it has limitations, including an inability to determine genetic vulnerability to the disease or to distinguish clinically insignificant tumors that can be actively monitored from those that are likely to be aggressive and require immediate treatment.

Although PSA testing has revolutionized prostate cancer screening, enabling more patients with early-stage disease to be identified, it remains imprecise, and its utility has been called into question. In 2012, the United States Preventive Services Task Force (USPSTF) recommended eliminating screening for men in the general population, regardless of age.¹ The recommendation did not extend to PSA surveillance following diagnosis or treatment of prostate cancer.¹ The USPSTF’s stance has since softened. Although it still recommends against broad PSA-based screening in men aged ≥70 years, it encourages clinicians to discuss the benefits and harms of testing with men aged 55 to 69 years to enable them to make their own determination.²

Data on Heritability

Although some harms have been associated with PSA-based screenings, such as complications from potentially unnecessary biopsies, many clinicians have expressed concerns about eliminating PSA-based screenings altogether, including risks associated with not screening men who have a strong family history of prostate cancer or other heritable cancers that have been associated with prostate cancer.³It has been recognized for some time that certain populations are at increased risk of prostate cancer, even after adjusting for socioeconomic and other factors.³ In the Detroit Surveillance, Epidemiology, and End Results registry database, black men were 4 times as likely to develop advanced prostate cancer as their white counterparts, suggesting prostate cancer grows more rapidly in black than in white men or that black men have earlier transformation from latent to aggressive disease.⁴

Many of these disparities in prostate cancer center around genetic susceptibility, with environment, behavioral, and healthcare factors contributing.⁵ Eliminating prostate cancer disparities requires understanding the role that genes play and how they interact with a variety of non-gene—related factors to drive prostate cancer.⁵ As the Peer Exchange^® panelists noted, this is an exceptionally challenging endeavor with prostate cancer because studies continue to show just how clinically and genetically heterogeneous these cancers are, with many somatic and germline mutations contributing, adding to the challenge of deciphering the constantly evolving data.

Michael A. Carducci, MD, explained the difference between germline and somatic mutations, both of which can have risk and treatment implications. “Germline means you’re born with it—it’s in every cell, and it’s going to be with you from the beginning to the end—whereas somatic are things that happen over time, particularly in tumor cells. As genes mutate, they can mutate again, and there’s an ongoing process that, whether our therapies affect that or just the environment, multiple hits occur over time,” he explained.

Challenges of Genetic Testing

Recent data have suggested that germline mutations are particularly prevalent in men with advanced prostate cancer.⁶ “[Approximately] 12% of patients with metastatic prostate cancer will have germline alterations,” said panelist Evan Y. Yu, MD. In contrast, such germline alterations have been reported in 4.6% of men with localized prostate cancer and in 2.7% of men in the Exome Aggregation Consortium, which includes approximately 53,000 persons without a known cancer diagnosis.⁶ The deleterious germline alterations identified largely involve genes that mediate DNA-repair processes, such as BRCA2, ATM, CHEK2, BRCA1, RAD51D, and PALB2. ⁶ “[These genes] are not all created equal, and we don’t really understand just how important each one is to the development and progression of prostate cancer, but these are genes that clearly can be inherited and can predispose to the risk of prostate cancer,” Yu emphasized.A major hurdle with genetic testing has been determining which patients are candidates for these tests; however, the panelists agreed that genetic testing is crucial for individuals at high risk of developing prostate cancer. To improve identification of such individuals, they urged urologists and other clinicians to do a more thorough job of obtaining an in-depth family history, which can help clinicians guide at-risk patients to appropriate genetic counseling and testing.

“In the field of urologic oncology, if we do a family history, we might ask, ‘Do you have a family history of any genitourinary malignancies, prostate cancer, or bladder cancer?’ I bet most people don’t ask about breast cancer, ovarian cancer, or gastrointestinal malignancies, yet a lot of these can travel in some of these families that have germline alterations, so it’s important for us to all work toward taking better family histories,” said Yu.

Studies have shown that risk is increased not only in families with a significant history of prostate cancer but also in those with a history of a variety of other heritable cancers and related syndromes, including breast (male and female), renal, ovarian, colon, pancreatic, and bladder cancers, as well as melanoma and Lynch syndrome.³ The list of associated hereditary cancers is likely to grow as more studies are conducted and the role of various genes is worked out.

Genetic testing was also tentatively recommended for all patients with metastatic prostate cancer. “If you asked a trained geneticist when you should screen somebody, they would tell you that if the incidence is over 10%, you should look. And in looking at it—11.8%, almost 12% [of patients with metastatic prostate cancer have germline mutations]—one could argue that maybe we should be testing everyone with metastatic prostate cancer,” said Yu.

To better guide genetic testing and counseling referrals in the setting of inherited prostate cancer risk, a consensus statement was issued by the Sidney Kimmel Cancer Center and the Foundation for Breast and Prostate Health.⁷ The recommendations were presented at the 2017 American Urology Association Annual Meeting (Table 1).⁸ Full consensus guidelines have yet to be published, but a manuscript has been submitted. “Hopefully, that’ll come out in the near term,” said Shore. However, he acknowledged that “there was not [always] a tremendous amount of consensus among a lot of experts,” which he attributed to genetic testing still being in its infancy for prostate cancer.

Table 1. Inherited Prostate Cancer Risk: Consensus Recommendations for Genetic Counseling and Genetic Testing⁸

Other major challenges with genetic testing include determining which test to use and finding a genetic counselor who can properly interpret the results. “There are many companies that are out there that will do this genetic testing. It’s easy to do. You get it from saliva, or you can get it from blood, and most of them are offering some form of 1-800 call-in numbers and information,” said Shore.

However, not all provide comprehensive genetic counseling, and there are some concerns over marketing claims and data presentation, which prompted the Federal Trade Commission to issue a fact sheet to provide guidance to consumers seeking out direct-to-consumer testing services.⁹ However, even in the setting of physician-ordered genetic testing, there are not enough genetic counselors in the United States to interpret the results.

“My understanding is there are only about 3000 counselors nationally,” noted Shore. “And so, at many of our best academic institutions, there’s a several-month waiting list to get in, even in these places of higher learning and more sophistication. In most of the rest of the community, you might have to drive hours to find someone.”

Furthermore, although the significance of certain genetic mutations has been established, such as in BRCA2 and ATM, there are many genetic variants that have yet unknown or uncertain significance. “These variants may pan out to be something in the future. That’s when you really need a genetic counselor or somebody to do adequate follow-up as time goes on. It’s not a trivial issue that we can just all run off and do on our own in our clinics. We really have to do it right,” said Yu.

Role of Genomic Testing

Some institutions, such as Johns Hopkins, have tumor boards to assist physicians in interpreting the significance of patients’ test results, noted Carducci. “These are people who really know genetics, who can look through these panels to figure out what you should really be communicating to the patient,” he said.In addition to testing for heritability, numerous genomic tests are available to better characterize existing tumors and determine patients’ risk of developing aggressive disease (Table 2).^10-15 “There are panels of genes that tell you that you’re going to recur or you’re not going to recur...Urologists use [these tests] more frequently to predict whether a patient should go on active surveillance or whether they should get combination radiation therapy or other types of approaches,” said Carducci. “Patients need to know what test they are getting and what it means.”

Table 2. Common Genomic Tests for Men With Prostate Cancer^10-15

Considering Patient Choice

“The key question patients and their physicians have to ask is, ‘Is this a potentially lethal prostate cancer or a potentially indolent one?’ While we use clinicopathologic features to try to sort that out, we know that’s insufficient. So, we now use genomic tools that help us add information to the discussion,” said panelist Glen Gejerman, MD. “For example, the patient’s biopsy indicates he’s got low-to-intermediate risk cancer. We discuss the PSA and the Gleason score, but that patient probably should have an Oncotype DX study to give them a sense of their odds of progressive disease. It’s always important to discuss this with patients,” he said.Importantly, patient choice needs to be factored into the testing equation, said Shore. Patients need to be aware of the ethical, legal, and social implications of any test they are receiving. Common concerns with testing might be employment or insurance discrimination. Currently, the Genetic Information Nondiscrimination Act, which was passed as federal law in 2008, protects against such discrimination, although its protections do not extend to military members or to long-term care insurance, and there is always the risk of repeal.¹⁶

Take-Home Message

Other patients might simply not want to know whether they are predestined to develop a disease or may not want to share that information with their family. “For some people that just might be too much [information] from an emotional standpoint—from a psychological standpoint. That’s a heavy load,” said Concepcion. These are other issues a genetics consultation can help patients work through.There are still many complex issues to be worked out and many more questions may arise before the role of genetic testing is clearly defined in prostate cancer. Until more clarity is provided, the panelists urged clinicians to continue to follow the data to the best of their ability and to improve their taking of family histories.

“Something that we can all do right now is take a better family history. It’s a little bit of a different take because it’s not just about potential therapeutic or prognostic implications for patients but has potential implications for patients’ family members,” said Yu. “In oncology, we always want to cure cancer if we can. If we can’t, our goal is to at least extend survival and improve quality of life. But this is an opportunity where we might be able to prevent cancers—to get them before they even start by identifying patients and families that are at risk.”

References

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9. Federal Trade Commission. Direct-to-consumer genetic tests. consumer.ftc.gov/articles/0166-direct-consumer-genetic-tests. Published January 2014. Accessed August 3, 2017.
10. Genomic Health Inc. OncotypeIQ. About the Oncotype DX genomic prostate score assay. oncotypeiq.com/en-US/prostate-cancer/healthcare-professionals/oncotype-dx-genomic-prostate-score/about-the-test. Accessed August 4, 2017.
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