Hereditary Prostate Cancer—What Urologists Should Know

Lawrence I. Karsh, MD

Prostate cancer is the most prevalent solid tumor in men over 50 years of age and the second-leading cause of cancer-specific mortality in the United States today. It was estimated that in 2018 alone, 165,000 men would be given a diagnosis of prostate cancer and more than 29,000 men would die from the disease.¹ Most cases are localized at the time of diagnosis, but de novo metastatic disease is on the rise and may represent 4% of initial presentations. The median ages at diagnosis and death are 66 and 80 years, respectively. The statistics are worse for African American men, who are nearly twice as likely as Caucasian men to develop prostate cancer and more than twice as likely to die of the disease.² In addition, African American men with prostate cancer are more likely than Caucasian men (7.3% vs 2.2%) to have mutations in the DNA repair genes BRCA1 and BRCA2 and thus experience more aggressive prostate cancer with a shorter time to metastasis.³ Estimates vary, but 20% to 30% of all men treated for localized disease develop biochemical recurrence and eventually progress to terminal metastatic castration-resistant prostate cancer (mCRPC).⁴

Historically, urologists have been the primary caretakers for men with localized prostate cancer. The first decade of the 21st century heralded a renaissance of drug development for the management of patients with mCRPC. Seven new therapies gained FDA approval for both metastatic and nonmetastatic CRPC. Many of these agents are oral and have a very manageable adverse event profile. As a result, urologists have become more active in the delivery of oncologic care across the spectrum of prostate cancer, even for patients with advanced prostate cancer.

In March 2007, the US Department of Health & Human Services launched the Personalized Health Care Initiative with the goal of integrating gene-based technologies into healthcare delivery so that therapies would be better tailored to individual patients.5 A year later, with the goal of barring the use of genetic information in health insurance or employment, Congress enacted the Genetic Information Nondiscrimination Act (GINA). Although far from perfect, it prevents employers from using genetic information as the basis for denial of health insurance and decisions about hiring, firing, and promotions.

The drive toward precision medicine has resulted in a deeper understanding of the molecular biology of cancer development. There are still gaps in the understanding of the respective roles of genetics and gene mutations, diet, and the environment. These factors, particularly the genetic component, are key to malignant cell development and, ultimately, cancer. As a result, there is a growing need to incorporate genetic counseling and testing into comprehensive cancer care.

Along these lines, urologists are becoming more and more aware that lethal prostate cancer has a distinct hereditary component. Just as hereditary testing has been incorporated into comprehensive care models for many specialties, this evolving platform must now be incorporated into advanced prostate cancer care. The tools for doing this are becoming increasingly available. The FDA recently approved a next-generation sequencing (NGS) testing panel for several hundred genes in solid tumors, thus advancing the current era of personalized molecular oncology. This test may justify the use of specific therapies across tumor types, regardless of initial labeling.

Although the term genetics has traditionally comprised individual genes and their inheritance patterns (some diseases, such as sickle cell anemia and cystic fibrosis, result from alterations in an isolated gene), the modern definition includes multiple gene inheritance patterns. Thus, modern genetic testing relies on genomics, encompassing an organism’s entire genetic makeup (genome) and an extensive number of genes interacting with one another and the environment.

Germline mutations are almost always inherited. They are present in every cell of the body but only half of all eggs and sperm. A child of a germline mutation carrier has a 50% chance of inheriting that gene. Multigene panels evaluate blood or saliva cells for the presence of these germline mutations. Somatic mutations develop when a cell becomes malignant. These changes can be found only in the tumor. When a germline mutation is present in a tumor suppressor gene, such as BRCA, it may accelerate the accumulation of somatic mutations, thus increasing the chance that cancer will develop.

NGS is performed mainly with tumor tissue, but liquid biopsies (blood based) are under development, using different assay types including circulating tumor cells (CTCs) and cell-free DNA. These new technologies may give us real-time information about tumors as they progress and mutate further. Urologists are familiar with somatic genomic tissue-based tests that inform treatment decision making by identifying patients with localized prostate cancer who may benefit from active surveillance versus treatment. However, when it comes to germline genetic testing, we have not caught up with our oncology brethren. Perhaps this is partly due to the prior lack of data on the hereditary component of prostate cancer.⁶

Whereas all cancer is genetic but not all cancer is hereditary, the risk for cancer can be categorized as sporadic, familial, and hereditary.

Sporadic cancers are the most common and occur by chance. Typically, the patient does not have relatives with the same type of cancer.

Familial cancer is likely to be caused by a combination of inherited genetic and environmental factors. Patients with familial cancer may have 1 or more relatives with the same type of cancer, but there does not appear to be a specific pattern of inheritance. Familial patterns are seen in certain cancers (eg, breast, colon, and prostate).

Hereditary cancer involves an altered gene passed down from parent to child (germline). A single mutation is not likely to cause cancer; however, it will increase an individual’s chances. With 1 damaged gene already present, it would take fewer mutation-causing events over a patient’s lifetime for cancer to result. In hereditary cancer, patients are more likely to have relatives with the same or related types of cancer. The hallmark of hereditary cancer is the potential development of multiple cancers, rare cancers, and, often, cancers that are more aggressive biologically than sporadic cancers. Hereditary cancers may occur at earlier ages (<50 years) than other cancers but not always. In addition, some races and ethnicities may have a greater risk for hereditary cancer (eg, Ashkenazi Jewish individuals).

Hereditary-linked cancers represent 5% to 10% of patients with prostate cancer. BRCA1/2 mutations are linked to prostate cancer, and germline BRCA1/2 mutations are associated with worse prostate cancer outcomes, as reported by Castro et al in a study evaluating response of BRCA carriers versus others to conventional treatments.⁷ Another study found that 11.8% of 692 unselected men (regardless of family history) with metastatic prostate cancer demonstrated an inherited pathogenic mutation and concluded that routine testing for all men with metastatic prostate cancer may be justified. Among 16 identified genes, BRCA2 was the most common (45% of total). Other genes included ATM, CHEK2, BRCA1, and PALB2, as well as Lynch syndrome mutations MLH1, MSH2, MSH6, and PMS2, among others. The same study found that 4.6% of 498 unselected men (regardless of family history) with localized prostate cancer (any Gleason score) had a pathogenic mutation.⁶

Hereditary cancers of interest to urologists include hereditary breast and ovarian cancer (HBOC)syndrome as well as Lynch syndrome. HBOC links BRCA1/2 genes to prostate cancer and can cause melanoma and breast, ovarian, pancreatic, and male breast cancers. Lynch syndrome is associated with DNA mismatch repair genes (MMRs) and is linked to colorectal, uterine, ovarian, stomach, prostate, and brain cancers, as well as leukemia and urothelial carcinomas of the renal pelvis and ureter. Keeping these associations top of mind could affect medical decision making and help prevent future cancers in patients and their family members. For example, active surveillance for localized prostate cancer would not be advised in men with BRCA mutations. Radiation therapy may not be advisable for patients with prostate cancer with Lynch syndrome because of the increased risk of colorectal cancer.

The caveat when using multigene panels to identify risk for prostate cancer is that we do not know the clinical relevance of very many genes, and most are not actionable. This leads to questions: What is a positive result? Can the lab find all the variants, and does the lab classify variants correctly? Does the variant increase the risk of cancer? Often the answers are not black-and-white, and there are many shades of gray. New prostate cancer genetic panels are becoming available commercially but need validation. Because of these issues, it is important to involve the services of a genetic counselor before and after testing. Trained, professional genetic counselors can compile detailed personal and family cancer histories. They can explain all aspects of genomics and genetic testing, such as hereditary cancer issues; genetic test options, including individual and cascade testing (testing of multiple family members); and costs. They can also address the implications of genetic test results so that patients and their families can make informed decisions about therapeutic options. As therapies evolve, genetic information will be a powerful tool in healthcare. However, because of the limitations of GINA, it is important that trained professionals be available to inform patients about the benefits and risks of genetic testing. Although gene panels are commercially available, urologists should inform patients about the potential for adverse consequences.

Table 1. Gene Mutations Associated With PCa and Common Testing Panels

In March 2017, the Philadelphia Prostate Cancer Consensus Conference (PPCCC) convened an expert panel to develop a multidisciplinary perspective on the role of genetic testing for inherited prostate cancer in the era of multigene testing. Specifically, the panel addressed referral criteria, genetic counseling, genetic testing, and management.⁸ Prior to the PPCCC, there was a major unmet need for comprehensive guidelines on prostate cancer genetic testing from urology and oncology associations. In its own guidelines, the National Comprehensive Cancer Network (NCCN) previously focused on just BRCA1/2 testing. There were no specific guidelines regarding genetic counseling and testing for prostate cancer or interpretation of genomic profiles of tumors provided by commercial gene panels. The PPCCC group of international experts reviewed recent studies and cited high-level evidence in support of testing for not only BRCA1/2 but also HOXB13 and MMR mutations associated with Lynch syndrome (Table 1).⁹ Most of these specific mutations have been included in NCCN guidelines version 4.2018 for prostate cancer, which contain recommendations for germline testing. This latest version has expanded genetic testing guidelines for all risk categories (Table 2).¹⁰ The PPCCC panel also recommended genetic counseling.

Identifying patients at risk for hereditary cancer is now a standard of care.Obtaining a good family history is recommended as part of the initial prostate cancer diagnosis guideline. This version recommends hereditary cancer testing for patients with prostate cancer who have meta- static prostate cancer or Gleason 7 or higher disease or any one of the following close blood relatives: 1 or more family members (<50 years) with breast cancer; 1 or more family members (any age) with ovarian cancer; or 2 or more family members (any age) with breast, pancreatic, or prostate cancer (Gleason 7 or higher or metastatic). Close blood relatives include parents, children, siblings, grandparents, great-grandparents, aunts and uncles, nieces and nephews, and first cousins. Genetic counseling is recommended for anyone with 3 or more of the following cancers: prostate, pancreatic, melanoma, uterine, kidney, sarcoma, adrenal, brain tumors, colon, and leukemia.

Table 2. NCCN Guidelines on Germline Testing for Prostate Cancer (Version 4.2018)¹⁰

In December 2018, the Society of Urologic Oncology (SUO) issued a statement on genetic counseling and genetic testing in the management of prostate cancer that incorporates NCCN genetic evaluation criteria merged from Breast and Ovarian Version 2.2019 as well as Prostate Version 4.2018: “The SUO supports genetic testing of men with prostate cancer meeting the NCCN criteria as noted... and endorses the need for appropriate genetic counseling for men with prostate cancer before or after genetic testing as a central concept. This should also include considering the needs of the patient’s family as well.”

The era of precision medicine emphasizes the need for genetic testing to inform cancer treatment, especially in the advanced-stage setting.Studies reported by Mateo¹¹ and Kaufman¹² demonstrated prolonged tumor responses for PARP inhibitors across a spectrum of solid tumor malignancies. This suggests that PARP inhibitors may have overall survival benefits in patients with metastatic castration-resistant prostate cancer. Consequently, breakthrough designations have been issued for olaparib (Lynparza) and more recently rucaparib (Rubraca) in patients with BRCA1/2 or ATM mutation—positive mCRPC who have progressed after next-generation oral oncolytics or chemotherapy (these patients may respond to platinum-based chemotherapy as well). Further, these agents offer value across solid-tissue tumor types with BRCA1/2 or ATM gene mutations, making them agnostic by indication, nonspecific to organ of origin, and specific based on genetic mutations. The accelerated approval of the immune checkpoint inhibitor pembrolizumab (Keytruda) for microsatellite instability-high or MMR-deficient cancers across all solid tumor types, including prostate cancer, gives this agent an agnostic indication as well. Thus, multigene testing for inherited prostate cancer is now critical for prostate cancer risk determination, screening, and treatment implications.

So how should urologists incorporate genetic testing into clinical practice? The most important thing to do is capture detailed family histories to identify appropriate patients and their families for multigene testing. Consider referral to a genetics counselor to navigate patients and their families before and after hereditary testing. If patients with mCRPC progress after next-generation oral oncolytics or chemotherapy, genetic testing in and outside the context of clinical trials will inform available treatment options such as PARP and immune checkpoint inhibitors as well as platinum chemotherapy. There are still many unanswered questions: Where exactly are we regarding hereditary genetics in prostate cancer? Do we know who should undergo genetic testing and counseling? What genes and gene panels should be tested? Should genetic testing inform screening or guide treatment of different stages of prostate cancer? The field is evolving and so are the answers to these questions.

References

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ACKNOWLEDGEMENT: Lauren R. Karsh, MD, assisted with the medical writing of this article.