Germline Testing for Men With Prostate Cancer

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•This review described the prevalence of germline mutations in prostate cancer and presented three different models for incorporation of targeted counseling and testing into practice.

•This review should serve as a valuable resource for those wishing to better understand the utility of germline testing and looking to develop or improve a systematic approach to introducing it into practice, even in cases where genetic counselors may not be readily available.

– Joshua Cohn, MD

Germline genetic testing is revolutionizing prostate cancer (PCA) care, with studies revealing inherited mutations (pathogenic variants) in a spectrum of cancer risk genes.1-5 Analyses from clinical cohorts of men with PCA have reported germline mutation rates of 15% to 17% regardless of stage,1,4,5 with rates of DNA repair mutations reported to be approximately 12% in men with metastatic PCA.2 Mutations in multiple genes including BRCA1, BRCA2, HOXB13, ATM, DNA mismatch repair genes, NBN, and CHEK2 confer variable estimates of risk for PCA predisposition, aggressive disease, and lifetime risk.1-5 The highest level of PCA risk has been reported for mutations in BRCA2, and HOXB13, with BRCA2 mutations associated with poor outcomes.1 Genetic testing for men with PCA is being driven increasingly by precision therapy and precision management considerations affecting oncology and urology. For example, olaparib was given Breakthrough Therapy designation by the US Food and Drug Administration for BRCA1/2- or ATM-positive metastatic castration-resistant prostate cancer (mCRPC) on the basis of the TOPARP-A trial demonstrating improved responses particularly in patients with DNA repair mutations.6 Rucaparib was also granted Breakthrough Therapy designation for men with BRCA1/2-positive mCRPC after at least one androgen receptor–directed therapy and taxane-based chemotherapy on the basis of the TRITON2 study.7 Pembolizumab was granted US Food and Drug Administration accelerated approval for patients with unresectable or metastatic, microsatellite instability–high or mismatch repair deficient solid tumors that have progressed after prior treatment without other treatment alternatives.8 Men with mCRPC carrying BRCA or ATM mutations have been reported to have improved progression-free and overall survival with abiraterone and enzalutamide, with a subsequent study reporting improved cause-specific and progression-free survival among men with mCRPC and BRCA2 mutations treated with first-line abiraterone or enzalutamide over taxanes.9,10 Indeed, mutations in multiple genes (BRCA2, BRCA1, ATM, CHEK2, PALB2, RAD51D, NBN, MLH1, MSH2, PMS2, and MSH6) may provide clinical trial options for men with mCRPC, because genetically informed trials are expanding for PCA treatment.11

Furthermore, clinical trials are emerging that are focused on genetically informed response to treatment, such as with poly (ADP-ribose) polymerase inhibitors, in men with biochemical recurrence after prostatectomy (ClinicalTrials.gov identifier: NCT03047135),11 increasing the need to perform genetic testing sooner in the treatment algorithm. Genetic results may also be important for the management of men with early-stage PCA, with National Comprehensive Cancer Network (NCCN) guidelines stating that BRCA1/2 status should be considered in active surveillance discussions.12 Prior studies have reported the association of germline mutations in BRCA1, BRCA2, ATM, and CHEK2 (1100delC) with lethal PCA,13,14 with implications for early-stage management. BRCA1/2 and ATM mutations have also been associated with grade reclassification among men undergoing active surveillance.15 Thus, the clinical role of genetic testing in PCA treatment and management is expanding, requiring a greater percentage of men with PCA to undergo genetic evaluation. This demand for genetic assessment is posing a strain on genetic counseling services and genetics programs, raising the controversial question: Should oncologists and urologists perform genetic testing in their clinical practice? Given the lack of evidence-based data to answer this question, we herein discuss provider responsibilities of three potential models of genetic evaluation for men with PCA: (1) refer for genetic counseling, testing, and disclosure (model 1); (2) conduct pretest informed consent and post-test disclosure all within oncology or urology practices (model 2); (3) adopt a hybrid model of performing pretest informed consent and test ordering within treatment-based practices and post-test disclosure by cancer genetics professionals (model 3; Table 1).

Table

TABLE 1. Proposed Models of Genetic Evaluation of Men with Prostate Cancer: Responsibilities and Areas of Knowledge Needed

TABLE 1.Proposed Models of Genetic Evaluation of Men with Prostate Cancer: Responsibilities and Areas of Knowledge Needed

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Oncologists and urologists need to be familiar with current NCCN PCA genetic testing guidelines. Supported by expert consensus opinion,18 current testing criteria per NCCN guidelines may be summarized as follows: (1) all men with metastatic PCA regardless of family history; (2) all men with high-risk to regional disease per NCCN risk categories regardless of family history; (3) men with very low to unfavorable intermediate risk disease with brother, father, or multiple male relatives diagnosed with PCA at younger than 60 year of age, known germline DNA repair mutation in the family, or greater than one relative with family history suggestive of hereditary breast and ovarian cancer (HBOC) or Lynch syndrome; (4) men with Gleason score of 7 or greater with one or more blood relative with ovarian cancer, pancreatic cancer, metastatic PCA, or breast cancer younger than 50 years of age or two or more relatives with breast or prostate cancer (any grade) at any age, or Ashkenazi Jewish ancestry; or (5) BRCA mutations in tumor profiling.12,19 Therefore, in their practices, providers must perform intake of maternal and paternal family cancer history that covers a broad spectrum of cancers. Men meeting any of these criteria should consider genetic testing, necessitating that these men understand the implications of genetic testing for themselves and their families to make an informed decision, as advocated by multiple national organizations.12,19-24

There are many advantages to referring men with PCA to a cancer genetics counselor or provider (model 1) to discuss the complexities, uncertainties, and implications of genetic testing.20,25 Genetic counselors have graduate-level training in medical genetics and can discuss cancer inheritance, how genetic test results may inform cancer risk for patients and their families, and uncertainties regarding how genetic results may or may not provide information on the primary cancer of concern. Unanticipated cancer risks may be uncovered by test results (eg, male breast cancer, pancreatic cancer, or melanoma risks for men with BRCA2 mutations). Although genetic testing using a premade PCA panel is available through many commercial genetic testing laboratories and can ease test ordering, the patient’s personal or family history may dictate that additional genes be tested. Genetic counselors coordinate genetic testing, have insights into which laboratories have the highest-quality testing for the genes of interest, and discuss how insurance coverage may be affected by the choice of testing laboratory. Counselors provide letters of preauthorization or medical necessity and discuss results with laboratories when there is a lack of clarity. Counselors also discuss the types of test results and their implications with patients. Pathogenic or likely pathogenic variants (clinically significant mutations) may be actionable in the management of PCA, may inform additional cancer screening recommendations, and may guide cascade testing in blood relatives. Variants of uncertain significance (VUS) are reported in at least 30% of men with PCA who have undergone genetic testing4,5 and do not affect recommendations at the time of reporting. However, a small fraction of VUS are reclassified as pathogenic or likely pathogenic over time.26 These reclassifications are reported back to ordering providers who have the responsibility to discuss the information and make appropriate recommendations with patients on an ongoing basis. VUS rates can also vary on the basis of assay and variant classification schema across laboratories. Finally, if a test result is negative, recommendations for cancer screening are based on family history; therefore, a working knowledge of all NCCN guidelines is needed. In addition, counselors help coordinate cascade testing of relatives when a proband or familial mutation has been identified to inform important and potentially life-saving cancer risk, screening, and management recommendations across cancer types.

Of importance is the need to discuss the Genetic Information Nondiscrimination Act (GINA) of 2008, regarding its implications for men with PCA and their families, in the pretest counseling session.27 GINA generally provides protections for mutation carriers from health insurance discrimination and employment discrimination (with the exception of small businesses with fewer than 15 employees). Importantly, GINA does not apply to life, disability, or long-term care insurance. GINA also does not apply to Veterans’ health plans, federal employee health benefits plans, or Indian Health Service,27 although many of these have their own protections in place. Although these issues may not be imminently relevant for men with mCRPC, many men with earlier-stage disease will enter survivorship and these issues will need to be discussed so that these men can understand the potential financial impact of genetic test results.20 This law becomes relevant when discussing genetic testing for unaffected men and cascade testing of unaffected family members.

The expansion of genetic testing in men with PCA has placed a strain on cancer genetics clinics. The United States has approximately 4,000 genetic counselors, insufficient to meet the growing demand for counseling.28 Many genetic programs have long wait times for appointments, with many comprehensive genetic services located in academic cancer centers, which may pose access challenges. The process of genetic referral, evaluation, results disclosure, and communication back to providers can also create delays in management decisions. Therefore, in the era of precision oncology and precision management, oncologists and urologists are increasingly considering performing pretest consent, ordering their own genetic testing, and discussing genetic test results to streamline the process (model 2; Table 1). Providers who opt to perform the entire genetic evaluation process must have a working knowledge of several topics related to cancer genetics and testing, knowledge of the current guidelines, and must consider the responsibilities of ordering, interpreting, and following up with test results as performed by genetic counselors and discussed earlier in the text (Table 1). Follow-up of variant reclassification also becomes the responsibility of oncologists and urologists in model 2. Resources for education, as well as certification programs, are available (Table 1), with PCA genetics education in need of development.

A hybrid model (model 3) that oncologists and urologists are discussing increasingly is performing pretest informed consent and ordering genetic testing in their practice, with referral to genetic counselors to discuss results and recommendations (Table 1). Here, providers will still need to address questions regarding cancer inheritance, genes to be tested, and limitations of tests, potential results, coordinate testing with genetic laboratories, and address the GINA law. In this model, follow-up of variant reclassification also becomes the responsibility of oncologists and urologists. Although this may address the needs of rapid test ordering linked with disclosure of genetic results by a genetics professional, this approach can lead to miscommunication among patients and providers. Counselors may have chosen a different testing laboratory because of quality issues or have tested additional genes, which could create a potential added cost for patients. Patients may misunderstand the goals of testing or experience confusion over interpretation of results because of multiple providers being involved in their care. These issues need to be vetted carefully before embarking on this model. Alternative delivery of genetic counseling, involving genetic education videos and telegenetics, is worth studying in this context in men with PCA.29

Regardless of the model, it is important for all providers to discuss men’s psychosocial and quality-of-life issues, which may affect their genetic evaluation experience. Although a substantial amount of research has been conducted regarding the psychosocial needs of women undergoing genetic evaluation,30-33 there exists a major gap in understanding the psychosocial needs of men. While discussing considerations of genetic testing, such as potential uncertainty with test results, limitations of testing, implications of testing for hereditary cancer risk for family members, and insurance discrimination, feelings of worry, anxiety, guilt, fear, and future financial strain may be exacerbated or compounded by quality-of-life concerns that men may be experiencing. Men with early-stage PCA may be experiencing urinary incontinence and erectile dysfunction from radical prostatectomy, urinary or bowel toxicity and fatigue from radiation, and the fear of possible cancer progression with active surveillance.34 In the metastatic setting, a substantial proportion of men with PCA on androgen-deprivation therapy experience significant adverse effects,35 and those treated with chemotherapy may also deal with long-term toxicity. Many men deal with depression, a feeling of loss of masculinity, and a negative impact on sexual relationships.36 This area now deserves focused study regarding the impact of psychosocial needs and worries on men’s informed decision making for PCA genetic testing, understanding of results, and opportunities to intervene.

In summary, there is no final answer to the question: Should oncologists and urologists perform genetic testing in their practice? There are other models to consider beyond those proposed here, such as collaborative models, that also deserve study. Until evidence-based studies are available that focus on the various models of pretest and post-test genetic evaluation for men with PCA, oncologists and urologists should start building collaborative relationships with cancer genetics professionals and counselors to establish clinical flow for men with PCA who need genetic assessment. This brand new era of genetic testing for precision therapy and precision management is challenging the paradigm of genetic evaluation, which is in need of greater research. Thus, a more global dialogue across oncology, urology, genetic counseling, and population scientists is now imperative to meet the needs of men undergoing germline testing for inherited PCA.

© 2019 by American Society of Clinical Oncology

Journal of Clinical Oncology

Germline Testing for Men With Prostate Cancer: Navigating an Expanding New World of Genetic Evaluation for Precision Therapy and Precision Management

J. Clin. Oncol 2019 Apr 12;[EPub Ahead of Print], VN Giri, C Hyatt, LG Gomella

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.