Abstract

The results of multiple studies have shown that a substantial proportion of men with advanced prostate cancer carry germline DNA repair mutations. Germline testing in prostate cancer may inform treatment decisions and consideration for clinical trials. There are 2 FDA approved PARP inhibitors (PARPi), olaparib (Lynparza) and rucaparib (Rubraca), for the treatment of advanced prostate cancer with DNA repair deficiency. Increasing demand for germline testing in prostate cancer and a shortage of genetic counselors have created a need for alternative care models and encouraged oncologists to take a more active role in performing germline testing. This article summarizes recommendations for germline testing in prostate cancer and describes care models for providing counseling and testing.

Genetic testing in men with prostate cancer has become more widespread since the discovery that men with metastatic prostate cancer are more likely to carry germline DNA repair gene mutations and the approval of PARP, or poly adenosine diphosphate-ribose polymerase, inhibitors (PARPi) for prostate tumors with DNA repair deficiency. The resulting substantial increase in men with prostate cancer who are eligible for germline testing, with time-sensitive treatment implications, challenges the traditional in-person, time- and resource-intensive cancer genetics care delivery model, and calls for alternative approaches. Urologists, oncologists, and other medical providers are encouraged to take a more active role in delivering germline testing, and they should be aware of current guidelines and optimal pretest and posttest counseling components. This article focuses on the implementation of germline testing in the care of patients with prostate cancer.

Germline genetic testing evaluates for inherited mutations (otherwise known as pathogenic or likely pathogenic variants) that are found in virtually all cells of the body and are derived from the fundamental DNA of an individual. DNA from no cancerous, healthy cells (eg, leucocyte or saliva/buccal swab cells) are used for germline genetic testing. The goals of germline genetic testing are to evaluate for an inherited cancer syndrome; to inform individual and family cancer risks; and to guide cancer prognosis and treatment decisions. Germline testing should be distinguished from recreational and somatic (tumor-specific) testing. Direct-to-consumer recreational genetic testing consists of an at-home test that is advertised to help understand the customers ancestry. Recreational genetic panels look for inherited variants in saliva/buccal swab cells to inform genealogy, and they are not primarily intended to guide medical decisions as they lack gene coverage and clinical-grade precision. None of the recreational genetic tests include a comprehensive assessment of the BRCA1/2 or other DNA damage repair genes and are inadequate for medical purposes. Somatic testing panels are designed to identify alterations in a tumors DNA. A somatic test may occasionally identify mutations expected to be germline, in which case follow-up dedicated germline tests are needed. Examples of somatic panels that report germline mutations include Tempus and UW-Oncoplex. However, many somatic panels use bioinformatics algorithms that may filter out, miss, and/or choose not to report germline mutations. Thus, in general, somatic panels should not be considered adequate for germline conclusions; at most, they should prompt confirmatory germline testing. This articlefocuses on dedicated clinical-grade germline testing.

Germline testing in men with prostate cancer is being performed more often since an important number of prostate cancer cases have a heritable component.1,2 Germline mutations in DNA repair genes, such as BRCA1/2, contribute to hereditary prostate cancer risk and are present in up to 11.8% of men with metastatic prostate cancer,3 compared with 4.6% among men with localized prostate cancer and 2.7% in persons without a known cancer diagnosis.3,4

Germline BRCA1/2 mutations are associated with increased risk of prostate cancer: up to a 3.8-fold increase with BRCA1 and an 8.6-fold increase with BRCA2 mutations.5 Men who carry germline BRCA1/2 mutations are not only at increased risk of developing prostate cancer but are also at risk of a more aggressive prostate cancer phenotype. In their study, Castro et al found that patients with prostate cancer with germline BRCA1/2 mutations at the time of diagnosis were more likely to have higher Gleason score (8) and more advanced stage (T3/4, nodal involvement, and metastases) compared with noncarriers. Men with germline BRCA1/2 mutations also had shorter cancer-specific survival (CSS) than noncarriers (15.7 vs 8.6 years; P=.015).6 Men with localized prostate cancer and germline BRCA1/2 mutations have worse outcomes after definitive treatment with surgery or radiation compared with noncarriers: 5-year metastasis-free survival, 72% vs 94%; P <.001; 5-year CSS, 76% vs 97%; P <.001.7 The prospective PROREPAIR-B study found that germline BRCA2 status is an independent prognostic factor for CSS in patients with metastatic castration-resistant prostate cancer (mCRPC; 17.4 vs 33.2 months; P = .027).8

Based on the study results above and others, the current National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer (version 1.2022)9 recommend germline testing for the subsets of patients with prostate cancer who are more likely to have germline DNA repair mutations (Figure 1).

The NCCN guidelines recommend offeringgermline testing to the following groups of patients with prostate cancer9:

I. Men with node positive, high-risk or very highrisk localized prostate cancer

II. Men with metastatic prostate cancer

III. Men meeting family history criteria (Table 1)

NCCN recommends considering germline testing for men with personal history of prostate cancer and:

I. intermediate risk prostate cancer and intraductal/cribriform histology

II. personal history of exocrine pancreatic, colorectal, gastric, melanoma, pancreatic, upper tract urothelial, glioblastoma, biliary tract or small intestinal cancers

Several commercial vendors provide germline testing panels, including Invitae, Color, and Ambry. Further details and information on available panels can be found on the vendors websites. Panel sizes vary from dedicated BRCA1/2 testing to 91-gene panels. The NCCN guidelines for prostate cancer9 recommend that germline testing panels include genes associated with Lynch syndrome (MLH1, MSH2, MSH6, PMS2) and homologous recombination genes (BRCA1/2, ATM, PALB2, CHEK2).9,10 Broader panels might be appropriate for men with mCRPC, especially if clinical trial participation is being considered. Average turnaround time for germline testing is between 10 and 30 days, which varies depending on the particular panel. The cost of germline testing varies depending on insurance coverage. Some companies offer provide testing for a flat out-of-pocket fee (eg, $250), and a benefit of participating in certain research studies may be no-cost testing.

NCCN guidelines recommend germline testing for a large subset of patients with prostate cancer, but the best care model to offer education and testing is unclear. The traditional clinical care delivery model for cancer genetics includes 2 in-person visits with a genetic counselor, the first for pretest risk assessment and education and the second to discuss the results. This is the most established pathway and, historically, has been utilized the most. However, broadening recommendations for germline testing create great demand that cannot be currently met in a timely fashion by the approximately 4000 genetic counselors in the United States.11,12 Therefore, oncologists and other providers are increasingly performing pretest counseling, ordering genetic testing, and providing posttest counseling for their patients, or following hybrid models (Table 2).13

The provider-led germline testing model has been tested in breast and ovarian cancer but is new in prostate cancer.14-18 Scheinberg et al reported results of a multicenter prospective study evaluating provider-led germline testing for men with prostate cancer. Twelve oncologists received training about the role of germline testing and in counseling patients, and then offered germline testing to patients with mCRPC in their practice. Those patients who accepted germline testing received pretest counseling and educational materials, and later discussed test results in the oncologists office. If a germline mutation was identified, the patient was referred to a genetic counselor to discuss the further implications of the results and to initiate cascade testing. Most patients (63 of 66; 95%) accepted the germline testing and high satisfaction rates were achieved among both oncologists and patients.19 A provider-led germline testing model in the Veterans Affairs health care system was also evaluated. Patients with metastatic prostate cancer were offered germline testing by their oncologists during regular clinic visits. Pretest counseling was provided by oncologists and study coordinators and saliva for the test was collected in the clinic. Posttest counseling sessions with genetic counselors were provided over the phone by the testing panel company. Again, most patients (190 of 227 approached veterans; 84%) accepted testing, and the test completion rate was 80% (182/227).20 Results of early studies suggest that provider-led germline testing in prostate cancer could be effective and satisfactory for both patients and providers.

The need to streamline germline testing also calls for the utilization of new technologies, such as video- or phone-based counseling. The EMPOWER study (NCT04598698) assessed mens preference of in-person genetic counseling vs video-based genetic education21; results indicated that in-person genetic counseling was preferred by men with less education and higher anxiety levels, and it resulted in greater improvement of cancer genetics knowledge. The rates of genetic testing uptake were similar for video-based and in-personcounseling groups.21 Video-based counseling was also evaluated by Tong et al, who compared 2 models of streamlined germline testing in prostate cancer: (a) a take-home genetic kit provided by an oncologist, followed by referral to a genetic counselor if subsequent results are concerning; and (b) a genetic testing station, at which the patient participated in a video call from a genetic counseling assistant for genetics education and collection of family history, which was followed by saliva sample collection and, later, referral to a genetic counselor if any mutation was identified. The latter approach resulted in a lower rate of incomplete tests and a higher rate of follow-up with genetic counselors for positive results. Authors suggested that utilization of video education and involvement of genetic counselor assistants may improve access to germline testing among patients with prostate cancer.22 Several studies are ongoing to evaluate other care models to provide genetic testing in prostate cancer (eg, NCT02917798, NCT03076242, NCT03328091, NCT03503097).23

Oncologists who choose to perform germline testing need to be comfortable with several aspects of genetic counseling and to remain current on the ethics of informed consent and posttest counseling for germline testing (Figure 2). The 2019 Philadelphia Prostate Cancer Consensus Conference suggests that optimal pretest consent should include discussion of the purpose of testing, types of possible results (ie, pathogenic/likely pathogenic; benign/likely benign; variant of unknown significance; no variants identified), the possibility of identifying hereditary cancer syndrome and/or other cancer risks, testings potential cost, the importance of cascade family testing, and the Genetic Information Nondiscrimination Act (GINA) law.12 The GINA law protects against discrimination based on genetics in employment and health insurance; however, it is not applicable to life insurance, long-term care disability insurance, Indian Health services, and patients enrolled into federal employee, Veterans Administration, and US military health benefit plans.23,24 These gaps in protection by GINA law are important to discuss with patients, who may need to consider them before proceeding with the germline testing. Providers should also consider discussing the different panels available for testing, the privacy of genetic tests, and genetic laboratories policies related to sharing and selling of data.12

Providers ordering germline tests also must accept responsibility to follow up with patients if reclassification occurs of a variant of (currently) unknown significance (VUS). VUS are reported in about 30% of men with prostate cancer who undergo germline testing.4 VUS results do not change clinical recommendations, and the majority of them end up being reclassified as benign.25,26 In the Find My Variant Study, 38 of 63 VUS (61%) were reclassified: 32 of 38 (84%) as benign/likely benign and 6 of 38 (16%) as pathogenic/likely pathogenic.27,28 In the rare case when a VUS is reclassified as pathogenic or likely pathogenic, the provider who ordered the test is notified and they are responsible for disclosing the reclassification to the patient. Regardless of the model used, genetic counselor referral is recommended if a patient has a germline mutation identified and/or if clinical suspicion is high for an inherited cancer predisposition. Collaborative efforts are needed to educate oncology providers on aspects of germline testing counseling and to create shared printed and video resources for patients to facilitate informed consent.

Germline testing in men with prostate cancer can potentially benefit not only the patient but also family members. If a germline mutation is identified in a patient, testing for the same mutation in family members (cascade testing) should be performed. For instance, identifying family members with BRCA1/2 mutations could inform potentially lifesaving risk-reducing interventions, eg, prophylactic salpingo-oophorectomy for female BRCA1 mutation carriers. The IMPACT study (Identification of Men with a Genetic Predisposition to Prostate Cancer: Targeted screening ingBRCA1/2mutation carriers and controls) evaluated the utility of prostate-specific antigen (PSA) screening in men aged 40 to 69 years with germline BRCA1/2 mutations compared with its utility in noncarriers.29,30 The study enrolled 3027 men with no personal history of prostate cancer: 919 BRCA1 carriers, 902 BRCA2 carriers, 709 BRCA1 noncarriers, and 497 BRCA2 noncarriers. Preliminary results, reported after 3 years of follow-up, showed that BRCA2 mutation carriers, compared with noncarriers, have a higher incidence of prostate cancer and a younger age of diagnosis. The results for BRCA1 carriers were not definitive, and further investigation is needed. The results from IMPACT suggest annual PSA screening for BRCA2 mutation carriers aged between 40 and 69 years, using PSA cutoff of 3.0 ng/ml.30 Studies evaluating the predictive value of lower PSA cutoff and prostate MRI are ongoing (eg, NCT03805919, NCT01990521).

Advanced disease

PARPi. Patients with DNA repair mutations have higher responserates toPARPiand platinum chemotherapy.31,32 In 2020, two PARPi received FDA approval for treatment of mCRPC with germline or somatic DNA damage repair gene mutations. Rucaparib was approved based on the phase 2 TRITON2 (NCT02952534) study; it reported a 51% (50/98) radiographic response rate among men with mCRPC and BRCA1/2 alterations.33 The benefit for men with non-BRCA DNA repair mutations was less clear, and rucaparib is currently approved only for carriers of BRCA1/2 mutations. 33-35 The olaparib label includes a larger number of mutated genes eligible for treatment (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L), based on results of the phase 3 ProFOUND study (NCT02987543). ProFOUND compared olaparib with enzalutamide or abiraterone and showed improved radiographic progression-free survival (5.8 months vs 3.5 months) with olaparib. 36 Several other ongoing studies are evaluating the efficiency of PARPi monotherapy and combined therapies in mCRPC. Table 3 summarizes study results reporting response rates to PARPi in prostate cancer. 37

Platinum chemotherapy. Historically, platinum chemotherapy has been used to treat tumors, such as ovarian or pancreatic cancer, that have a high frequency of DNA repair mutations.38,39 Early data suggest that platinum chemotherapy is also effective in prostate tumors with DNA repair deficiency.40-43 A retrospective case series by Cheng et al showed that 3 of 3 patients with prostate cancer who had biallelic inactivation of BRCA2 had an exceptional response to platinum chemotherapy after progressing on several therapies.40 The results of a larger retrospective study supported this observation, reporting that 75% (6/8) of patients with mCRPC and withgermline BRCA2 mutations had a PSA50 response (ie, decline of prostate-specific antigen by 50% from baseline) to platinum chemotherapy compared with 17% (23/133) of mCRPC patients without gBRCA2 mutations.41 Mota et al reported a 53% (8/15) PSA50 response to platinum chemotherapy among men with mCRPC and DNA damage repair mutations (ie, BRCA2, BRCA1, ATM, PALB2, FANCA, and CDK12).43

NCCN guidelines recommend considering DNA repair mutation status when discussing the possibility of active surveillance. Germline mutations in BRCA1/2 or ATM are associated with a higher likelihood of grade reclassification among men undergoing active surveillance.44 Mutation carriers should be closely monitored; they could potentially benefit from an earlier definitive treatment approach.

BRCA1/2 carriers have worse outcomes with conventional definitive therapies. Castro et al evaluated the response of BRCA1/2 carriers with localized prostate cancer to 2 radical treatmentsdefinitive radiation and radical prostatectomyand reported that BRCA status is an independent prognostic factor for metastasis-free survival (HR, 2.36; P = .002) and CSS (HR, 2.17; P = .016).7 New treatment approaches in earlier disease stages are being evaluated in clinical trials for patients with prostate cancer and DNA repair deficiency. Targeted therapies, such as PARPi, are being actively investigated in the biochemically recurrent stage of prostate cancer (eg, NCT03047135, NCT03810105, NCT04336943, NCT0353394) and as neoadjuvant therapy in localized disease (eg, NCT04030559).

Germline testing is becoming more commonplace with advances in precision oncology and expanding treatment implications of the results of this testing. The NCCN prostate cancer guidelines recommend germline testing for men with high-risk or very highrisk localized prostate cancer; men with metastatic prostate cancer; patients with intraductal histology of the prostate; and patients meeting family history criteria. These recommendations have created a need for germline testing of many prostate cancer patients, which calls for a change in the traditional cancer genetics delivery model to meet the new demand.45 Oncologists are encouraged to take a more active role in performing germline testing, but the optimal approach is unclear. Until the results of larger trials focusing on various testing delivery models are available, joint efforts are needed to build collaborative relationships between oncologists and genetic specialists. Further efforts are required to create dedicated resources to support providers in this new era of genetic testing and precision oncology in prostate cancer, which is marked by near-constant change.

ACKNOWLEDGMENTS: We gratefully acknowledge support from the Institute for Prostate Cancer Research, NIH/NCI CCSG P30CA015704, NIH SPORE CA097186, NCI T32CA009515 award, Congressional Designated Medical Research Program (CDMRP) award W81XWH-17-2-0043, and the Prostate Cancer Foundation.

Conflict of interest/disclosures: AOS has no conflicts to disclose; HHC receives research funding to her institution fromClovis Oncology, Color Genomics, Janssen Pharmaceuticals, Medivation, Inc. (Astellas Pharma Inc), Phosplatin Therapuetics, and Sanofi S.A., and has a consulting or advisory role withAstraZeneca.

Sokolova is from the Division of Medical Oncology at Oregon Health Science University (OHSU) and the OHSU Knight Cancer Institute.

Cheng is from the Division of Medical Oncology at the University of Washington and the Division of Clinical Research at Fred Hutch Cancer Research Center.

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Germline Testing in Prostate Cancer: When and Who to Test - Cancer Network

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