Germline Testing for DNA Repair Mutations in Prostate Cancer: Who, When and How?

Germline testing indications for prostate cancer (PCa) have rapidly expanded and have been catapulted by precision medicine and precision management.1,2 In particular, testing for mutations in DNA repair genes such as in BRCA2, BRCA1, ATM, and other DNA repair genes, has taken front-stage due to the clinical activity of poly (ADP-ribose) polymerase (PARP) inhibitors in metastatic, castration-resistant prostate cancer (mCRPC).3-7 Phase II trial data supported the U.S. Federal Drug Administration (FDA) designations for olaparib, rucaparib, and niraparib due to demonstrated response rates particularly among men with BRCA2 mutations along with other DNA repair genes.5-7 Excitingly, the FDA has recently approved two PARP inhibitors for mCRPC. Rucaparib was granted accelerated approval for BRCA1/2-mutated mCRPC with prior treatment with androgen receptor-directed therapy and taxane-based chemotherapy based on TRITON2.5 Olaparib was FDA-approved for the treatment of mCRPC in men with deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutations who have progressed following prior treatment with enzalutamide or abiraterone based on PROfound.4 These approvals provide exciting therapeutic options for men with mCRPC and will increase the role of germline testing for DNA repair mutations. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines recommend germline testing for DNA repair mutations in all men with mCRPC, with additional testing criteria proposed.8,9 The international Philadelphia Prostate Cancer Consensus Conference 2019 has provided significant multidisciplinary guidance regarding germline testing for DNA repair mutations across the stage spectrum, along with strategies for implementation of genetic counseling and germline testing.1 Therefore, understanding the role of germline testing in PCa is now critical to urologic and oncology practice for this disease. Here, we will address who should be considered for germline testing, when germline testing may influence treatment and management, and how to implement germline testing involving provider practices and genetic counseling.

Who should consider germline testing?

NCCN guidelines address germline testing for PCa. The NCCN Prostate Cancer Guideline (Version 4.2019) addresses candidacy for germline testing based upon risk category, pathology, and family history.8 There is a recommendation for germline testing for all men with metastatic PCa, as well as those men with high-risk or very high-risk disease based upon NCCN risk groups. For men with very low-risk to intermediate-risk PCa, the recommendation for germline testing is made if family history is suspicious or if there is intraductal pathology. Suspicious family history is determined based upon strong family history of prostate cancer which consists of brother, father, or multiple family members diagnosed with PCa at age less than 60 or who died from PCa (with the exception of Grade Group 1), Ashkenazi Jewish ancestry, or having three or more cancers on the same side of the family consistent with hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (especially if diagnosed at a young age). This guideline discusses germline testing for BRCA1, BRCA2, PALB2, ATM, CHEK2, and the DNA mismatch repair genes, and HOXB13.8

The NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Guideline (Version 1.2020) also address germline testing for PCa.9 This guideline indicates testing should include high penetrance genes such as BRCA1 and BRCA2 for PCA risk. Indications for testing include men with any of the following: (1) metastatic PCa or having intraductal pathology; (2) men with Gleason ≥7 of Ashkenazi Jewish ancestry; (3) ≥1 close blood relative with breast cancer at age ≤50 or ovarian/pancreatic/metastatic PCa/intraductal PCa at any age; (4) ≥2 close blood relatives with breast cancer or PCa (any Gleason score) at any age.9

The recent Philadelphia Prostate Cancer Consensus Conference 2019 was an international effort to garner consensus with thought-leaders spanning medical oncology, urology, genetic counseling, radiation oncology, cancer genetics, implementation science, population science/epidemiology, patient advocates, and NCCN leaders to arrive at uniform guidelines for germline testing for PCa and guidance for implementation of germline testing given the rapid expansion of indications impacting urology and oncology practices.1 This consensus conference stated that germline testing be recommended for men with metastatic castration-resistant and castration-sensitive PCa and for men with strong PCa family history of brother/father/two or more male relatives diagnosed with PCa at age <60/died from PCa/metastatic disease. Additional criteria garnered moderate agreement and were suggested as considerations for testing. These included pathologic criteria (advanced disease of T3a or higher; intraductal/ductal pathology; or Grade Group 4 or above) and family history criteria (two or more cancers in the HBOC or Lynch syndrome spectrum especially if diagnosed at age <50 or having Ashkenazi Jewish ancestry).1

Another indication for germline testing may arise in the context of somatic testing for targeted therapy. It is well-recognized that most of the testing assessing candidacy for PARP inhibitors, immunotherapy, or precision medicine trials involve next-generation sequencing (NGS) of prostate tumors which may uncover pathogenic variants in genes of possible germline origin. Questions arise regarding the best way to confirm whether a pathogenic mutation is of germline origin. The NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Guideline (Version 1.2020) states to consider germline testing if a mutation is identified on tumor testing particularly with suspicious personal or family history.9 The Philadelphia Prostate Cancer Consensus Conference 2019 recommended confirmatory germline testing for tumor BRCA2 mutations, and to consider the same for BRCA1, ATM, and DNA mismatch repair mutations identified in tumors especially if supported by personal and family history.1 Given that NCCN guidelines and consensus statements agree to perform germline testing for all men with mCRPC, one strategy would be to perform paired tumor and germline testing for all men with mCRPC to optimize detection of tumor mutations for therapeutic targets, identify germline mutations that may be potentially missed from somatic testing alone, and for automatic confirmatory germline testing of pathogenic variants identified in tumors. A more targeted approach to confirmatory germline testing of tumor mutations is to assess multiple other factors that may raise the suspicion that a tumor mutation may be germline in origin such as high variant allele fraction (>50%), founder mutations, or personal/family history consistent with the tumor mutation. There may be limitations in knowledge of this information and may hinder pretest likelihood assessment of whether a tumor mutation is of germline origin and should be considered in clinical practice.

When should germline testing be considered?

There are multiple scenarios when providers, such as urologists and oncologists, may consider germline testing for PCa. A key reason for germline testing in oncology is to assess candidacy for PARP inhibitors among men with mCRPC.3-7 The NCCN Prostate Cancer Guideline (Version 4.2019) states to consider tumor mutations in BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA, and RAD51D for early use of platinum-based chemotherapy, candidacy for PARP inhibitors, or for clinical trials eligibility with consideration for genetic counseling.8  Even in the setting of mCRPC, patients harboring these mutations may benefit from parallel germline testing as well given the NCCN indications for germline testing of all men with metastatic PCa, and especially if there is strong family cancer history or personal history. Another scenario to consider germline testing is in the active surveillance setting. Early data have been reported that men with early-stage disease who carry BRCA2 mutations have upgrading of biopsies while on an active surveillance approach,10 and thus knowledge of BRCA2 mutation status may inform active surveillance discussions. The 2019 Philadelphia Prostate Cancer Consensus Conference recommended BRCA2 status be included in active surveillance discussions, with an added consideration of ATM mutations for these discussions recognizing that more data will be needed for definitive recommendations.1  Another scenario to consider germline testing is in the PCA screening or early detection setting. The NCCN Prostate Cancer Early Detection Guideline (Version 2.2019) states to consider BRCA1/2 status in shared decision-making discussions for PCA screening starting at 40 or to consider annual screening vs. every two-year screening among BRCA1/2 mutation carriers.11 The NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Guideline (Version 1.2020) recommends prostate-specific antigen (PSA) screening start at age 40 for male BRCA2 carriers, and to consider the same in male BRCA1 carriers.9  The 2019 Philadelphia Prostate Cancer Consensus Conference recommended that BRCA2 mutation status be a part of PCa screening discussions, and to start PCa screening at age 40 or 10 years prior to the youngest PCa diagnosed in a family.1 The consensus conference also stated to consider additional genes in PCa screening discussions; these genes included BRCA1, HOXB13, ATM, and DNA mismatch repair genes (particularly MSH2) for consideration to start PCa screening at age 40 or 10 years prior to the youngest PCa diagnosed in a male blood relative.1

An important consideration is the identification of hereditary cancer syndromes which spans across clinical scenarios. PCa has been implicated in HBOC which is associated with increased risk for cancers of the breast, ovary, pancreas, prostate, and melanoma classically linked with BRCA1/2  mutations.12 PCa also has been implicated in Lynch syndrome which has multiple hereditary cancer risks including colorectal cancer, ovarian cancer, uterine cancer, pancreatic cancer, upper bowel cancers, urinary tract cancers, and sebaceous carcinoma.12 Genes linked with Lynch syndrome include MLH1, MSH2, MSH6, PMS2, and EPCAM.12 Of course, PCa may be part of classic hereditary PCa in families with generational PCa, multiple members of a nuclear family with PCa, or early-onset PCa.12 HOXB13 has been associated with classic hereditary PCa.12 Thus, germline testing may be indicated for clinical management and/or to identify hereditary cancer risk for men and their male and female relatives.

How can practices consider implementing germline testing?

As germline testing for PCa has increasing clinical implications, urology and oncology practices are faced with the implementation of germline testing for their patients. There are multiple considerations regarding the implementation of germline testing in practice.1 The classical scenario had been to refer all patients to genetic counseling for germline testing. However, with the rising population in need of germline testing, this upfront referral model has been difficult to sustain due to the rising demand for genetic counselors. In order to have timely germline testing for rapid return of results for therapeutic decision-making, urologists and oncologists are having to consider responsible strategies to implement germline testing. Proactive collaboration with genetic counseling is very important given the implications of germline testing for men and their families.

One important consideration is the quality of testing for germline mutations. It is paramount to choose a laboratory that has long-standing experience with germline testing and variant classification approaches. Labs of choice for clinical testing must perform gene sequencing, deletion/duplication testing, rearrangement testing for specific genes, confirmatory Sanger sequencing when indicated per standard laboratory protocols, and variant reclassification. It is also important to choose a lab that offers multiple types of panels for testing, including focused cancer panels, large cancer panels, and reflex testing. Patients should be given a choice of panels to address their cancer risk or treatment questions while mitigating potential anxiety that may arise from the receipt of variants of uncertain significance (VUS) which are reported at higher rates from larger panels.1 VUS are genetic changes that do not meet full criteria for classification as “pathogenic/likely pathogenic” and do not impact recommendations at the time of reporting. However, laboratories may reclassify a minority of VUS over time to “pathogenic/likely pathogenic” based on supporting data. Therefore, providers should understand the variant reclassification program and process of labs they are choosing for germline testing of patients. Providers are encouraged to discuss optimal labs of choice with genetic counselors for cohesive testing approaches.

Another important aspect to consider is the collection of family history. As already described, multiple cancers may be associated with PCa risk and may inform genetic testing and subsequent recommendations. Ideal family history collection includes three generations, cancer diagnoses in male and female blood relatives, age at diagnosis, and extent of disease/death from cancer. If a practice has chosen traditional upfront referral to genetic counseling, this full family history would be collected by the genetics professional. If a practice has chosen to have provider-initiated testing with downstream referral to genetic counseling (collaborative or hybrid model of genetic evaluation), intake of full family history by the provider vs. the genetic specialist needs to be addressed (Figure 1).1

Pretest genetic education and informed consent elements are critical to consider when implementing germline testing for PCa. Germline testing may uncover additional cancer risks with management recommendations for men and their families. The 2019 Philadelphia Prostate Cancer Consensus Conference delineated minimal informed consent elements for PCa germline testing, which included discussing purpose of genetic testing, potential to identify hereditary cancer syndromes/multiple cancer risks, possible results (pathogenic/likely pathogenic, VUS, negative, or other complex findings), potential cost of genetic testing, and cascade testing.1 An important consideration is the Genetic Information Nondiscrimination Act (GINA) of 2008 which provides protection from genetic discrimination in most health insurance plans and most employment scenarios (except small businesses with <15 employees). However, GINA does not cover life insurance, long-term care, or disability insurance, which men need to understand prior to proceeding with genetic testing.  Further considerations of informed consent included providing men with options for testing (focused panels vs. large panels vs. reflex testing) and genetic privacy.1 Collaboration with genetic counseling is critical to address the needs of men with strong personal/family history, complex genetic results, anxiety, or preference for full disclosure regardless of results.

In summary, germline testing for PCa is rapidly increasing particularly in the current era of precision medicine. Key genes in DNA repair such as BRCA1 and BRCA2 are paramount to test especially given the recent FDA approvals for PARP inhibitors in the metastatic setting. Additional genes may also need to be tested based upon clinical scenario, personal history of the patient, family history, and for clinical trials eligibility. Germline testing is making an impact in PCa care across the stage and risk spectrum. Urologists and oncologists now find themselves in a unique practice opportunity to address germline testing for DNA repair genes for men with PCa in their practices and are urged to proactively develop collaboration strategies with genetic counseling for comprehensive streamlined genetic evaluation of their patients. 

Written by: Veda N. Giri, MD, Associate Professor, Director, Jefferson Clinical Cancer Genetics Service, Jefferson University Hospital, Philadelphia, Pennsylvania

Published June 2020

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Written by: Veda N. Giri, MD
References: 1. Giri, Veda N., Karen E. Knudsen, William K. Kelly, Heather H. Cheng, Kathleen A. Cooney, Michael S. Cookson, William Dahut et al. "Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019." Journal of Clinical Oncology (2020): JCO-20.
2. Cheng, Heather H., Alexandra O. Sokolova, Edward M. Schaeffer, Eric J. Small, and Celestia S. Higano. "Germline and somatic mutations in prostate cancer for the clinician." Journal of the National Comprehensive Cancer Network 17, no. 5 (2019): 515-521.
3. Mateo, Joaquin, Suzanne Carreira, Shahneen Sandhu, Susana Miranda, Helen Mossop, Raquel Perez-Lopez, Daniel Nava Rodrigues et al. "DNA-repair defects and olaparib in metastatic prostate cancer." New England Journal of Medicine 373, no. 18 (2015): 1697-1708.
4. de Bono, Johann, Joaquin Mateo, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N. Chi et al. "Olaparib for metastatic castration-resistant prostate cancer." New England Journal of Medicine 382, no. 22 (2020): 2091-2102.
5. Abida, Wassim, David Campbell, Akash Patnaik, Jeremy D. Shapiro, Brieuc Sautois, Nicholas J. Vogelzang, Eric G. Voog et al. "Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: Analysis From the Phase II TRITON2 Study." Clinical Cancer Research 26, no. 11 (2020): 2487-2496.
6. Mateo, Joaquin, Nuria Porta, Diletta Bianchini, Ursula McGovern, Tony Elliott, Robert Jones, Isabel Syndikus et al. "Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial." The Lancet Oncology 21, no. 1 (2020): 162-174.
7. Smith, M. R., S. K. Sandhu, W. K. Kelly, H. I. Scher, E. Efstathiou, P. N. Lara, E. Y. Yu et al. "LBA50 Pre-specified interim analysis of GALAHAD: A phase II study of niraparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD)." Annals of Oncology 30, no. Supplement_5 (2019): mdz394-043.
8. National Comprehensive Cancer Network Clinical Guidelines in Oncology (NCCN Guidelines®): Prostate Cancer (Version 4.2019). Accessed June 6, 2020. Available at NCCN.org.
9. National Comprehensive Cancer Network Clinical Guidelines in Oncology (NCCN Guidelines®): Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 1.2020). Accessed June 6, 2020. Available at NCCN.org.
10. Carter, H. Ballentine, Brian Helfand, Mufaddal Mamawala, Yishuo Wu, Patricia Landis, Hongjie Yu, Kathleen Wiley et al. "Germline mutations in ATM and BRCA1/2 are associated with grade reclassification in men on active surveillance for prostate cancer." European urology 75, no. 5 (2019): 743-749.
11. National Comprehensive Cancer Network Clinical Guidelines in Oncology (NCCN Guidelines®): Prostate Cancer Early Detection (Version 2.2019). Accessed June 6, 2020. Available at NCCN.org.
12. National Cancer Institute Genetics of Prostate Cancer (PDQ®)–Health Professional Version. Accessed June 9, 2020. Available at: https://www.cancer.gov
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