Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019
2Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
3Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
4Department of Medicine, University of Washington, and Fred Hutchinson Cancer Research Center, Division of Clinical Research, Seattle, WA
5Duke University School of Medicine and Duke Cancer Institute, Durham, NC
6University of Oklahoma College of Medicine, Norman, OK
7Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
8National Society of Genetic Counselors, Chicago, IL
9Prostate Cancer Foundation, Santa Monica, CA
10Yale Cancer Center, New Haven, CT
11Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
12Dana-Farber Cancer Institute, Boston, MA
13Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
14Department of Laboratory Medicine, University of Washington, Seattle, WA
15The University of Texas MD Anderson Cancer Center, Houston, TX
16Fox Chase Cancer Center, Philadelphia, PA
17Roswell Park Comprehensive Cancer Center, Buffalo, NY
18Moores UC San Diego Comprehensive Cancer Center, San Diego, CA
19Department of Urology, University of California, San Francisco, San Francisco, CA
20James Comprehensive Cancer Center and Department of Internal Medicine, The Ohio State University, Columbus, OH
21University of California, San Francisco, Cancer Genetics and Prevention Program, San Francisco, CA
22Center for Health Research, Genomic Medicine Institute, Geisinger, Danville, PA
23Duke University Medical Center, Durham, NC
24North Shore University Health System, Evanston, IL
25Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
26Northwestern University, Chicago, IL
27Departments of Radiation Oncology, Urology, and Medicine, University of California, San Francisco, San Francisco, CA
28Advocate Aurora Health, Milwaukee, WI
29University of Pennsylvania, Basser Center for BRCA, Philadelphia, PA
30Integra Connect, West Palm Beach, FL
31University of Washington, Seattle, WA
32American Cancer Society, Atlanta, GA
33Urology at Royal Melbourne Hospital, North Melbourne, VIC, Australia
34Johns Hopkins Medical Institutions, Baltimore, MD
35Tulane University, New Orleans, LA
36Brady Urological Institute, Johns Hopkins Medicine, Baltimore, MD
37City of Hope Comprehensive Cancer Center, Duarte, CA
38Washington University School of Medicine, St Louis, MO
39Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
40Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
41The Ohio State University, Columbus, OH
42Henry Jackson Foundation for the Advancement of Military Medicine, Center for Prostate Disease Research, Department of Surgery, Uniformed Services University and the Walter Reed National Military Medical Center, Bethesda, MD
43University of California, San Diego, La Jolla, CA
44Memorial Sloan Kettering Cancer Center, New York, NY
45University of Chicago, Chicago, IL
46Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
47National Cancer Institute, National Institutes of Health, Bethesda, MD
48Mayo Clinic, Rochester, MN
49Department of Urology and Population Health, New York University and Manhattan Veterans Affairs, New York, NY
50Harvard Medical School, Boston, MA
51University of Pennsylvania, Philadelphia, PA
51Brown University, Providence, RI
53University of Michigan, Ann Arbor, MI
54Midlantic Urology, Phoenixville, PA
55Department of Epidemiology, Harvard TH Chan School of Public Health, Boston MA
56University of Utah, Huntsman Cancer Institute, Salt Lake City, UT
57Abington-Jefferson Hospital, Abington, PA
58Prostate Conditions Education Council, Elizabeth, CO
59University of Texas Southwestern Medical Center at Dallas, Dallas, TX
60University of Minnesota and Masonic Cancer Center, Madison, WI
61Cedars-Sinai Medical Center, Los Angeles, CA
62Prostate Cancer International, Virginia Beach, VA
63Northwestern Medical Group, Urology Department, Chicago, IL
64University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA
Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services.
A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider).
Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches.
The role of germline testing (GT) for prostate cancer (PCA) has increased, with growing precision treatment implications and expanded testing options.1,2 A primary driver for GT is now precision therapy for metastatic disease where genetic results inform options and strategies for targeted treatment, therapeutic planning, and clinical trials.1-4 Approximately 12% to 17% of men with metastatic PCA harbor germline mutations, primarily in DNA repair genes, such as BRCA2, CHEK2, BRCA1, ATM, PALB2, and the DNA mismatch repair (MMR) genes,5 which are increasingly informing options for poly (ADP-ribose) polymerase (PARP) inhibitors, immune checkpoint inhibitors, platinum chemotherapy, and clinical trials.1-4,6 In early-stage disease, emerging data suggest that men with germline BRCA2 mutations, and possibly ATM mutations, have higher rates of upgrading of prostate biopsies while on active surveillance (AS).7 GT results are considered increasingly in PCA early detection discussions, particularly for men with BRCA2 mutations for which data support higher rates of PCA detection, younger age at diagnosis, and more clinically significant disease.8-10 Many of the genes that are important for PCA therapy, management, and early detection are associated with hereditary cancer syndromes.11 Pathogenic variants in BRCA1 and BRCA2 are associated with hereditary breast and ovarian cancer (HBOC). DNA MMR genes—MLH1, MSH2, PMS2, MSH6, and EPCAM—are associated with Lynch syndrome.11-16 These and other hereditary cancer syndromes confer risks for multiple cancers that must be addressed for men and their kindred.8,16
As PCA GT has increased, new practice and implementation challenges have emerged in three major areas: expanded options for multigene panels, with a resultant lack of clarity regarding optimized panel use and priority genes to test; variability in guidelines regarding GT indications and genetically based management that incorporates emerging data; and a shortage of genetic services.1,17-21 Testing options have expanded rapidly, which include focused, guideline-based, comprehensive, and reflex panels.17,18 Panels include genes with strong, limited, and unknown risk for PCA and that yet confer risks for multiple cancers.18 There is a need for clarity on panel choice and priority genes to test in men with metastatic PCA, nonmetastatic PCA, and men at high risk for PCA that balances the benefits of expanded testing (eg, identifying actionable mutations) with considerations (eg, higher rates of variants of uncertain significance [VUS]).3,8,10
Uniform guidance is also needed regarding GT indications and genetically based PCA management that incorporates rapidly emerging, sometimes conflicting, data. Current National Comprehensive Cancer Network (NCCN) guidelines have variability regarding GT on the basis of pathologic—stage and Gleason/Grade Group—and family history (FH) criteria.3,8,9 Management guidance is also needed in multiple areas with consideration of gene-specific outcomes, such as treatment of metastatic disease with variable responses by DNA repair mutations1-4,6; AS discussions that consider strong data for BRCA2, but limited data for BRCA1 and ATM7; and broader consideration of genes for PCA early detection.1,2,11 In particular, strategies for PCA early detection need clarification regarding age to begin screening on the basis of genetic status.8,9
Furthermore, the rising need for PCA GT has created a critical shortage of genetic counseling (GC) services.1,19 Health care providers, such as oncologists and urologists, increasingly are ordering PCA GT to expedite testing for management.20,21 Concerns include limited guidance on optimal pretest informed consent, optimal panel testing strategies for comprehensive genetic evaluation, inclusion of personal history and FH, and balancing timely GT with appropriate referral to GC to address patient and family needs.1,20,21 As referral of all men to GC for PCA GT is not sustainable, health care and genetic providers need implementation strategies that incorporate alternate genetic evaluation models for the timely and responsible delivery of PCA GT for men and their families.1,19
The 2019 Philadelphia Prostate Cancer Consensus Conference was convened to address challenges in PCA germline evaluation and implementation with attention to evolving genetic and precision medicine data. This meeting was a follow-up to the 2017 Philadelphia Consensus Conference, which focused on the role of GT for inherited PCA risk.18 The 2019 conference had the following 3 goals: to define optimal GT strategies that incorporate expansion of panel testing options and evolving genetic data, to propose consistent PCA GT indications and management, and to propose alternate genetic evaluation models to address the GC shortage. An expert, consensus-driven genetic implementation framework was developed for health care and genetic providers to streamline GT for PCA in the precision medicine era.
The following questions were primary drivers of the conceptual framework:
Which men should be considered for germline PCA genetic testing?
Which panels should be considered and which genes should be prioritized for testing?
What PCA-specific recommendations should be considered on the basis of genetic results?
What is optimal informed consent for PCA GT?
What collaborative strategies may facilitate PCA genetic evaluation between health care and genetic providers?
What post-test disclosure strategies are most appropriate on the basis of genetic results?
What barriers must be addressed to enhance PCA GT?
The Consensus Conference included 97 participants spanning the fields of urology, medical oncology, radiation oncology, clinical genetics, genetic counseling, primary care, pathology, implementation science, population science, epidemiology, and basic science. Patient stakeholders and advocates were active participants. Members of several national organizations, which included NCCN representatives, also participated. Academic and community practices were represented, and panelists were from multiple regions of the United States, as well as Europe and Australia. The final voting panel included 76 participants (Table 1).
The modified Delphi model was followed that incorporated elements of the Delphi process as previously published.18,22,23 Literature was provided to panel members before the meeting. Multiple expert presentations summarizing evidence relevant to genetic implementation were delivered. Evidence review is summarized in the Data Supplement.
Thematic topics included: genetic contribution to PCA risk/aggressiveness24-54; germline mutations by PCA clinical and molecular characteristics5,55-66; PCA clinical multigene testing data60,61,67; germline mutations in diverse populations5,24,30,49,61,68-74; PCA genetic testing capabilities and considerations17,75-81 (Fig 1); implementation of GC1,3,8,9,17,76,82-93; NCCN PCA genetic testing guidelines and current variability3,8,9; GT for PCA precision medicine in the metastatic setting2,4,6,56,58,94-99; germline implications for AS of early-stage PCA7,35,99,100,101; and germline implications for PCA early detection.8-10,102 Table 2 provides a summary of genetic data for PCA risk and aggressiveness. Full evidence summary is provided in the Data Supplement.
Votes were cast anonymously using a Web-based polling platform. Strength of consensus was ≥ 75% agreement for strong consensus, 50% to 74% agreement for moderate consensus, and < 50% agreement for lack of consensus.22,23
A conceptual framework for PCA genetic evaluation and management was developed (Fig 2). Criteria that achieved strong consensus were designated as “Recommend” and those with moderate consensus were designated as “Consider” in the final framework.
The following are guiding principles for clinical genetic evaluation:
Men should engage in informed decision making for genetic testing (Recommend).
Building collaborations between health care and genetics providers is important for optimal genetic evaluation (Recommend).
NCCN guidelines (NCCN Prostate Version 4.2019 and NCCN Breast/Ovary Version 3.2019) at the time of the 2019 Consensus meeting had varying indications for PCA GT.3,8 Data regarding clinical, pathologic, and FH features were summarized (Data Supplement).
Any one of the following criteria may prompt GT:
Men with metastatic PCA (castration resistant or castration sensitive; Recommend).
Men with nonmetastatic PCA—one of the following:
○ Ashkenazi Jewish ancestry (Consider).
○ Advanced disease (T3a or higher; Consider).
○ Intraductal/ductal pathology (Consider).
○ Grade Group 4 (Gleason sum 8) or above (Consider).
○ PCA FH criteria:
• Men with one brother or father or two or more male relatives with one of the following:
•Diagnosed with PCA at age < 60 years (Recommend).
• Any of whom died of PCA (Recommend).
•Any of whom had metastatic PCA (Recommend).
○ FH of other cancers:
• Two or more cancers in HBOC or Lynch spectrum in any relatives on the same side of the family (especially if diagnosed at age < 50 years; Consider).
FH consistent with hereditary PCA achieved a strong recommendation for GT. Additional FH criteria were expanded to consider 2 or more cancers in the HBOC or Lynch spectrum to account for limitations in self-reported FH. Genes corresponding to specific cancers are listed in Table 2. Of note, an unremarkable FH does not necessarily negate consideration of GT, particularly for treatment decisions in the metastatic setting.
All pathologic criteria achieved moderate agreement. Universal screening for Lynch syndrome in PCA is not current practice; however, if immunohistochemistry is performed on a prostate specimen revealing loss of the DNA MMR genes, and particularly MSH2, the recommendation is to proceed with GT to determine if the patient has Lynch syndrome given the significant cancer risks and potential treatment implications. Panelists noted that many centers do not report intraductal/ductal pathology or immunohistochemistry for Lynch syndrome markers, which must be addressed with pathologists.
Although multiple unique questions were posed specifically regarding GT for African American men, none met consensus agreement as a result of limited data. Until additional research is completed, testing guidelines as described herein should be applied in under-represented populations.
Guidance on the use of various gene panels adapted to clinical scenarios is needed given the rapid expansion of panel options and the inclusion of genes with limited association to PCA risk or PCA treatment implications (Fig 1). Furthermore, NCCN guidelines vary regarding genes to test,3,8 necessitating consensus prioritization of genes for testing (Data Supplement).
Focused—guidelines-based—panels (approximately 5 to 6 genes), PCA-specific panels (approximately 10 to 15 genes), comprehensive cancer panels (approximately 80 genes), and reflex panels (initial set of genes tested followed by broad gene testing) were considered. Benefits and limitations of various panels were also considered (Data Supplement).
BRCA1, BRCA2, HOXB13, CHEK2, ATM, NBN, MSH2, MSH6, MLH1, PMS2, PALB2, BRIP1, TP53, and Fanconi anemia genes were considered.
○ Comprehensive (large) panel testing for therapy/clinical trial eligibility (Recommend).
○ Priority germline testing:
• BRCA2/BRCA1 (Recommend).
• DNA MMR genes (Recommend).
• ATM (Consider).
• Test additional genes on the basis of personal or FH (Recommend).
○ Somatic testing:
• Somatic next-generation sequencing for all men with metastatic PCA (Recommend).
• Confirmatory germline testing for somatic mutations:
• BRCA2 (Recommend).
• BRCA1, DNA MMR genes, ATM (Consider).
• Test additional genes on the basis of personal or FH (Table 2; Recommend).
○ Reflex testing may be optimal (Consider).
○ Priority genes particularly to inform AS:
• BRCA2 (Recommend).
• ATM (Consider).
• Test additional genes on the basis of personal or FH (Table 2; Recommend).
Men without a diagnosis of PCA meeting FH testing criteria:
○ Reflex testing may be optimal (Consider).
○ Priority genes for risk assessment:
• BRCA2 (Recommend).
• HOXB13 (Recommend).
• BRCA1, ATM, DNA MMR genes (Consider).
• Test additional genes on the basis of personal or FH (Table 2; Recommend).
For men with metastatic PCA, broader panel testing may be appropriate, particularly if considering treatment or clinical trial options (Table 2, Fig 2, and Data Supplement). Reflex testing may be considered for all patients, but especially for men with nonmetastatic disease considering AS or men without PCA for early detection, which allows for initial testing of genes that inform management (Data Supplement). Reflex testing also allows for testing of additional genes to account for personal cancer or FH at a later time for comprehensive genetic evaluation and may also be more amenable to collaborative genetic evaluation models (see below).
Among MMR genes, MSH2 has the strongest association to PCA; however, it is recognized that MLH1, PMS2, MSH6, and EPCAM also need to be tested to establish the diagnosis of Lynch syndrome. Full MMR testing also may be important for treatment consideration or clinical trials in the metastatic setting; therefore, full Lynch syndrome testing is recommended as indicated.
In addition, confirmatory GT is recommended for men with somatic BRCA2 mutations and may be beneficial for somatic mutations in BRCA1, MMR genes, and ATM to identify hereditary cancer predisposition. Additional GT beyond these genes may also be recommended on the basis of personal and FH. Consultation with a genetics professional is advised.
There is a need for consensus agreement on genetically informed PCA treatment, management, and early detection1,2 (Data Supplement). An additional challenge is inconsistency in NCCN genetically based PCA early detection recommendations regarding which genes to consider and the age at which to begin screening8,9 (Data Supplement).
Genes considered included BRCA1, BRCA2, HOXB13, CHEK2, ATM, NBN, MSH2, MSH6, MLH1, PMS2, PALB2, BRIP1, TP53, and Fanconi anemia genes.
Metastatic PCA: GT to inform precision therapy:
○ Enrollment of men with PCA in precision medicine trials is endorsed (Recommend).
○ Mutations in the following genes may inform response to PARP inhibitors:
• BRCA2 (Recommend).
• BRCA1 (Consider).
○ Mutations in the following genes may inform response to platinum-based chemotherapy:
• BRCA2 (Consider).
• BRCA1 (Consider).
○ Men with DNA repair gene mutations, after progression on abiraterone, may proceed with PARP inhibitor rather than taxane (Consider).
○ Germline mutations in the following genes may inform response to anti–programmed death 1 (PD-1) therapy:
• DNA MMR genes (Consider).
• NOTE. The US Food and Drug Administration has granted accelerated approval for anti–PD-1 therapy for microsatellite instability-high/MMR-deficient tumors.
Nonmetastatic PCA: to inform AS discussions:
○ BRCA2 (Recommend).
○ ATM (Consider).
Men without a PCA diagnosis to inform PCA early detection:
○ Referral to specialty PCA high-risk clinics and/or early detection trials was endorsed (Recommend).
○ PCA early detection starting at age 40 years or 10 years before the youngest PCA diagnosis in family:
• BRCA2 (Recommend).
• BRCA1, HOXB13, ATM, and DNA MMR genes (particularly MSH2; Consider).
In the metastatic setting, a broad spectrum of genes may be important in determining clinical trial eligibility, and emerging data should continue to refine recommendations. ATM garnered consideration for testing, primarily for clinical trial eligibility; however, the panel did not feel that there was sufficient data to endorse ATM for informing therapy to PARP inhibitors off study because of the limited independent association to PARP inhibitor response at this time (Data Supplement). ATM also garnered moderate consensus for informing AS, but there are limited data at this time (Data Supplement).
For anti–PD-1 therapy, the US Food and Drug Administration has granted accelerated approval for tumors that are microsatellite instability-high or MMR deficient. The panel had moderate consensus regarding a definitive recommendation for anti–PD-1 therapy off study for men with germline MMR mutations, with stronger consideration for clinical trials.
Regarding AS discussions, clinicopathologic criteria, age, and overall health must be considered. BRCA1 did not achieve consensus for inclusion in AS as a result of limited data for PCA aggressiveness (Data Supplement). Polygenic risk score data were reviewed77-81 and did not achieve consensus.
Current practice guidelines do not provide guidance to health care providers regarding optimal informed consent for PCA GT.
Recommend discussing: (1) the purpose of GT; (2) the possibility of uncovering hereditary cancer syndromes; (3) potential types of test results; (4) the potential to uncover additional cancer risks; (5) potential out-of-pocket cost; (6) Genetic Information Nondiscrimination Act law and other laws that address genetic discrimination; and (7) cascade testing/additional familial testing.
Consider discussing: (1) multigene panel options; (2) data sharing/data selling policies of genetic laboratories; and (3) the privacy of genetic tests.
These elements of pretest informed consent apply to all men who are considering PCA GT76,82-84 (Fig 2). Such GC aids as handouts or videos may be useful to deliver this information. However, informed consent is a process during which patients have opportunities to ask questions76,82-84; therefore, a question-and-answer process must be available before testing. Clinicians without specific training/expertise in GC/GT are urged to refer patients to GC before ordering GT. Furthermore, it is important to remain current on the ethics/informed consent process for GT because of the rapidly evolving nature of precision medicine.
Multidisciplinary guidance on the implementation of collaborative models between health care providers and GC is currently lacking.103 There is a need to address alternate GC models for timely GT with attention to appropriate pretest informed consent and comprehensive evaluation.
The following strategies were endorsed (Data Supplement and Fig 3):
Practices should consider multiple models to address patients’ needs (Fig 3), including point-of-care models with limited or full pretest FH collection as well as traditional model with upfront referral to GC (Recommend).
Videos may be useful to deliver pretest informed consent (Recommend).
In point-of-care models, reflex genetic testing may be optimal to enable additional testing on the basis of personal/FH (Consider).
Telehealth/telephone delivery of GC is a suitable alternative to in-person GC (Recommend for men with PCA; Consider for unaffected males).
If limited pretest FH is collected, practices must proactively address the collection of FH in the post-test setting. Reflex testing enables future testing to account for personal/FH. Telehealth/telephone GC was endorsed to address geographic barriers to GC, although patient outcomes data in males are lacking. Key process questions for practices to consider when implementing point-of-care versus traditional GC models were discussed (Data Supplement).
Joint guidance from oncologists, urologists, and genetic counselors for referral to GC is currently lacking.
Referral to a GC for pathogenic/likely pathogenic results (Recommend).
Patients should receive FH-based recommendations, either in health care or genetic practices (Recommend).
Cascade/additional familial testing should be conducted in consultation with a genetic professional (Recommend).
There was no consensus regarding referral of men with VUS or negative results; therefore, providers will need to determine their ability to discuss VUS results and FH-based recommendations. VUS reclassification to “pathogenic/likely pathogenic” and subsequent management are critical for ordering providers to consider and may support the referral of select men with suspicious VUS to GC. Men with FH of cancers may also warrant referral to GC.
Multiple practice, research, and policy gaps pose barriers to PCA GT.
The following areas achieved strong or moderate consensus to address:
As GT for PCA has rapidly increased, responsible implementation of testing and management are of primary concern.1,2,19,23 Current practice challenges that pose barriers to operationalizing PCA GT include the variability in testing indications and genetically based management, the need for guidance on panels and priority genes to test, and guidance regarding alternate evaluation models to address GC demand. The 2019 Philadelphia Prostate Cancer Consensus Conference was a focused attempt to address these critical challenges and practice gaps by developing a first-in-field working framework for PCA genetic evaluation, management, and implementation informed by best evidence and expert guidance.
The strength of the consensus framework is the creation of a unified approach regarding GT indications, genetically informed management and treatment, and the integration of GC. Multiple aspects of the framework had strong evidence and strong expert agreement to deem a definitive action of “Recommend”. The strongest recommendations encompassed testing all men with metastatic PCA or men with FH suggestive of hereditary PCA. Priority genes for testing included BRCA2, BRCA1, and the DNA MMR genes in metastatic disease to inform treatment or clinical trials; BRCA2 for AS discussions; and BRCA2 and HOXB13 for PCA early detection discussions. This was the first formal, multidisciplinary endorsement for broad panel testing among men with metastatic PCA, recognizing that genetic information may enable men to enroll in clinical trials. Consensus emerged regarding strategies for PCA early detection on the basis of genetic status. For male carriers of BRCA2, a recommendation was made to begin PSA screening at age 40 years or 10 years before the youngest PCA diagnosis in a family and is modeled after colorectal cancer guidelines.16
An important aspect to the genetic evaluation framework was the integration of care processes and GC to account for the increasing need for GC. Strong recommendations were made for optimal pretest informed consent. Recommended strategies to deliver GC included collaborative GC models, videos, and telehealth to facilitate GT through health care practices and to collaborate with GC. Reflex testing garnered moderate consensus and may be considered, particularly when using collaborative counseling models to enable upfront testing by health care providers, followed by testing additional genes using GC for comprehensive genetic evaluation. In the post-test setting, strong recommendations were made to refer all men with pathogenic mutations to GC, to conduct cascade testing of relatives under the care of genetics professionals, and to determine the delivery of FH-based recommendations.
The panel dealt with many uncertainties in recommendations which garnered moderate consensus. Whereas many genes have a lower level of evidence for PCA risk, aggressiveness, or treatment response, several clinically available multigene panels include lower evidence genes. To indicate these nuances in limited data or moderate consensus, many criteria were designated as “Consider” in the framework. Pathologic criteria for testing, such as disease stage, intraductal/ductal histology, or Grade Group ≥ 4, garnered moderate consensus and therefore are included as suggestive criteria for testing.63,65,66 Ashkenazi Jewish ancestry as a standalone criterion achieved moderate consensus, but may be a stronger consideration for testing for men with higher Gleason score per current NCCN guidelines.8 Whereas PCA has been linked with HBOC and Lynch syndrome, a working definition of familial features that increase the likelihood of detecting germline mutations is needed. As such, having two or more relatives with cancers in the HBOC or Lynch syndrome spectrum garnered moderate consensus as standalone criteria and may be considered for GT on the basis of patient preference and insurance coverage.
Priority genes to test also presented challenges, particularly regarding ATM, DNA MMR genes, and HOXB13. Initial data have reported that men with ATM mutations experienced clinical response to PARP inhibitors94; however, follow-up studies have reported a limited independent effect of ATM.99 Similarly, studies in AS had limited association of ATM mutations alone with upgrading of biopsies.7 Until additional data are available, ATM was given a designation of “Consider” for testing, recognizing the potential for clinical trial options for ATM carriers. Additional uncertainties were encountered regarding prioritizing MMR genes for GT. Among MMR genes, MSH2 has the highest reported association to PCA.41 Although other MMR genes have lower or limited association to PCA, the potential to uncover Lynch syndrome and clinical trial eligibility drove the suggestion to consider full Lynch syndrome testing. MSH2 status may be more informative for PCA early detection discussions.41 HOXB13 has strong association to PCA risk and early-onset disease, though screening outcomes data are limited. Therefore, the consensus panel recommended testing for HOXB13 and to consider the results in early detection discussions. Overall, BRCA1, HOXB13, and MMR genes were designated as “Consider” for beginning screening at age 40 years or 10 years before the youngest PCA diagnosis in the family because of the currently limited screening data.9 Data from screening studies, such as IMPACT and the National Cancer Institute (ClinicalTrials.gov identifier: NCT03805919), will be important to reconsider strengthening these recommendations.10 However, this is the first time that screening strategies based on a larger genetic spectrum have been proposed. Additional research in African American males is vitally needed. Future consideration of circulating tumor and cell-free DNA is also warranted.
In conclusion, the 2019 Consensus Conference created the first multidisciplinary PCA genetic implementation framework tailored to the precision medicine era. The framework, which importantly had input from NCCN panel leaders, provides guidance to a spectrum of providers to facilitate timely and responsible PCA GT for the benefit of men and their families.
Supported by National Institutes of Health Cancer Center Support Grant 5P30CA056036-19, Foundation Medicine, Myriad, Bayer, Clovis Oncology, BioReference Laboratories, Ferring Pharmaceuticals, Philadelphia Father’s Day Run, Invitae, AstraZeneca, Janssen Oncology, Roche, UroSeq, Color, OncLive, Physician Education Resource, and MDx Health.
The contents of this manuscript are not to be construed as official or reflecting the views of the Department of Defense, the Uniformed Services University of the Health Sciences, or any other agency of the US Government. This manuscript does not constitute endorsement or implied endorsement on the part of the Department of Defense or any component agency.
Conception and design: Veda N. Giri, Karen E. Knudsen, William K. Kelly, William Dahut, Howard R. Soule, Adam P. Dicker, Amanda E. Toland, Mary B. Daly, Peter R. Carroll, Amie Blanco, Ashley Woodson, Mary-Ellen Taplin, Jacqueline Powers, Richard Wender, Anthony Costello, Anne Calvaresi, Thenappan Chandrasekar, James Eastham, Costas Lallas, Ana Maria Lopez, Mark Mann, Martin M. Miner, Lorelei Mucci, Ronald E. Myers, Brock O’Neil, Peter Pinto, Timothy R. Rebbeck, Charles Ryan, E. Michael D. Scott, Leonard G. Gomella
Administrative support: Leonard G. Gomella
Provision of study materials or patients: Veda N. Giri, Leonard G. Gomella
Collection and assembly of data: Veda N. Giri, William K. Kelly, Heather H. Cheng, Kathleen A. Cooney, Scott Weissman, Adam P. Dicker, Saud AlDubayan, Amanda E. Toland, Colin C. Pritchard, Curtis A. Pettaway, Mary B. Daly, James L. Mohler, Peter R. Carroll, Ashley Woodson, Alanna Rahm, Mary-Ellen Taplin, Thomas J. Polascik, Brian T. Helfand, Colette Hyatt, Alicia K. Morgans, Felix Feng, Raoul Concepcion, Daniel W. Lin, Richard Wender, James Ryan Mark, William B. Isaacs, Jianfeng Xu, Jeffrey Weitzel, Lindsey Byrne, Anne Calvaresi, Thenappan Chandrasekar, Patrick T. Gomella, Nathan Handley, Joseph Izes, R. Jeffrey Karnes, Ana Maria Lopez, S. Bruce Malkowicz, Mark Mann, Patrick Mille, Sarah M. Nielsen, Brock O’Neil, Peter Pinto, Wendy Poage, Timothy R. Rebbeck, Howard Sandler, E. Michael D. Scott, Brittany Szymaniak, Neha Vapiwala, Charnita Zeigler-Johnson, Leonard G. Gomella
Data Analysis and interpretation: Veda N. Giri, William K. Kelly, Heather H. Cheng, Kathleen A. Cooney, Michael S. Cookson, William Dahut, Scott Weissman, Daniel P. Petrylak, Colin C. Pritchard, Curtis A. Pettaway, James L. Mohler, J. Kellogg Parsons, Peter R. Carroll, Robert Pilarski, Ashley Woodson, Alanna Rahm, Mary-Ellen Taplin, Thomas J. Polascik, Brian T. Helfand, Alicia K. Morgans, Felix Feng, Michael Mullane, Richard Wender, Arthur L. Burnett, Oliver Sartor, Jeffrey Weitzel, Gerald L. Andriole, Himisha Beltran, Alberto Briganti, David Y. T. Chen, Robert B. Den, Albert Dobi, E. David Crawford, James Eastham, Scott Eggener, Matthew L. Freedman, Marc Garnick, Mark D. Hurwitz, Joseph Izes, R. Jeffrey Karnes, Lucia Languino, Stacy Loeb, Ana Maria Lopez, Kevin R. Loughlin, Grace Lu-Yao, S. Bruce Malkowicz, Mark Mann, Patrick Mille, Martin M. Miner, Todd Morgan, Jose Moreno, Wayne Pinover, Peter Pinto, Ganesh V. Raj, Matthew Schiewer, William Tester, Edouard J. Trabulsi, Neha Vapiwala, Evan Y. Yu, Leonard G. Gomella
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
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Stock and Other Ownership Interests: Pfizer, Genomic Health
Honoraria: CellCentric, Sanofi
Consulting or Advisory Role: CellCentric, Sanofi, Atrin Pharmaceuticals, Context Therapeutics
Research Funding: Celgene
Travel, Accommodations, Expenses: Sanofi, Genentech
Honoraria: Janssen Oncology, Bayer
Consulting or Advisory Role: Merck Sharp & Dohme
Research Funding: Sanofi (Inst), Novartis (Inst), Janssen Oncology (Inst), Bayer (Inst), Exelixis (Inst), Seattle Genetics (Inst), Endocyte (Inst), Amgen (Inst), BioClin Therapeutics (Inst), Sarah Cannon Research Institute (Inst), F Hoffman-La Roche (Inst)
Travel, Accommodations, Expenses: Janssen Oncology, Merck Sharp & Dohme
Research Funding: Inovio Pharmaceuticals (Inst), Sanofi (Inst), Astellas Medivation (Inst), Janssen Oncology (Inst), Clovis Oncology (Inst), Color Foundation (Inst)
Patents, Royalties, Other Intellectual Property: Patent awarded for discovery of HOXB13 as prostate cancer susceptibility gene (Inst)
Travel, Accommodations, Expenses: Boston Scientific (I)
Honoraria: Merck, Janssen Biotech, Bayer, Astellas Pharma, Myovant Sciences
Consulting or Advisory Role: Merck, Janssen Biotech, MDxHealth, Bayer, Astellas Pharma, Myovant Sciences, TesoRx Pharma, Genomic Health, Ferring Pharmaceuticals, Precision Biopsy
Employment: Genome Medical
Stock and Other Ownership Interests: Genome Medical
Consulting or Advisory Role: Compugen, WindMIL
Travel, Accommodations, Expenses: Compugen, Sanofi, WindMIL
Stock and Other Ownership Interests: Bellicum Pharmaceuticals, TYME
Consulting or Advisory Role: Bayer, Exelixis, Pfizer, Roche, Astellas Pharma, AstraZeneca, Eli Lilly, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Incyte, Janssen Oncology, Pharmacyclics, Seattle Genetics, Urogen Pharma, Advanced Accelerator Applications, Ipsen
Research Funding: Progenics (Inst), Sanofi (Inst), Endocyte (Inst), Genentech (Inst), Merck (Inst), Astellas Medivation (Inst), Novartis (Inst), AstraZeneca (Inst), Bayer (Inst), Eli Lilly (Inst), Innocrin Pharma (Inst), MedImmune (Inst), Pfizer (Inst), Roche (Inst), Seattle Genetics (Inst), Clovis Oncology (Inst), Bristol Myers Squibb (Inst), Advanced Accelerator Applications (Inst)
Expert Testimony: Celgene, Sanofi
Leadership: Department of Defense-Prostate Cancer Research Program, NRG Oncology, American Society for Radiation Oncology
Stock and Other Ownership Interests: Oncohost, Self Care Catalyst
Consulting or Advisory Role: EMD Serono, Janssen Oncology, Self Care Catalyst, Celldex, Johnson & Johnson, Roche, Apex, Cybrexa Therapeutics, Oncohost, Thirdbridge, Accordant
Research Funding: Prostate Cancer Foundation
Patents, Royalties, Other Intellectual Property: Recently filed patent “Doped BEO Compounds for Optically Stimulated Luminescence (OSL) and Thermoluminescence (TL) Radiation Dosimetry”
Expert Testimony: Wilson, Socini
Travel, Accommodations, Expenses: Merck, Ferring Pharmaceuticals, Self Care Catalyst, EMD Serono, Oncohost
Other Relationship: Dreamit Ventures
Uncompensated Relationships: Google
Consulting or Advisory Role: Promega
Consulting or Advisory Role: Wolters-Kluwer
Research Funding: Beckmann-Coulter, MDxHealth
Patents, Royalties, Other Intellectual Property: Mohler JL, Fiandalo M, Watt D, Sviripa V: Compounds and methods to impair androgen receptor (AR) activation, impair dimerization, and/or impair AR transregulation. US provisional patent application 62/839,676, filed 4/27/2019, by Health Research & University of Kentucky Research Foundation (Inst); Mohler JL, Fiandalo M, Watt D, Sviripa V: Inhibitors of androgen receptor activation and methods of making and using same. US provisional patent application 62/890,292, filed 8/22/2019, by Health Research & University of Kentucky Research Foundation (Inst); Mohler JL, Fiandalo M, Watt D, Sviripa V: Spirocyclic dihydrotestosterone as ligand for proteolysis chimeras for AR degradation, imaging agents, and screening tools for the treatment of prostate cancer. US provisional patent application 62/844,062, filed 5/6/2019, by Health Research & University of Kentucky Research Foundation (revised; Inst)
Stock and Other Ownership Interests: Urigen, Pfizer, Johnson & Johnson, Omega Healthcare Investors
Honoraria: Sophiris Bio
Travel, Accommodations, Expenses: Sophiris Bio
Other Relationship: MDxHealth
Honoraria: Intuitive Surgical
Consulting or Advisory Role: Nutcracker Therapeutics
Employment: Biomarin (I)
Stock and Other Ownership Interests: Biomarin (I)
Employment: Genome Medical
Travel, Accommodations, Expenses: Genome Medical
Honoraria: Janssen-Ortho, Clovis Oncology, Astellas Pharma, Incyte, UpToDate, Research to Practice, Pfizer, Bayer, Amgen, AstraZeneca, Progenics, Guidepoint Global, Celegen, Merck
Consulting or Advisory Role: Janssen-Ortho, Bayer, Guidepoint Global, Best Doctors, UpToDate, Clovis Oncology, Research to Practice, Myovant Sciences, Incyte, Pfizer, AstraZeneca
Research Funding: Janssen-Ortho (Inst), Medivation (Inst), Bayer (Inst), Pfizer (Inst)
Travel, Accommodations, Expenses: Medivation, Janssen Oncology, Tokai Pharmaceuticals, Astellas Pharma, Incyte, Pfizer, Clovis Oncology, Bayer
Speakers' Bureau: Exact Sciences, Ambry Genetics
Stock and Other Ownership Interests: GenomeSmart
Consulting or Advisory Role: GenomeSmart
Honoraria: Genentech, Janssen Oncology, Sanofi, AstraZeneca, Astellas Scientific and Medical Affairs, Astellas Colombia, Janssen Oncology, Bayer
Consulting or Advisory Role: Genentech, AstraZeneca, Sanofi, Bayer, Astellas Pharma, Janssen Oncology
Research Funding: Bayer, Seattle Genetics, Astellas Pharma, Genentech, AstraZeneca
Travel, Accommodations, Expenses: Sanofi
Leadership: PFS Genomics
Stock and Other Ownership Interests: PFS Genomics, Nutcracker Therapeutics, SerImmune
Consulting or Advisory Role: Bayer, Blue Earth Diagnostics, Celgene, Medivation, Astellas Pharma, Sanofi, Genzyme, EMD Serono, Janssen Biotech
Research Funding: Zenith Epigenetics
Patents, Royalties, Other Intellectual Property: Develop a molecular signature to predict radiation resistance in breast cancer, and this signature was patented by the University of Michigan; in the process of being licensed to PFS Genomics, a company that the author helped found (Inst)
Employment: Carevive Systems
Honoraria: CureConnect, Myriad Genetics
Consulting or Advisory Role: Carevive Systems
Travel, Accommodations, Expenses: Hospital of the University of Pennsylvania
Honoraria: Clovis Oncology, InVitae
Consulting or Advisory Role: IntegraConnect
Speakers' Bureau: Astellas Medivation, Janssen Oncology, Dendreon, Amgen
Consulting or Advisory Role: Astellas Pharma, Clovis Oncology, Dendreon
Research Funding: Genomic Health (Inst), GenomeDx (Inst), MDxHealth (Inst), Magforce
Honoraria: Myriad Genetics, Novartis Pharmaceuticals, Futura Medical, Astellas Pharma, Boston Scientific (Inst)
Consulting or Advisory Role: Myriad Genetics, Novartis Pharmaceuticals, Futura Medical, Astellas Pharma
Patents, Royalties, Other Intellectual Property: Patents for the development of devices that may be used in pelvic surgeries, such as penile prosthesis implantation
Uncompensated Relationships: Comphya, Reflexonic
Stock and Other Ownership Interests: Eli Lilly, GlaxoSmithKline, AbbVie, Cardinal Health, United Health Group, Varian Medical Systems, PSMA Therapeutics
Consulting or Advisory Role: Bayer, Johnson & Johnson, Sanofi, AstraZeneca, Dendreon, Endocyte, Constellation Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol Myers Squibb, Bavarian Nordic, EMD Serono, Astellas Pharma, Progenics, Noxo, Blue Earth Diagnostics, Myovant, Myriad Genetics, Novartis, Clovis Oncology, Novartis
Research Funding: Bayer (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Endocyte (Inst), Innocrin Pharma (Inst), Merck (Inst), InVitae (Inst), Constellation Pharmaceuticals (Inst), Advanced Accelerator Applications (Inst), AstraZeneca (Inst), Dendreon (Inst), SOTIO
Expert Testimony: Sanofi
Travel, Accommodations, Expenses: Bayer, Johnson & Johnson, Sanofi, AstraZeneca, Progenics
Travel, Accommodations, Expenses: AstraZeneca
Patents, Royalties, Other Intellectual Property: US9534256 B2: Methods and compositions for correlating genetic markers with risk of aggressive prostate cancer; US9534256 B2: Methods and compositions for correlating genetic markers with risk of aggressive prostate cancer; US9732389 B2: Methods and compositions for correlating genetic markers with prostate cancer risk; informal title: 33 SNPs for PCa risk
Speakers' Bureau: AstraZeneca
Consulting or Advisory Role: Janssen Oncology, Genzyme, GlaxoSmithKline, AbbVie, Astellas Pharma, AstraZeneca, Pfizer
Research Funding: Janssen Oncology (Inst), AbbVie (Inst), Stemcentrx (Inst), Eli Lilly (Inst)
Travel, Accommodations, Expenses: Janssen Oncology
Consulting or Advisory Role: Astellas Pharma, Janssen-Cilag, OPKO Health, MDxHealth, Ferring Pharmaceuticals
Speakers' Bureau: Astellas Pharma
Research Funding: Sandoz-Novartis, Merck Sharp & Dohme
Stock and Other Ownership Interests: Pfizer, Pfizer (I)
Employment: Alpha TAU
Patents, Royalties, Other Intellectual Property: Inventor of the ERG monoclonal antibody 9FY, licensed by the Biocare Medical; inventor of a urine biomarker panel, licensed by Exosome Diagnostics
Speakers' Bureau: Bayer, Ferring Pharmaceuticals
Stock and Other Ownership Interests: 3D Biopsy
Consulting or Advisory Role: Sophiris Bio, Francis Medical, InSightec, Profound Medical
Speakers' Bureau: Janssen Pharmaceuticals
Travel, Accommodations, Expenses: Janssen Biotech, InSightec, Sophiris Bio
Uncompensated Relationships: Steba Biotech
Stock and Other Ownership Interests: Immunogen, Exelixis, Dr. Consulta (Sao Paulo Brazil), Myovant
Consulting or Advisory Role: Dr. Consulta (Sao Paulo Brazil), Eli Lilly, Amag, Steba Biotech, Agile Therapeutics, Janssen Oncology, Karyop
Expert Testimony: Fitzpatrick Cella Harper and Scinto, US Department of Justice, Meyers ad Flowers
Research Funding: Nektar Therapeutics (Inst)
Consulting or Advisory Role: Neotherma
Speakers' Bureau: Pyrexar
Patents, Royalties, Other Intellectual Property: Provision patent holder for hyperthermia delivery system
Patents, Royalties, Other Intellectual Property: GenomeDx
Travel, Accommodations, Expenses: GenomeDx
Stock and Other Ownership Interests: Johnson & Johnson
Stock and Other Ownership Interests: Gilead Sciences (I)
Consulting or Advisory Role: Bayer, Lumenis
Travel, Accommodations, Expenses: Sanofi
Employment: Sun Pharma Advanced Research Company (I)
Leadership: Sun Pharma Advanced Research Company (I)
Stock and Other Ownership Interests: Merck (I)
Consulting or Advisory Role: Myriad Genetics, TerumoBCT
Research Funding: Myriad Genetics (Inst), MDxHealth (Inst), GenomeDx (Inst)
Stock and Other Ownership Interests: Illumina, Invitae, ThermoFisher Scientific, Exact Sciences, Guardant Health, Bio-Techne
Research Funding: Janssen Pharmaceuticals, Pfizer, Pillar Biosciences
Research Funding: Sanofi (Inst), Astellas Pharma (Inst), Bayer (Inst), Janssen Pharmaceuticals (Inst)
Consulting or Advisory Role: Exact Sciences
Stock and Other Ownership Interests: Invitae
Consulting or Advisory Role: AstraZeneca, Merck, Myriad Genetics
Speakers' Bureau: AstraZeneca
Travel, Accommodations, Expenses: Myriad Genetics, AstraZeneca, Invitae
Patents, Royalties, Other Intellectual Property: Royalties from US Patent No. 8948845: “System, methods, and instrumentation for image guided prostate treatment”, with inventors/authors Brad Wood and Peter Pinto; the National Institutes of Health (NIH) and Philips (InVivo) have a licensing agreement. NIH does not endorse or recommend any commercial products, processes, or services. The views and personal opinions of authors expressed herein do not necessarily state or reflect those of the US Government, nor any official recommendation or opinion of the NIH or National Cancer Institute.
Stock and Other Ownership Interests: 3D Biopsy
Honoraria: Janssen Oncology, Myriad Genetics
Travel, Accommodations, Expenses: Pfizer, Dendreon, Janssen Oncology, Myriad Genetics
Stock and Other Ownership Interests: EtiraRx,C-Diagnostics
Honoraria: Medivation, Janssen Biotech, Sanofi, Astellas Pharma
Consulting or Advisory Role: Pfizer, Bayer
Speakers' Bureau: Astellas Pharma
Research Funding: Janssen Biotech, Bayer
Patents, Royalties, Other Intellectual Property: Licensing
Honoraria: AstraZeneca (I)
Consulting or Advisory Role: AstraZeneca (I)
Honoraria: Janssen Oncology, Bayer
Consulting or Advisory Role: Bayer, Dendreon, AAA
Research Funding: Clovis Oncology (Inst), Sanofi (Inst), Genzyme (Inst)
Stock and Other Ownership Interests: Radiogel
Consulting or Advisory Role: Janssen Pharmaceuticals
Other Relationship: Caribou Publishing
Employment: Johnson & Johnson (I), Ex Archa, Calcium USA
Consulting or Advisory Role: Vavotar Life Sciences
Travel, Accommodations, Expenses: Vavotar Life Sciences
Other Relationship: International Myeloma Foundation, Prostate Cancer International
Honoraria: DAVA Pharmaceuticals
Consulting or Advisory Role: Janssen Oncology
Consulting or Advisory Role: GenomeDx
Speakers' Bureau: Johnson & Johnson, Janssen Oncology, Astellas Medivation, Pfizer
Consulting or Advisory Role: Magellan HealthRx
Consulting or Advisory Role: Janssen Oncology, Bayer, Merck, AstraZeneca, Amgen, QED, Dendreon, Seattle Genetics, Pharmacyclics, Clovis Oncology, Advanced Accelerator Applications, Sanofi, AbbVie, Myovant Sciences
Research Funding: Dendreon (Inst), Merck (Inst), Seattle Genetics (Inst), Daiichi Sankyo (Inst), Taiho Pharmaceutical (Inst), Pharmacyclics (Inst)
Consulting or Advisory Role: Janssen Oncology, Astellas Pharma, Pfizer, Clovis Oncology, Bayer
Patents, Royalties, Other Intellectual Property: Patents held by Thomas Jefferson University
No other potential conflicts of interest were reported.
The authors are grateful to patients and patient advocates who participated in the Consensus Conference: Buehler J., Hegedus A., Kaye P., Martin S., and Waxman S.P.
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