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.

This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

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.

Overarching Questions Addressing Implementation Gaps

The following questions were primary drivers of the conceptual framework:

  1. Which men should be considered for germline PCA genetic testing?

  2. Which panels should be considered and which genes should be prioritized for testing?

  3. What PCA-specific recommendations should be considered on the basis of genetic results?

  4. What is optimal informed consent for PCA GT?

  5. What collaborative strategies may facilitate PCA genetic evaluation between health care and genetic providers?

  6. What post-test disclosure strategies are most appropriate on the basis of genetic results?

  7. What barriers must be addressed to enhance PCA GT?

Consensus Conference Participants

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).

Table

TABLE 1. Characteristics of Voting Consensus Participants

Consensus Process

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.

Evidence Review

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.

Table

TABLE 2. Genetic Contribution to PCA Risk, Aggressiveness, and Proposed Clinical Implications

Strength of Consensus

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

Development of PCA Genetic Evaluation and Management Framework

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.

Key premises

The following are guiding principles for clinical genetic evaluation:

Premises based on prior literature and Consensus Conference expert guidance:

  • In-person GC is a gold standard of genetics practice.2,76,82-84

  • Patients’ psychosocial needs or preferences should dictate the mode of counseling.1,82-84

  • Full FH is important to collect during the genetic evaluation process:1,82-84

Premises based on consensus voting:

  • 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).

1. Which Men Should Be Considered for Germline PCA Genetic Testing?
Gaps addressed.

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).

Criteria for testing.

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).

  • FH criteria:

    • 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).

Additional considerations.

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.

2. Which Panels Should Be Considered and Which Genes Should Be Prioritized for Testing?
Gaps addressed.

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).

Panels considered.

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).

Genes considered.

BRCA1, BRCA2, HOXB13, CHEK2, ATM, NBN, MSH2, MSH6, MLH1, PMS2, PALB2, BRIP1, TP53, and Fanconi anemia genes were considered.

Panels and genes prioritized for testing:

  • Metastatic PCA:

    • ○ 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).

  • Nonmetastatic PCA:

    • ○ 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).

Additional considerations.

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.

3. What PCA-Specific Recommendations Should Be Considered on the Basis of Genetic Results?
Gaps addressed.

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).

Genetically based recommendations.

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).

Additional considerations.

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.

4. What Is Optimal Informed Consent for PCA GT?
Gaps addressed.

Current practice guidelines do not provide guidance to health care providers regarding optimal informed consent for PCA GT.

Optimal pretest informed consent elements.

Ethical considerations of GC were reviewed (Data Supplement). The following elements garnered strong or moderate consensus to discuss with men before GT (Fig 2 and Table 3):

Table

TABLE 3. Priority Elements of Informed Consent for Prostate Cancer Germline Testing

  • 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.

Additional considerations.

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.

5. What Collaborative Strategies May Facilitate PCA Genetic Evaluation Between Health Care and Genetic Providers?
Gaps addressed.

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.

Alternate genetic evaluation delivery strategies.

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).

Additional considerations.

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).

6. What Post-Test Disclosure Strategies Are Most Appropriate Based on Genetic Results?
Gaps addressed.

Joint guidance from oncologists, urologists, and genetic counselors for referral to GC is currently lacking.

Optimal post-test disclosure strategies:

  • 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).

Additional considerations.

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.

7. What Barriers Must Be Addressed to Enhance PCA GT?
Gaps addressed.

Multiple practice, research, and policy gaps pose barriers to PCA GT.

Areas in need of additional attention.

The following areas achieved strong or moderate consensus to address:

  • Genetic education for providers not formally trained in cancer genetics/genetic counseling (Appendix Table A1, online only, and Data Supplement).

  • Barriers to implementation of PCA GT (Appendix Table A2, online only).

  • Research priorities (Appendix Table A3, online only).

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.

© 2020 by American Society of Clinical Oncology
SUPPORT

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

Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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Veda N. Giri

Stock and Other Ownership Interests: Novopyxis (I)

Karen E. Knudsen

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

William K. Kelly

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

Heather H. Cheng

Research Funding: Inovio Pharmaceuticals (Inst), Sanofi (Inst), Astellas Medivation (Inst), Janssen Oncology (Inst), Clovis Oncology (Inst), Color Foundation (Inst)

Kathleen A. Cooney

Patents, Royalties, Other Intellectual Property: Patent awarded for discovery of HOXB13 as prostate cancer susceptibility gene (Inst)

Travel, Accommodations, Expenses: Boston Scientific (I)

Michael S. Cookson

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

Scott Weissman

Employment: Genome Medical

Stock and Other Ownership Interests: Genome Medical

Howard R. Soule

Leadership: WindMIL

Consulting or Advisory Role: Compugen, WindMIL

Travel, Accommodations, Expenses: Compugen, Sanofi, WindMIL

Daniel P. Petrylak

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

Adam P. Dicker

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

Colin C. Pritchard

Consulting or Advisory Role: Promega

Curtis A. Pettaway

Consulting or Advisory Role: Wolters-Kluwer

Research Funding: Beckmann-Coulter, MDxHealth

James L. Mohler

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)

J. Kellogg Parsons

Stock and Other Ownership Interests: Urigen, Pfizer, Johnson & Johnson, Omega Healthcare Investors

Honoraria: Sophiris Bio

Travel, Accommodations, Expenses: Sophiris Bio

Other Relationship: MDxHealth

Peter R. Carroll

Honoraria: Intuitive Surgical

Consulting or Advisory Role: Nutcracker Therapeutics

Amie Blanco

Employment: Biomarin (I)

Stock and Other Ownership Interests: Biomarin (I)

Ashley Woodson

Employment: Genome Medical

Travel, Accommodations, Expenses: Genome Medical

Mary-Ellen Taplin

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

Thomas J. Polascik

Honoraria: Endocare

Brian T. Helfand

Speakers' Bureau: Exact Sciences, Ambry Genetics

Colette Hyatt

Employment: GenomeSmart

Stock and Other Ownership Interests: GenomeSmart

Consulting or Advisory Role: GenomeSmart

Alicia K. Morgans

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

Felix Feng

Leadership: PFS Genomics

Stock and Other Ownership Interests: PFS Genomics, Nutcracker Therapeutics, SerImmune

Honoraria: Genentech

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)

Jacqueline Powers

Employment: Carevive Systems

Honoraria: CureConnect, Myriad Genetics

Consulting or Advisory Role: Carevive Systems

Travel, Accommodations, Expenses: Hospital of the University of Pennsylvania

Raoul Concepcion

Honoraria: Clovis Oncology, InVitae

Consulting or Advisory Role: IntegraConnect

Speakers' Bureau: Astellas Medivation, Janssen Oncology, Dendreon, Amgen

Daniel W. Lin

Consulting or Advisory Role: Astellas Pharma, Clovis Oncology, Dendreon

Research Funding: Genomic Health (Inst), GenomeDx (Inst), MDxHealth (Inst), Magforce

Anthony Costello

Honoraria: Sandoz

Arthur L. Burnett

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

Oliver Sartor

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

William B. Isaacs

Honoraria: AstraZeneca

Travel, Accommodations, Expenses: AstraZeneca

Jianfeng Xu

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

Jeffrey Weitzel

Speakers' Bureau: AstraZeneca

Himisha Beltran

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

Alberto Briganti

Consulting or Advisory Role: Astellas Pharma, Janssen-Cilag, OPKO Health, MDxHealth, Ferring Pharmaceuticals

Speakers' Bureau: Astellas Pharma

Research Funding: Sandoz-Novartis, Merck Sharp & Dohme

David Y. T. Chen

Stock and Other Ownership Interests: Pfizer, Pfizer (I)

Robert B. Den

Employment: Alpha TAU

Albert Dobi

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

E. David Crawford

Speakers' Bureau: Bayer, Ferring Pharmaceuticals

James Eastham

Stock and Other Ownership Interests: 3D Biopsy

Scott Eggener

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

Marc Garnick

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

Nathan Handley

Research Funding: Nektar Therapeutics (Inst)

Mark D. Hurwitz

Honoraria: Pyrexar

Consulting or Advisory Role: Neotherma

Speakers' Bureau: Pyrexar

Patents, Royalties, Other Intellectual Property: Provision patent holder for hyperthermia delivery system

R. Jeffrey Karnes

Patents, Royalties, Other Intellectual Property: GenomeDx

Travel, Accommodations, Expenses: GenomeDx

Lucia Languino

Stock and Other Ownership Interests: Johnson & Johnson

Stacy Loeb

Stock and Other Ownership Interests: Gilead Sciences (I)

Consulting or Advisory Role: Bayer, Lumenis

Travel, Accommodations, Expenses: Sanofi

Grace Lu-Yao

Employment: Sun Pharma Advanced Research Company (I)

Leadership: Sun Pharma Advanced Research Company (I)

Stock and Other Ownership Interests: Merck (I)

Todd Morgan

Consulting or Advisory Role: Myriad Genetics, TerumoBCT

Research Funding: Myriad Genetics (Inst), MDxHealth (Inst), GenomeDx (Inst)

Jose Moreno

Stock and Other Ownership Interests: Illumina, Invitae, ThermoFisher Scientific, Exact Sciences, Guardant Health, Bio-Techne

Research Funding: Janssen Pharmaceuticals, Pfizer, Pillar Biosciences

Lorelei Mucci

Research Funding: Sanofi (Inst), Astellas Pharma (Inst), Bayer (Inst), Janssen Pharmaceuticals (Inst)

Ronald E. Myers

Consulting or Advisory Role: Exact Sciences

Sarah M. Nielsen

Employment: Invitae

Stock and Other Ownership Interests: Invitae

Consulting or Advisory Role: AstraZeneca, Merck, Myriad Genetics

Speakers' Bureau: AstraZeneca

Travel, Accommodations, Expenses: Myriad Genetics, AstraZeneca, Invitae

Peter Pinto

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.

Wendy Poage

Employment: Servier

Stock and Other Ownership Interests: 3D Biopsy

Honoraria: Janssen Oncology, Myriad Genetics

Travel, Accommodations, Expenses: Pfizer, Dendreon, Janssen Oncology, Myriad Genetics

Ganesh V. Raj

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

Timothy R. Rebbeck

Honoraria: AstraZeneca (I)

Consulting or Advisory Role: AstraZeneca (I)

Charles Ryan

Honoraria: Janssen Oncology, Bayer

Consulting or Advisory Role: Bayer, Dendreon, AAA

Research Funding: Clovis Oncology (Inst), Sanofi (Inst), Genzyme (Inst)

Howard Sandler

Stock and Other Ownership Interests: Radiogel

Consulting or Advisory Role: Janssen Pharmaceuticals

Other Relationship: Caribou Publishing

E. Michael D. Scott

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

William Tester

Honoraria: DAVA Pharmaceuticals

Consulting or Advisory Role: Janssen Oncology

Edouard J. Trabulsi

Consulting or Advisory Role: GenomeDx

Speakers' Bureau: Johnson & Johnson, Janssen Oncology, Astellas Medivation, Pfizer

Neha Vapiwala

Consulting or Advisory Role: Magellan HealthRx

Evan Y. Yu

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)

Leonard G. Gomella

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.

Table

TABLE A1. Priority Topics for Provider Education

Table

TABLE A2. PCA Genetic Testing Implementation Barriers

Table

TABLE A3. Research Priorities to Advance PCA Genetics Knowledge and Practice

ACKNOWLEDGMENT

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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ARTICLE CITATION

DOI: 10.1200/JCO.20.00046 Journal of Clinical Oncology 38, no. 24 (August 20, 2020) 2798-2811.

Published online June 09, 2020.

PMID: 32516092

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