Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017

Abstract

Purpose

Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management.

Methods

An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review.

Results

Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy.

Conclusion

To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA—a clinically heterogeneous disease.

INTRODUCTION

Prostate cancer (PCA) is the third leading cause of cancer-related death in US men, accounting for 26,730 deaths in 2017.¹ There is increasing evidence that PCA has substantial inherited predisposition,^2,3 with higher risks conferred by BRCA2 and BRCA1 (associated with hereditary breast and ovarian cancer [HBOC] syndrome), and HOXB13 (associated with hereditary prostate cancer [HPC]).^4-24 Furthermore, BRCA2 mutations have been associated with poor PCA-specific outcomes.^9-13 There is also emerging evidence of the link between PCA and DNA mismatch repair (MMR) gene mutations (accounting for Lynch syndrome [LS]).^25-30 Furthermore, inherited genetic mutations are being uncovered in up to 12% of men with metastatic PCA, primarily in DNA repair genes such as BRCA1, BRCA2, and ATM,^31,32 with improved clinical outcomes by specific targeted agents.^33,34 Identifying genetic mutations of inherited PCA, therefore, has implications for cancer risk assessment for men and their families,^35,36 for precision treatment of metastatic disease,^33,34 and is being incorporated into guidelines for individualized PCA screening strategies specifically for male BRCA1/2 mutation carriers.^35,37

However, no centralized guidelines exist regarding genetic counseling and genetic testing for PCA or optimal use and interpretation of multiple genes now available on commercial PCA gene panels (Table 1).³⁸ At least three commercial laboratories have PCA multigene panels available that include BRCA1, BRCA2, HOXB13, DNA MMR genes, and multiple additional genes (such as ATM, CHEK2, and NBN; Table 1). Some of these genes provide actionable PCA risk information, whereas data for PCA risk is limited for other genes on these panels. Therefore, testing capability has created a dilemma regarding optimal application of genetic tests for counseling and evaluation of inherited PCA.

Table 1.

Current Genes on PCA Multigene Panels, Evidence Summary for PCA Risk, and Guidelines Available

Genetic counseling is a dynamic process in which trained cancer genetic counseling professionals perform detailed intake of personal history and family cancer history, discuss genetic inheritance of cancer and genetic test options, address implications of genetic test results with patients and their families, and clarify patient preferences regarding genetic testing to make an informed decision for proceeding with testing.^39,40 However, guidelines are limited regarding genetic counseling and genetic testing for PCA (Table 2) and focus only on BRCA1/2 testing. Current National Comprehensive Cancer Network (NCCN) Genetic/Familial High-Risk Assessment: Breast and Ovarian (Version 2.2017) guidelines address BRCA1/2 testing for men with a personal history of PCA limited to Gleason ≥ 7 and specific family history (FH) features.³⁵ An additional criterion for germline genetic testing is BRCA1/2 mutation detected on somatic tumor testing.³⁵ Although these expert panel guidelines begin to address BRCA1/2 testing for PCA, they exclude addressing other genes now available through multigene panels, several of which are implicated in PCA predisposition (Table 1).

Table 2.

Gaps in Genetic Evaluation of Inherited PCA Addressed by Consensus Criteria

Genetic testing has potential to inform PCA screening and targeted treatment, as exemplified in other cancers.^35,36,41 NCCN guidelines (Genetic/Familial High-Risk Assessment: Breast and Ovarian) state that PCA screening should begin at age 45 years for male BRCA2 mutation carriers and to consider this recommendation for BRCA1 carriers.³⁵ Current NCCN Prostate Cancer Early Detection Panel (Version 2.2016) agreed that men should be asked about the presence of known BRCA1/2 mutations in their families.³⁷ The group added consideration of FH of BRCA1/2 mutations to the baseline discussion of risks and benefits of PCA screening but believed that data are insufficient to change screening and biopsy recommendations.³⁷ Given increasing knowledge of genetic contribution to PCA (such as from HOXB13 and DNA MMR genes) and expanding availability of commercial multigene panels (Table 1), there is a need for enhanced guidance on how multigene testing may be incorporated in PCA screening discussions.

Finally, precision medicine is catapulting the need for genetic testing to inform cancer treatment, particularly in the advanced-stage setting. Emerging studies report clinical activity of polyadenosine diphosphate-ribose polyermerase (PARP) inhibitors in metastatic PCA, particularly for men with DNA repair mutations.^33,34 Recent accelerated US Food and Drug Administration approval of immune checkpoint inhibitors for microsatellite instability-high and MMR-deficient cancers further highlights the increasing role of genetic testing in cancer treatment,⁴² with implications for PCA. Thus, comprehensive guidance for multigene testing for inherited PCA is now critical for cancer risk, screening, and treatment implications.

Because multigene testing capability for PCA is now a reality, a consensus conference was convened to address the clinical genetic evaluation spectrum for inherited PCA. The Philadelphia Prostate Cancer Consensus 2017 was held in Philadelphia, Pennsylvania on March 3 and 4, 2017 and focused on the role of genetic testing for inherited PCA risk as well as genetic counseling, screening, and management on the basis of genetic findings. The conference was attended by stakeholders involved in PCA early detection, treatment, research, and patient advocacy. This was the first centralized, multidisciplinary conference, to our knowledge, focused on addressing and developing a working framework for the comprehensive genetic evaluation of inherited PCA in the multigene testing era.

METHODS

Panel Members

The panel included 71 experts from the United States, Canada, England, and the Netherlands. Panel selection criteria included consideration of stakeholders with expertise in PCA early detection, treatment, genetic counseling, clinical cancer genetics, research, bioethics, and advocacy, along with patient advocates (Appendix Table A1, online only).

Consensus Model and Evidence Review

An expert opinion consensus model was used to address gaps in evidence-based guidelines for multigene testing for PCA. A modified Delphi model was followed, which incorporated elements of the Delphi process and prior expert opinion consensus conferences relevant to cancer risk and screening (Appendix Fig A1, online only).^43,44 Literature was provided to panel members ahead of the meeting, with initial presentations focused on evidence review by experts. Grade of evidence was summarized as follows, with grade designations adapted from prior literature and consensus models^44,45: (A) High-grade evidence: at least one prospectively-designed study, or three or more large validation studies, or three or more descriptive studies; (B) Moderate-grade evidence: two cohort or case-control studies; (C) Emerging data: increasing data in support of association to PCA but not yet moderate-grade evidence; (D) Low/Insufficient: limited data or not studied in the context of PCA (Table 1; Appendix Tables A2-A6, online only).

Development of Genetic Evaluation Framework

A conceptual framework was developed to address elements of genetic evaluation, including genetic counseling and genetic testing criteria, genes to test, and screening/management (Fig 1). FH criteria for genetic testing focused on established hereditary cancer syndromes in which PCA has been implicated, as well as broader FH to account for limitations in obtaining detailed FH information.^46,47 Genetic testing consensus discussions focused on genes currently included on commercially available multigene panels (Table 1).

Fig 1.

Framework for genetic evaluation of inherited prostate cancer (PCA).

A series of questions were posed to address the genetic evaluation framework (Fig 1). The following overarching questions were addressed:

• (1) Which men should undergo genetic counseling and genetic testing for PCA (Fig 1A)? Principles and elements of genetic counseling were presented to panelists, including discussion of cancer genetics, benefits and limitations of genetic testing, financial considerations, implications for the patients and families, and genetic discrimination laws.^39,40 Ethical considerations of genetic testing and the need to clarify patient preferences were also reviewed.^48,49 Genetic testing criteria were based on various personal cancer and FH features. FH considerations included meeting established criteria for HBOC/LS/HPC. Furthermore, considering limitations of obtaining accurate FH information,^46,47 these criteria included FH where at least two close blood relatives have cancers in the HBOC/LS/HPC spectrum as per the NCCN model.^35,36 Finally, metastatic PCA and tumor sequencing were specifically addressed.^31,32 This consensus statement also developed suggested genetic counseling referral criteria following the NCCN model^35,36 (Table 2).

• (2) Which genes should be tested based on clinical and/or familial scenarios (Fig 1B)? These questions focused on genes present on current PCA multigene panels (Table 1; Appendix Tables A2-A6). Considerations regarding personal history of PCA included Gleason score, stage, and tumor sequencing results. FH considerations included meeting established criteria for HBOC/LS/HPC or having at least two close blood relatives with cancers in the HBOC/LS/HPC spectrum to address FH limitations. Tumor sequencing results were also considered.

• (3) How should genetic test results inform PCA screening (Fig 1C)? This set of criteria focused on genes that inform PCA risk and may be considered in PCA screening discussions. Risk for PCA was reviewed as well as association to aggressive PCA (Appendix Tables A2-A6). Baseline age to check prostate-specific antigen (PSA) and interval to screen based on genetic test results were adapted from other NCCN guidelines.^35,37 PCA screening guidelines by various professional organizations were also reviewed.^37,50-53 Finally, ongoing PCA screening studies incorporating genetic status were summarized.⁵⁴

• (4) Should genetic test results inform management of early-stage/localized, advanced/high-risk, or metastatic, castration-resistant PCA (mCRPC; Fig 1D)? These questions overall focused on genes on current PCA multigene panels (Table 1) and if they should be factored into management discussions with patients in the setting of early-stage/localized disease, advanced/high-risk disease, or mCRPC. Evidence for PCA aggressiveness was of primary consideration, which was high grade for BRCA2, emerging for ATM, and limited for other genes on multigene panels (Appendix Tables A2-A6). Genetically informed treatments, such as PARP inhibition and immune checkpoint inhibition, were also considered.^33,34,42

Strength of Consensus

Votes were cast anonymously using an electronic audience response system. Postconsensus refinement process included readministering select questions where there was debate among panelists. Strength of expert opinion consensus was determined by percentage of agreement with an answer choice: ≥ 75% for strong consensus, 50% to 74% for moderate consensus, and < 50% for lack of consensus. Table 2 provides a comparison of current NCCN guidelines to consensus criteria and identifies the gaps in practice addressed by this consensus statement.

RESULTS

Evidence Review

Various studies were considered in review of evidence for specific genes on multigene panels and PCA risk, including tumor sequencing studies (Table 1; Appendix Tables A2-A6). Current evidence linking BRCA1 and BRCA2 mutations to PCA risk was considered high grade, with stronger association for BRCA2. Furthermore, BRCA2 mutations are associated with poor PCA-specific outcomes as well as poorer survival. Evidence linking HOXB13 mutations to PCA was considered high grade. Evidence of DNA MMR gene mutations to PCA risk was considered moderate grade. Data regarding ATM and NBN mutations and PCA risk are emerging in favor of association to PCA but are not yet at the level of moderate grade at this time. Other genes on panels have low/insufficient data for PCA risk (Appendix Tables A2-A6).

Consensus Responses

Responses are summarized by overarching questions addressing the genetic evaluation framework, focused on criteria that garnered strong to moderate consensus supported by high- to moderate-grade evidence (Table 2; Appendix Tables A2-A6). Additional considerations are provided to add context to the various criteria, to provide more details regarding discussion that did not make the cutoff for consensus, and to add considerations raised by panel members regarding need for additional discussion or research.

(1) Which men should undergo genetic counseling and genetic testing for prostate cancer (Fig 1A)?

Criteria.

Men meeting any one of the following suggested criteria should undergo genetic counseling and genetic testing:

• All men with PCA from families meeting established testing or syndromic criteria for the following:

  • ○ HBOC (Consensus: 93%)

  • ○ HPC (Consensus: 95%)

  • ○ LS (Consensus: 88%)

• Men with PCA with two or more close blood relatives on the same side of the family with a cancer in the following syndromes (broader FH):

  • ○ Postconsensus discussion included consideration of age cutoff for this criterion. A specific age cutoff will require additional data, and age at diagnosis is important to inquire in the genetic counseling session with patients.

    • ▪ HBOC (Consensus: 93%)

    • ▪ HPC (Consensus: 86%)

    • ▪ LS (Consensus: 86%)

• All men with mCRPC should consider genetic testing (Consensus: 67%). Postconsensus discussion also included consideration of testing men with metastatic, hormone-sensitive PCA to identify germline mutations to inform potential future treatment options and cascade testing in families.

• Men with tumor sequencing showing mutations in cancer-risk genes should be recommended for germline testing, particularly after factoring in additional personal history and FH (Consensus: 77%).

Additional considerations.

The consensus panel had strong agreement that patients should engage in shared decision making for genetic testing for PCA (Consensus: 77%). Suggested criteria to refer men for genetic counseling included young age at PCA diagnosis (≤ 55 years) in the patient or a first-degree relative, death as a result of PCA in a first-degree relative younger than 60 years, or having FH suggestive of HBOC, HPC, or LS (Table 2). Additional suggested referral criteria include tumor sequencing showing mutations in hereditary cancer genes or metastatic disease (Table 2). The panel achieved strong consensus that African American males should follow the same criteria as males of other race groups until additional genetic data in African American males are available (Consensus: 75%). For males unaffected with PCA and no affected male relatives to test, FH criteria similar to men with PCA would apply.

(2) Which genes should be tested based on clinical and/or familial scenarios (Fig 1B)?

Criteria.

Criteria with highest consensus are as follows:

• The following genes should be tested in males with PCA meeting criteria for the corresponding syndrome:

  • ○ HOXB13 (Syndrome: HPC) (Consensus: 95%)

  • ○ BRCA1/BRCA2 (Syndrome: HBOC) (Consensus: 97%)

  • ○ DNA MMR genes (Syndrome: LS) (Consensus: 73%)

• The following genes may be tested in men with PCA with two or more close blood relatives on the same side of the family with a cancer in the following hereditary cancer syndrome spectra (broader FH):

  • ○ Postconsensus discussion included consideration of age cutoff for this criterion. A specific age cutoff will require further data, and age at diagnosis is important to inquire in the genetic counseling session with patients.

    • ▪ BRCA1/BRCA2 (HBOC cancer spectrum: breast, ovarian, pancreatic, prostate cancers and melanoma) (Consensus: 98%)

    • ▪ DNA MMR genes (LS cancer spectrum: colorectal, endometrial, upper GI tract, ovarian, pancreatic, and upper urinary tract cancers along with sebaceous adenocarcinomas) (Consensus: 97%). Postconsensus discussion included the moderate nature of evidence of DNA MMR genes and PCA risk, with suggestions to institute immunohistochemistry testing of prostate tumors for LS to select men with greater chance of carrying a germline DNA MMR mutation.

• Men with prostate tumor sequencing showing mutations in the following cancer-risk genes should have confirmatory germline genetic testing for PCA predisposition: BRCA1/BRCA2 (Consensus: 89%), DNA MMR genes (Consensus: 88%), HOXB13 (68%), ATM (61%).

• If men with mCRPC undergo genetic testing for treatment determination, the following genes should be tested: BRCA1/2 (Consensus: 88%), ATM (Consensus: 62%).

(3) How should genetic test results inform PCA screening (Fig 1C)?

Criteria.

Criteria with highest consensus are as follows:

• BRCA2 mutation status should be factored into PCA screening discussions (Consensus: 80%).

  • ○ Screening strategy:

    • ▪ Baseline PSA at age 40 years or 10 years prior to youngest PCA diagnosed in family (Consensus: 56%)

    • ▪ Interval of screening yearly or determined by baseline PSA (Consensus: 76%)

• HOXB13 mutation status should be factored into PCA screening discussions (Consensus: 53%).

  • ○ Screening strategy:

    • ▪ Baseline PSA at age 40 years or 10 years prior to youngest PCA diagnosed in family (Consensus: 52%)

    • ▪ Interval of screening yearly or determined by baseline PSA (Consensus: 75%)

Additional considerations.

Postconsensus opinion was to consider a lower age limit to begin PSA screening, perhaps no younger than 35 years. There was strong agreement to perform PSA testing yearly or as dictated by the baseline PSA. This consensus aligns with NCCN Breast and Ovarian guidelines³⁵ but also expands on the guideline to factor in age at diagnosis of an affected male with PCA in the family for screening initiation as is modeled in colorectal cancer guidelines.³⁶ BRCA1 mutation status is part of the NCCN Breast and Ovarian guidelines regarding consideration of baseline PSA at age 45 years.³⁵

(4) Should genetic test results inform management of early-stage/localized PCA, advanced/high-risk PCA, and mCRPC (Fig 1D)?

Criteria.

Criteria with highest consensus are as follows:

• BRCA2 mutation status should be factored into management discussion of early-stage/localized PCA: (Consensus: 64%).

• BRCA2 (Consensus: 97%) and ATM (Consensus: 59%) mutation status should be factored into management discussion of high-risk/advanced PCA.

• BRCA1 (Consensus: 83%), BRCA2 (Consensus: 88%), ATM (Consensus: 56%) mutation status should be factored into mCRPC treatment discussions.

DISCUSSION

To our knowledge, the Philadelphia Prostate Cancer Consensus 2017 was the first attempt to garner expert opinion consensus on key areas in the genetic evaluation continuum for inherited PCA. Increasing scientific insights into the genetic predisposition to inherited PCA, growing multigene testing capabilities, and limited guidelines necessitated expert consensus to address genetic counseling and genetic testing, PCA screening, and management. This conference brought together key stakeholders in PCA treatment, genetic counseling, research, and advocacy to consider the evidence and develop a working framework for genetic counseling, genetic testing, and management of inherited PCA in the multigene testing era. Of particular note was the strong urologic representation at this consensus.

The conference addressed critical gaps in guidelines relevant to genetic evaluation for PCA. These gaps include consideration of FH in cancer syndromes relevant to PCA, consideration of metastatic disease in multigene testing, tumor sequencing, and review of genes on multigene panels for application of genetic testing to PCA. Our conference focused on inherited PCA, which complements a recent consensus conference that addressed germline testing for advanced PCA as part of the overall proceedings.⁵⁵ There was agreement in our consensus conference that men with FH meeting strict criteria for HBOC, HPC, or LS and men having FH of cancers in the spectrum of these cancer syndromes while not meeting strict syndromic criteria (broader FH) can be considered for genetic testing. This is an expansion on current NCCN High-Risk Assessment: Breast and Ovarian guidelines,³⁵ reflects the growing evidence of genetic contribution to PCA beyond BRCA1 and BRCA2, and takes into account limitations of obtaining detailed FH information that could affect meeting criteria for hereditary cancer syndromes.^46,47

Genetic counseling for PCA will need focused development. Overall, the genetic counseling model should include shared decision making between provider and patient regarding genetic testing. The discussion should clarify patient values and preferences related to screening, risk assessment, and treatment choice. Counseling elements of genetic education; discussion of benefits, risks, and limitations of genetic testing for patients and families; financial implications; and genetic discrimination laws are also important to discuss. Optimal delivery of pretest genetic counseling to patients in the multigene testing era, particularly for genetic testing for advanced/metastatic cancers for targetable mutations, is an area under development. ASCO policy statement 2015 recognized the need for more research on delivery of pretest counseling, particularly in the settings of multigene testing and tumor sequencing, and emphasized the importance of patients to receive genetic education and clarify patient preferences.⁵⁶ Furthermore, PCA germline multigene testing studies will help inform counseling discussions of potential results from genetic testing.³⁸ A closer working relationship between PCA care providers, primary care providers, and cancer genetics specialists will need to be developed to address treatment and management needs while providing patients with optimal genetic education and counseling. Incorporating a genetic counseling and evaluation process into a multidisciplinary PCA clinic setting is one approach.⁵⁷

The mCRPC setting is a unique area that will likely drive a significant proportion of genetic testing for PCA. With emerging insights into targeted therapy for PCA^33,34 and the promise of immunotherapy in MMR-deficient tumors,^42,58 a greater percentage of patients with mCRPC will likely undergo tumor sequencing to uncover targetable mutations, which can have germline implications. The panel had moderate agreement to test all men with mCRPC, which may be strengthened pending future data of germline mutations and targeted agents in mCRPC. Furthermore, some panelists raised questions on testing all men with metastatic PCA and not limiting testing to the castration-resistance setting. Because most of the current data on germline mutations are in the castration-resistant setting,^31-34 proposed criteria were focused on mCRPC, which may change over time. Postconsensus discussion also included the potential for broader scope of genetic testing criteria in the treatment setting versus the risk-assessment setting, which can be considered in future consensus updates. Greater information from this population regarding FH, age at diagnosis, and germline mutation spectrum will be crucial to advance and refine the understanding of genetic predisposition to lethal PCA.

Cost effectiveness of genetic testing for inherited PCA is an important consideration. Our consensus statement outlines targeted testing for selected individuals (in contrast to population-based screening) and is consistent with strategies for hereditary breast cancer testing of BRCA1/2. Research has shown that such targeted hereditary testing for a prevalent disease like breast cancer is cost effective under several different economic scenarios when directed at those at highest risk of carrying a mutation.^59-62 For PCA, there is a need to build on the findings of these studies and model survival and quality-adjusted life-years for patients who are at high risk versus those at population risk for PCA. Thus, as we define who should undergo genetic counseling and testing for inherited PCA, we also call for renewed emphasis on the economic evaluation of different strategies to promote patient-centric, high-value genetic evaluation and cancer care.

There are some limitations to consider. Grading of evidence was based on prior consensus conferences, with a noted need for a greater evidence base to inform future criteria development. Our objective was to address the application of multigene testing for PCA through consensus review of existing literature and develop a genetic evaluation framework that can be modified in the future. Another consideration is that the panel consisted of experts and stakeholders engaged in PCA genetics, research, treatment, and advocacy, which may have affected agreement due to breadth of expertise. However, a strength of the consensus was the broad input from thought leaders in various disciplines engaged with PCA, which provided balanced views toward criteria development. The consensus highlighted key areas in need of research, including developing a working definition of HPC in a clinical setting, expanding insights into genetic contribution to aggressive/lethal PCA, developing genetic counseling and referral strategies that engage urologists and primary care providers, addressing the urgent need for focused studies of genetic testing for African American males, evaluating clinical use of genetic testing in PCA screening and management, and expanding health services research for optimized delivery of genetic education to broader populations.

Overall, this consensus conference was a first step to understand the issues confronting application of genetic testing to PCA and develop a meaningful framework using the best evidence available. The need to revise and optimize consensus criteria is noted, based on the dynamic nature of knowledge and progress in this field. Several consensus panel members are also members of NCCN guidelines panels, which may lead to consideration of consensus review and criteria for incorporation into respective NCCN guidelines regarding genetic testing for inherited PCA. NCCN Prostate Cancer Early Detection guidelines will likely include stronger consideration of BRCA mutation status in PCA screening discussions and may consider this consensus statement in future guideline updates.

Appendix

The following series of tables highlight the studies referenced by the consensus panel concerning grade of evidence for prostate cancer (PCA) risk by genes on PCA multigene panels. Grade of evidence is provided in the titles of Tables A2-A6. (A) High-grade evidence: At least one prospectively designed study or three or more large validation studies or three or more descriptive studies; (B) Moderate-grade evidence: two cohort or case-control studies; (C) Emerging data: increasing data in support of association to PCA, but not yet moderate-grade evidence; (D) Low/insufficient: limited data or not studied in the context of PCA.

Fig A1.

Overall consensus model.

Table A1.

Consensus Conference Panel Members

Table A2.

Case Series of BRCA1 and BRCA2 and PCA Risk [BRCA1 and BRCA2 (Evidence: A)]

Table A3.

Case-Control Studies of BRCA1 and BRCA2 and Survival Outcomes (Evidence: A for BRCA2)

Table A4.

HOXB13 (G84E) and Association to PCA Risk (Evidence: A)

Table A5.

DNA MMR Genes, PCA Risk, and Molecular Data (Evidence: B)

Table A6.

Additional Genes on Multigene Panels and Association to PCA

Appendix References

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AUTHOR CONTRIBUTIONS

Conception and design: Veda N. Giri, Karen E. Knudsen, William K. Kelly, Leonard G. Gomella

Collection and assembly of data: Veda N. Giri, Leonard G. Gomella

Data analysis and interpretation: Veda N. Giri, Karen E. Knudsen, William K. Kelly, Wassim Abida, Gerald L. Andriole, Chris H. Bangma, Justin E. Bekelman, Mitchell C. Benson, Amie Blanco, Arthur Burnett, William J. Catalona, Kathleen A. Cooney, Matthew Cooperberg, David E. Crawford, Robert B. Den, Adam P. Dicker, Scott Eggener, Neil Fleshner, Matthew L. Freedman, Freddie C. Hamdy, Jean Hoffman-Censits, Mark D. Hurwitz, Colette Hyatt,William B. Isaacs, Christopher J. Kane, Philip Kantoff, R. Jeffrey Karnes, Lawrence I. Karsh, Eric A. Klein, Daniel W. Lin, Kevin R. Loughlin, Grace Lu-Yao, S. Bruce Malkowicz, Mark J. Mann, James R. Mark, Peter A. McCue, Martin M. Miner, Todd Morgan, Judd W. Moul, Ronald E. Myers, Sarah M. Nielsen, Elias Obeid, Christian P. Pavlovich, Stephen C. Peiper, David F. Penson, Daniel Petrylak, Curtis A. Pettaway, Robert Pilarski, Peter A. Pinto, Wendy Poage, Ganesh V. Raj, Timothy R. Rebbeck, Mark E. Robson, Matt T. Rosenberg, Howard Sandler, Oliver Sartor, Edward Schaeffer, Gordon F. Schwartz, Mark S. Shahin, Neal D. Shore, Brian Shuch, Howard R. Soule, Scott A. Tomlins, Edouard J. Trabulsi, Robert Uzzo, Donald J. Vander Griend, Patrick C. Walsh, Carol J. Weil, Richard Wender, and Leonard G. Gomella

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. 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/site/ifc.

Veda N. Giri

Stock or Other Ownership: Novopyxis (I)

Research Funding: Myriad Genetics

Karen E. Knudsen

Honoraria: Celgene

Consulting or Advisory Role: Sanofi

Research Funding: Celgene, Sanofi

Travel, Accommodations, Expenses: Sanofi

William K. Kelly

Consulting or Advisory Role: Sanofi, Janssen Pharmaceuticals

Research Funding: Sanofi (Inst), Novartis (Inst), Janssen Oncology (Inst)

Wassim Abida

Honoraria: CARET

Consulting or Advisory Role: Clovis Oncology

Research Funding: AstraZeneca, Zenith Epigenetics, Clovis Oncology

Travel, Accommodations, Expenses: GlaxoSmithKline

Gerald L. Andriole

Consulting or Advisory Role: Algeta/Bayer, 3D Biopsy, Augmenix

Chris H. Bangma

No relationship to disclose

Justin E. Bekelman

Consulting or Advisory Role: GLG

Mitchell C. Benson

Speakers’ Bureau: Janssen

Amie Blanco

Employment: Genentech (I)

Stock or Other Ownership: Genentech (I)

Arthur Burnett

No relationship to disclose

William J. Catalona

Consulting or Advisory Role: Beckman Coulter, OHMX

Research Funding: deCODE Genetics, provides free genotyping and DNA extraction

Patents, Royalties, Other Intellectual Property: OHMX

Kathleen A. Cooney

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

Matthew Cooperberg

Honoraria: Takeda Pharmaceuticals

Consulting or Advisory Role: Myriad Pharmaceuticals, Bayer, Astellas Pharma, Dendreon, Janssen, MDxHealth

Research Funding: Myriad Pharmaceuticals (Inst), Genomic Health (Inst), GenomeDx (Inst)

David E. Crawford

Employment: Dendreon (I)

Honoraria: Ferring Pharmaceuticals, Janssen, Astellas Pharma, MDxHealth

Speakers’ Bureau: Ferring Pharmaceuticals, Janssen

Research Funding: Janssen (Inst)

Travel, Accommodations, Expenses: Ferring Pharmaceuticals (I)

Robert B. Den

Consulting or Advisory Role: GenomeDx

Speakers’ Bureau: Bayer

Research Funding: Medivation/Astellas Pharma, GenomeDx

Travel, Accommodations, Expenses: GenomeDx

Adam P. Dicker

Honoraria: Merck KGaA, RedHill Biopharma

Consulting or Advisory Role: EMD Serono, Ferring Pharmaceuticals

Travel, Accommodations, Expenses: Merck KGaA, Ferring Pharmaceuticals

Other Relationship: NRG Oncology, Department of Defense Prostate Cancer Research Program

Scott Eggener

Consulting or Advisory Role: Janssen, MDxHealth, Profound Medical, InSightec

Speakers’ Bureau: OPKO Diagnostics

Research Funding: OPKO Diagnostics

Neil Fleshner

Leadership: Hybridyne Imaging Technologies

Honoraria: Amgen, AbbVie, Astellas Pharma, Bayer, Ferring Pharmaceuticals, Janssen, Sanofi, Hybridyne Imaging Technologies

Consulting or Advisory Role: AbbVie, Amgen, Astellas Pharma, Bayer, Ferring Pharmaceuticals, Janssen, Sanofi, Hybridyne Imaging Technologies

Research Funding: Ferring Pharmaceuticals (Inst), Astellas Pharma (Inst), Bavarian Nordic (Inst), Bayer (Inst), Janssen (Inst), Medivation (Inst), Nucleix (Inst), Progenics Pharmaceuticals (Inst), Sanofi (Inst), Spectracure (Inst)

Matthew L. Freedman

No relationship to disclose

Freddie C. Hamdy

Honoraria: Ferring Pharmaceuticals

Travel, Accommodations, Expenses: Ferring Pharmaceuticals

Jean Hoffman-Censits

Honoraria: Genentech

Consulting or Advisory Role: Genentech, Clovis Oncology, Foundation Medicine

Research Funding: Sanofi

Travel, Accommodations, Expenses: Genentech

Mark D. Hurwitz

Consulting or Advisory Role: NeoTherma Oncology

Speakers’ Bureau: Pyrexar Medical

Travel, Accommodations, Expenses: NeoTherma Oncology

Other Relationship: NeoTherma Oncology

Colette Hyatt

No relationship to disclose

William B. Isaacs

Research Funding: Tokai Pharmaceuticals

Patents, Royalties, Other Intellectual Property: DiagnoCure, MDxHealth

Christopher J. Kane

Stock or Other Ownership: SNP Bio

Honoraria: Janssen Pharmaceutical Products, SNP Bio

Consulting or Advisory Role: SNP Bio, National Comprehensive Cancer Network

Speakers’ Bureau: Janssen Pharmaceutical Products

Research Funding: PCF

Travel, Accommodations, Expenses: MDxHealth

Philip Kantoff

Stock or Other Ownership: Bellicum Pharmaceuticals, Metamark Genetics, Placon, Druggability Technologies, Tarveda Therapeutics

Consulting or Advisory Role: Bavarian Nordic, Janssen, Millennium Pharmaceuticals, MorphoSys, Pfizer, Astellas Pharma, Bellicum Pharmaceuticals, BIND Biosciences, Endocyte, Metamark Genetics, Medivation, Merck, MTG Therapeutics, OncoCell MDX, Oncogenex, Sotio, Sanofi, Tokai Pharmaceuticals, Bayer, Genentech, Cristal Therapeutics, Ipsen, Omnitura Therapeutics, MorphoSys, GTx, Tarveda Therapeutics, Druggability Technologies, Progenity

Research Funding: Medivation (Inst), Sanofi (Inst), Oncogenex (Inst), Aragon Pharmaceuticals (Inst), Amgen (Inst), Astellas Pharma (Inst), Bayer (Inst), Bavarian Nordic (Inst), Dendreon (Inst), Exelixis (Inst), Janssen (Inst)

Patents, Royalties, Other Intellectual Property: Method for predicting the risk of prostate cancer morbidity and mortality, predicting and treating prostate cancer, methods for predicting likelihood of responding to treatment, chromosome copy number gain as a biomarker of urothelial carcinoma lethality, drug combinations to treat cancer, somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma (patent), Up-to-Date royalties, Wolters Kluwer royalties

Expert Testimony: Sanofi, Janssen

Travel, Accommodations, Expenses: Sanofi, Janssen, BIND Biosciences, Bavarian Nordic, Millennium Pharmaceuticals

R. Jeffrey Karnes

Consulting or Advisory Role: Genomic Health

Research Funding: GenomeDx, GenomeDx (Inst)

Patents, Royalties, Other Intellectual Property: GenomeDx, GenomeDx (Inst)

Lawrence I. Karsh

Stock or Other Ownership: Swan Valley Medical

Honoraria: Astellas Pharma, Bayer, Dendreon, Janssen, Medivation/Astellas

Consulting or Advisory Role: Astellas Pharma, Bayer, Dendreon, Janssen, Medivation/Astellas Pharma

Speakers’ Bureau: Astellas Pharma, Bayer, Dendreon, Janssen, Medivation, Amgen

Research Funding: Astellas Pharma (Inst), Bayer (Inst), Dendreon (Inst), Janssen (Inst), Medivation/Astellas (Inst), Spectrum Pharmaceuticals

Travel, Accommodations, Expenses: Astellas Pharma, Bayer, Dendreon, Janssen, Medivation/Astellas, Spectrum Pharmaceuticals

Eric A. Klein

Consulting or Advisory Role: GenomeDx, Genomic Health

Speakers’ Bureau: Genomic Health

Daniel W. Lin

Consulting or Advisory Role: Astellas Pharma, Bayer, Myriad Genetics

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

Kevin R. Loughlin

Research Funding: Astellas Pharma

Grace Lu-Yao

Employment: Sun Pharmaceutical Industries (I)

Leadership: Sun Pharmaceutical Industries (I)

Stock or Other Ownership: Merck (I)

S. Bruce Malkowicz

Consulting or Advisory Role: Pacific Edge

Mark J. Mann

No relationship to disclose

James R. Mark

No relationship to disclose

Peter A. McCue

No relationship to disclose

Martin M. Miner

Expert Testimony: AbbVie

Todd Morgan

Consulting or Advisory Role: Myriad Genetics

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

Judd W. Moul

Stock or Other Ownership: Pfizer, Johnson & Johnson, Bavarian Nordic, Eli Lilly, Procter & Gamble, Walgreens, AstraZeneca, Novartis, Theralogix

Honoraria: AbbVie, Bayer, Ferring Pharmaceuticals, Dendreon, Janssen, Astellas Pharma, Sanofi, Genomic Health, GenomeDx, Pfizer

Consulting or Advisory Role: AbbVie, Bayer, Theralogix, Tolmar, Blue Earth Diagnostics

Speakers' Bureau: Bayer, Ferring Pharmaceuticals, Dendreon, Janssen, Sanofi, Genomic Health, GenomeDx

Research Funding: Astellas Pharma (Inst), Pfizer (Inst)

Ronald E. Myers

No relationship to disclose

Sarah M. Nielsen

No relationship to disclose

Elias Obeid

Honoraria: Guidepoint Global

Consulting or Advisory Role: Merck Sharp & Dohme

Research Funding: Merck, Genentech, Myriad Genetics

Christian P. Pavlovich

Stock or Other Ownership: Intuitive Surgical, Pfizer, Amgen, Celgene, United Therapeutics, Aimmune Therapeutics, DaVita, Gilead Sciences, Prometic Life Sciences

Honoraria: Genomic Health, Spectrum Pharmaceuticals, Hospira, Apotex, Exact Imaging (formerly Imagistx), Hybridyne Imaging Technologies

Research Funding: Exact Imaging (formerly Imagistx) (Inst)

Expert Testimony: Intuitive Surgical (through Skadden, Arps & Meagher attorneys at law)

Other Relationship: Da Vita dialysis centers (I)

Stephen C. Peiper

Patents, Royalties, Other Intellectual Property: St Jude Children's Research Hospital

Travel, Accommodations, Expenses: Roche Diagnostics

David F. Penson

Consulting or Advisory Role: Astellas, Medivation, Dendreon, Janssen Pharmaceuticals

Daniel Petrylak

Stock or Other Ownership: Bellicum Pharmaceuticals, Tyme Technologies

Honoraria: Bayer, Bellicum Pharmaceuticals, Sanofi, Johnson & Johnson, Exelixis, Ferring Pharmaceuticals, Medivation, Pfizer, Genentech, Astellas Pharma, Progenics, Merck Serono, AstraZeneca/MedImmune, Pfizer

Consulting or Advisory Role: Bayer, Bellicum Pharmaceuticals, Dendreon, Sanofi, Johnson & Johnson, Exelixis, Ferring Pharmaceuticals, Millennium, Medivation, Pfizer, Tyme Technologies

Research Funding: Oncogenex, Progenics, Johnson & Johnson, Millennium, Dendreon, Sanofi, Endocyte, Genentech, Merck, Astellas, Medivation, Novartis, Eli Lilly/ImClone, Merck, Pfizer, Agenysis

Expert Testimony: Celgene, Sanofi

Travel, Accommodations, Expenses: Bayer, Bellicum Pharmaceuticals, Dendreon, Sanofi, Exelixis, Ferring Pharmaceuticals, Medivation, Pfizer, Oncogenex, Progenics, Johnson & Johnson, Millennium, Celgene, Eli Lilly

Curtis A. Pettaway

Consulting or Advisory Role: Wolters Kluwer

Research Funding: Beckman Coulter

Travel, Accommodations, Expenses: Myriad Genetics

Robert Pilarski

No relationship to disclose

Peter A. Pinto

Patents, Royalties, Other Intellectual Property: Philips Healthcare and National Institutes of Health have licensing agreement for medical imaging that may result in royalties

Wendy Poage

Employment: Shire

Stock or Other Ownership: 3D Biopsy, Maximum Medical Solutions

Honoraria: Janssen

Consulting or Advisory Role: MDxHealth

Travel, Accommodations, Expenses: Janssen, Astellas Pharma, Sanofi, MDxHealth

Ganesh V. Raj

Leadership: Gaudium Rx, C-Diagnostics, EtiraRx

Honoraria: Bayer, Sanofi, Medivation, Astellas Pharma, Janssen

Consulting or Advisory Role: Janssen, Bayer

Speakers’ Bureau: Bayer, Medivation, Sanofi, Astellas Pharma, Janssen

Research Funding: Bayer

Patents, Royalties, Other Intellectual Property: Gaudium Rx, C-Diagnostics, EtiraRx

Timothy R. Rebbeck

No relationship to disclose

Mark E. Robson

Honoraria: AstraZeneca

Consulting or Advisory Role: McKesson, AstraZeneca

Research Funding: AstraZeneca (Inst), AbbVie (Inst), BioMarin Pharmaceutical (Inst), Medivation (Inst)

Travel, Accommodations, Expenses: AstraZeneca

Matt T. Rosenberg

Stock or Other Ownership: OPKO Diagnostics

Honoraria: OPKO Diagnostics, Astellas Pharma

Consulting or Advisory Role: OPKO Diagnostics, Astellas Pharma

Speakers’ Bureau: OPKO Diagnostics, Astellas Pharma

Travel, Accommodations, Expenses: OPKO Diagnostics, Astellas Pharma

Howard Sandler

Stock or Other Ownership: Advanced Medical Isotope

Consulting or Advisory Role: Janssen, Blue Earth Diagnostics, Ferring Pharmaceuticals, Dendreon

Other Relationship: Caribou Publishing

Oliver Sartor

Consulting or Advisory Role: Bayer, Bellicum Pharmaceuticals, Johnson & Johnson, Medivation, Oncogenex, Sanofi, Tokai Pharmaceuticals, AstraZeneca (Inst), Progenics (Inst), Dendreon

Research Funding: Bayer (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Dendreon (Inst), Endocyte (Inst), Innocrin Pharmaceuticals (Inst), Progenics (Inst), InVitae (Inst)

Travel, Accommodations, Expenses: Bayer, Bellicum Pharmaceuticals, Johnson & Johnson, Medivation, Oncogenex, Sanofi, Tokai Pharmaceuticals, AstraZeneca, Progenics

Edward Schaeffer

Consulting or Advisory Role: OPKO Diagnostics, AbbVie

Gordon F. Schwartz

No relationship to disclose

Mark S. Shahin

Honoraria: AstraZeneca, Clovis Oncology, Tesaro, Merck

Consulting or Advisory Role: AstraZeneca, Clovis Oncology, Tesaro, Merck

Speakers’ Bureau: AstraZeneca, Clovis Oncology, Tesaro, Merck

Neal D. Shore

Consulting or Advisory Role: Bayer, Janssen Scientific Affairs, Dendreon, Sanofi, Takeda, Tolmar, Ferring Pharmaceuticals, Medivation/Astellas

Brian Shuch

No relationship to disclose

Howard R. Soule

Leadership: WindMIL Therapeutics

Consulting or Advisory Role: Compugen

Travel, Accommodations, Expenses: Compugen, Sanofi

Scott A. Tomlins

Leadership: Strata Oncology

Honoraria: Astellas Medivation, Almac Diagnostics, Sanofi, Janssen

Consulting or Advisory Role: Strata Oncology

Research Funding: GenomeDx (Inst), Astellas Medivation (Inst)

Patents, Royalties, Other Intellectual Property: I am a coauthor on a patent issued to the University of Michigan on ETS gene fusions in prostate cancer. The diagnostic field of use has been licensed to Hologic/Gen-Probe, who has sublicensed some rights to Ventana Medical Systems/Roche.

Travel, Accommodations, Expenses: Thermo Fisher Scientific, Strata Oncology

Edouard J. Trabulsi

Consulting or Advisory Role: GenomeDx

Robert Uzzo

Consulting or Advisory Role: Johnson & Johnson, Myriad Genetics, Pfizer, Novartis, Genentech

Speakers’ Bureau: Janssen Oncology

Research Funding: Novartis

Donald J. Vander Griend

No relationship to disclose

Patrick C. Walsh

No relationship to disclose

Carol J. Weil

No relationship to disclose

Richard Wender

No relationship to disclose

Leonard G. Gomella

Consulting or Advisory Role: Astellas Pharma, Bayer, MDxHealth, Janssen, Pfizer

Patents, Royalties, Other Intellectual Property: Thomas Jefferson University (Inst)