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Germline and Somatic Mutations in Prostate Cancer for the Clinician

Heather H. Cheng, Alexandra O. Sokolova, Edward M. Schaeffer, Eric J. Small, and Celestia S. Higano

It is increasingly important for clinicians involved in the management of prostate cancer to understand the relevance of heritable (germline) mutations that, for select patients, affect prostate cancer risk and cancer biology, and acquired (somatic) mutations that occur in prostate cancer cells. In the advanced disease setting, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials. Similarly, microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors. Germline genetic testing has potential importance in the treatment and assessment of familial risk, and tumor-directed somatic sequencing may guide treatment decision-making. This review provides clinicians with knowledge of basic genetic terminology, awareness of the importance of family history of cancer (not limited to prostate cancer), contrasts between the different but potentially related objectives of germline versus somatic testing of tumor tissue, and indications for genetic counseling. Specific clinical scenarios, objectives of testing, and nature of the assays are reviewed. Germline and somatic mutations of known and potential relevance to prostate cancer are discussed in the context of treatment options, and algorithms to assist clinicians in approaching this area are proposed.

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Prostate Cancer, Version 2.2014

James L. Mohler, Philip W. Kantoff, Andrew J. Armstrong, Robert R. Bahnson, Michael Cohen, Anthony Victor D’Amico, James A. Eastham, Charles A. Enke, Thomas A. Farrington, Celestia S. Higano, Eric Mark Horwitz, Christopher J. Kane, Mark H. Kawachi, Michael Kuettel, Timothy M. Kuzel, Richard J. Lee, Arnold W. Malcolm, David Miller, Elizabeth R. Plimack, Julio M. Pow-Sang, David Raben, Sylvia Richey, Mack Roach III, Eric Rohren, Stan Rosenfeld, Edward Schaeffer, Eric J. Small, Guru Sonpavde, Sandy Srinivas, Cy Stein, Seth A. Strope, Jonathan Tward, Dorothy A. Shead, and Maria Ho

Prostate cancer has surpassed lung cancer as the most common cancer in men in the United States. The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer based on clinical evidence and expert consensus. NCCN Panel guidance on treatment decisions for patients with localized disease is represented in this version. Significant updates for early disease include distinction between active surveillance and observation, a new section on principles of imaging, and revisions to radiation recommendations. The full version of these guidelines, including treatment of patients with advanced disease, can be found online at the NCCN website.

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Prostate Cancer, Version 1.2016

James L. Mohler, Andrew J. Armstrong, Robert R. Bahnson, Anthony Victor D'Amico, Brian J. Davis, James A. Eastham, Charles A. Enke, Thomas A. Farrington, Celestia S. Higano, Eric M. Horwitz, Michael Hurwitz, Christopher J. Kane, Mark H. Kawachi, Michael Kuettel, Richard J. Lee, Joshua J. Meeks, David F. Penson, Elizabeth R. Plimack, Julio M. Pow-Sang, David Raben, Sylvia Richey, Mack Roach III, Stan Rosenfeld, Edward Schaeffer, Ted A. Skolarus, Eric J. Small, Guru Sonpavde, Sandy Srinivas, Seth A. Strope, Jonathan Tward, Dorothy A. Shead, and Deborah A. Freedman-Cass

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after an initial diagnosis of prostate cancer and management options for localized, regional, and metastatic disease. Recommendations for disease monitoring, treatment of recurrent disease, and systemic therapy for metastatic castration-recurrent prostate cancer also are included. This article summarizes the NCCN Prostate Cancer Panel's most significant discussions for the 2016 update of the guidelines, which include refinement of risk stratification methods and new options for the treatment of men with high-risk and very-high-risk disease and progressive castration-naïve disease.

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NCCN Guidelines® Insights: Prostate Cancer, Version 1.2023

Featured Updates to the NCCN Guidelines

Edward M. Schaeffer, Sandy Srinivas, Nabil Adra, Yi An, Daniel Barocas, Rhonda Bitting, Alan Bryce, Brian Chapin, Heather H. Cheng, Anthony Victor D’Amico, Neil Desai, Tanya Dorff, James A. Eastham, Thomas A. Farrington, Xin Gao, Shilpa Gupta, Thomas Guzzo, Joseph E. Ippolito, Michael R. Kuettel, Joshua M. Lang, Tamara Lotan, Rana R. McKay, Todd Morgan, George Netto, Julio M. Pow-Sang, Robert Reiter, Mack Roach III, Tyler Robin, Stan Rosenfeld, Ahmad Shabsigh, Daniel Spratt, Benjamin A. Teply, Jonathan Tward, Richard Valicenti, Jessica Karen Wong, Ryan A. Berardi, Dorothy A. Shead, and Deborah A. Freedman-Cass

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, recurrent, and metastatic disease. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. These NCCN Guidelines Insights summarizes much of the panel’s discussions for the 4.2022 and 1.2023 updates to the guidelines regarding systemic therapy for metastatic prostate cancer.

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Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology

James L. Mohler, Emmanuel S. Antonarakis, Andrew J. Armstrong, Anthony V. D’Amico, Brian J. Davis, Tanya Dorff, James A. Eastham, Charles A. Enke, Thomas A. Farrington, Celestia S. Higano, Eric Mark Horwitz, Michael Hurwitz, Joseph E. Ippolito, Christopher J. Kane, Michael R. Kuettel, Joshua M. Lang, Jesse McKenney, George Netto, David F. Penson, Elizabeth R. Plimack, Julio M. Pow-Sang, Thomas J. Pugh, Sylvia Richey, Mack Roach III, Stan Rosenfeld, Edward Schaeffer, Ahmad Shabsigh, Eric J. Small, Daniel E. Spratt, Sandy Srinivas, Jonathan Tward, Dorothy A. Shead, and Deborah A. Freedman-Cass

The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.

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Prostate Cancer, Version 4.2023, NCCN Clinical Practice Guidelines in Oncology

Edward M. Schaeffer, Sandy Srinivas, Nabil Adra, Yi An, Daniel Barocas, Rhonda Bitting, Alan Bryce, Brian Chapin, Heather H. Cheng, Anthony Victor D’Amico, Neil Desai, Tanya Dorff, James A. Eastham, Thomas A. Farrington, Xin Gao, Shilpa Gupta, Thomas Guzzo, Joseph E. Ippolito, Michael R. Kuettel, Joshua M. Lang, Tamara Lotan, Rana R. McKay, Todd Morgan, George Netto, Julio M. Pow-Sang, Robert Reiter, Mack Roach III, Tyler Robin, Stan Rosenfeld, Ahmad Shabsigh, Daniel Spratt, Benjamin A. Teply, Jonathan Tward, Richard Valicenti, Jessica Karen Wong, Dorothy A. Shead, Jenna Snedeker, and Deborah A. Freedman-Cass

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions regarding the workup of patients with prostate cancer, risk stratification and management of localized disease, post-treatment monitoring, and treatment of recurrence and advanced disease. The Guidelines sections included in this article focus on the management of metastatic castration-sensitive disease, nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). Androgen deprivation therapy (ADT) with treatment intensification is strongly recommended for patients with metastatic castration-sensitive prostate cancer. For patients with nonmetastatic CRPC, ADT is continued with or without the addition of certain secondary hormone therapies depending on prostate-specific antigen doubling time. In the mCRPC setting, ADT is continued with the sequential addition of certain secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, the presence or absence of visceral disease, symptoms, and potential side effects.

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NCCN Guidelines® Insights: Prostate Cancer, Version 3.2024

Featured Updates to the NCCN Guidelines

Edward M. Schaeffer, Sandy Srinivas, Nabil Adra, Yi An, Rhonda Bitting, Brian Chapin, Heather H. Cheng, Anthony Victor D’Amico, Neil Desai, Tanya Dorff, James A. Eastham, Thomas A. Farrington, Xin Gao, Shilpa Gupta, Thomas Guzzo, Joseph E. Ippolito, R. Jeffrey Karnes, Michael R. Kuettel, Joshua M. Lang, Tamara Lotan, Rana R. McKay, Todd Morgan, Julio M. Pow-Sang, Robert Reiter, Mack Roach III, Tyler Robin, Stan Rosenfeld, Ahmad Shabsigh, Daniel Spratt, Russell Szmulewitz, Benjamin A. Teply, Jonathan Tward, Richard Valicenti, Jessica Karen Wong, Jenna Snedeker, and Deborah A. Freedman-Cass

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

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NCCN Guidelines Insights: Prostate Cancer, Version 1.2021

Featured Updates to the NCCN Guidelines

Edward Schaeffer, Sandy Srinivas, Emmanuel S. Antonarakis, Andrew J. Armstrong, Justin E. Bekelman, Heather Cheng, Anthony Victor D’Amico, Brian J. Davis, Neil Desai, Tanya Dorff, James A. Eastham, Thomas A. Farrington, Xin Gao, Eric Mark Horwitz, Joseph E. Ippolito, Michael R. Kuettel, Joshua M. Lang, Rana McKay, Jesse McKenney, George Netto, David F. Penson, Julio M. Pow-Sang, Robert Reiter, Sylvia Richey, Mack Roach, III, Stan Rosenfeld, Ahmad Shabsigh, Daniel E. Spratt, Benjamin A. Teply, Jonathan Tward, Dorothy A. Shead, and Deborah A. Freedman-Cass

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarizes the panel’s discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer.