Should Screening be Altered Based on Germline and Family History?
Sigrid V. Carlsson, MD, PhD, MPH, explores the role of genetics in risk-stratified prostate cancer screening.
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germline testing
Putting Germline Testing into Context: A Primer and Current Knowledge
Alan H. Bryce, MD, explores the critical role of germline testing in prostate cancer, providing a primer on its current applications. He emphasizes identifying these genetic markers for patient management and familial risk assessment.
The 9-minute presentation considers the most relevant genes associated with prostate cancer risk, including BRCA1, BRCA2, and ATM. Dr. Bryce also highlights data problems with germline variants, questioning the representation of diverse racial and ethnic groups in clinical trials.
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Putting Germline Testing into Context – A Primer and Current Knowledge
Alan H. Bryce, MD, outlines the current state and potential future directions of germline testing in prostate cancer detection and treatment. He begins with a review of the currently known genetic mutations associated with prostate cancer.
Dr. Bryce then reviews the NCCN criteria for germline genetic testing for patients with new or previously diagnosed prostate cancer. He presents data that supports the idea that current testing guidelines are not effective in identifying the presence of known pathogenic germline variants (PVGs) in patients with prostate cancer.
Dr. Bryce then examines the relationship between disease progression and the presence of PVGs. He presents data illustrating the correlation of certain PVGs and the likelihood of disease progression.
Dr. Bryce concludes by highlighting the lack of available data for different racial groups. He notes that most of the available PGV data is based on the testing and surveillance of Caucasian males, leaving all other racial groups underrepresented in the data.
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New Standards of Care for Advanced Prostate Cancer
In this 20-minute presentation, William K. Oh, MD, Chief of the Division of Hematology and Medical Oncology at the Mount Sinai Health System and Deputy Director of The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, addresses new standards of care in 2021 for advanced prostate cancer and focuses on non-metastatic castration-resistant prostate cancer (nmCRPC), concluding that apalutamide, enzalutamide, and darolutamide improve MFS in men with nmCRPC by ~2 years; SPARTAN, PROSPER, and ARAMIS established favorable benefit-risk for patients with nmCRPC and PSADT<10 months; and these studies provide the best evidence supporting early treatment. He also focuses on metastatic, hormone-sensitive prostate cancer (mHSPC) and concludes that upfront treatment with either abiraterone + prednisone, apalutamide, enzalutamide, or docetaxel is the standard of care and he asserts that new evidence from PEACE-1 and ARASENS supports triple therapy with a novel hormonal therapy +ADT+docetaxel for chemotherapy patients.
Read MoreOverview of the State of Genetic Testing and Future Applications in Prostate Cancer
Brian T. Helfand, MD, PhD, Chief of the Division of Urology and the Ronald L. Chez Family and Richard Melman Family Endowed Chair at NorthShore University HealthSystem in Evanston, Illinois, discusses current and potential future applications of genetic testing in prostate cancer screening and treatment. He explains that genetic testing has applications throughout the patient journey. At the prevention and screening stage, genetic testing can determine which men will benefit from screening. At the diagnosis stage, it can determine which men will benefit from biopsy. During early-stage disease, genetic testing can help identify which men will benefit from definitive treatment. Finally, during late-stage disease, genetic testing can identify the men that will benefit from advanced therapies. Dr. Helfand notes that there are two kinds of genetic testing, germline and somatic, and not all tests are relevant at all stages of the patient journey. He then gives an overview of germline genetic testing’s role in screening, arguing that because family history, rare pathogenic mutations (RPMs), and genetic risk score (GRS) all measure risk independently, a comprehensive inherited risk assessment should include all three tools. Dr. Helfand particularly focuses on GRS, defining it as a number calculated based on the cumulative variation across multiple single nucleotide polymorphisms (SNPs), which is then used to provide an estimate of disease risk. He notes that GRS is simple to interpret and more informative than family history. Dr. Helfand also observes that GRS is correlated with number and laterality of tumor cores. GRS, he argues, is useful for risk stratification for both screening and active surveillance. He notes that RPMs can help with stratification in terms of disease aggressiveness. Dr. Helfand concludes by arguing that genetic testing for prostate cancer will be pivotal in the future and should be included in guidelines for both prevention and screening.
Read MoreGermline Genetics in Prostate Cancer
Brian T. Helfand, MD, PhD, Chief of the Division of Urology and the Ronald L. Chez Family and Richard Melman Family Endowed Chair at NorthShore University HealthSystem, Director of the Personalized Prostate Program, and Director of Clinical Research in the Program for Personalized Cancer Care, discusses germline genetic testing and its ability to support prostate cancer (PCa) diagnosis and prognosis when used effectively. He begins with the NCCN guidelines for PCa germline testing, detailing its recommended use for patients with: intermediate-risk, high-risk, regional or metastatic disease; intraductal histology; Ashkenazi Jewish ancestry; family history (FH) of high-risk germline mutations; and positive family history of cancer. Dr. Helfand then considers genetic assessments, stressing the importance of FH, rare pathogenic mutations (RPMs), and SNPs in reaching conclusions. He continues with an explanation of genetic risk score (GRS), a number calculated based on the cumulative variation across multiple SNPs which is then used to provide an estimate of disease risk, and shows data supporting the idea that GRS is more informative than FH. He looks at how to complete genetic testing with intention, suggesting screening with the goal of identifying men at risk of PCa and aggressive cancer, as well as identifying men who are likely to respond to specific chemotherapies. Dr. Helfand also reviews data from the UK biobank showing the associations FH, RPMs, and GRS have with PCa incidence and mortality. He also presents data on active surveillance showing that it should be used with caution if patients have any DNA damage repair genes. Dr. Helfand reviews data on DNA damage response and cancer therapy, showing that men with DNA double repair gene mutations are more responsive to PARP inhibitors and platinum-based chemo, while men with mismatch mutations are more responsive to immune checkpoint inhibitors. Dr. Helfand concludes by saying that genetic testing should be included in PCa decision-making more often and used to understand the future of PCa patients.
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Germline Genetics and Prostate Cancer Evolution and Aggressivity
Paul C. Boutros, PhD, MBA, Professor of Human Genetics and Urology at the University of California, Los Angeles, explains the relationship between the germline and cancer evolution, as well as the implications this relationship has for screening and care. Dr. Boutros begins by explaining why it makes sense to study the germline, noting that while cancer is a disease of somatic mutations, there are already many known germline risk factors and evidence suggests that 20% of prostate cancer biopsies could be avoided if patients received a polygenic risk score. Dr. Boutros then looks at the results of a study from his lab at UCLA which show that the germline drives somatic epigenomics and that some single nucleotide polymorphisms (SNPs) are prognostic. Another yet-to-be-published study by the same team suggests that the germline also drives somatic mutations, with multiple quantitative trait loci (QTLs) predicting somatic driver mutations. This means that mutations that occur early in tumor evolution and can increase the likelihood of aggressive cancer are more likely to occur in certain people based on genomic factors. This also appears to be the case with multiple cancer types. Dr. Boutros concludes by noting possible future directions for research in this area, including multi-ancestric studies and studies into germline influences on the transcriptome and proteome. He also observes that it is not yet clear how this research should be integrated with diagnostic and prognostic tests nor how it could influence decision-making.
Read MoreUniversal Germline Screening in Prostate Cancer: The Argument Against
Alan H. Bryce, MD, Medical Director of the Genomic Oncology Clinic at Mayo Clinic in Scottsdale, Arizona, argues against universal germline screening in prostate cancer in a point-counterpoint debate. While he agrees that identifying germline mutations is important and can have important implications for therapy and for patients’ families, Dr. Bryce observes that very few carriers are identified through germline testing. Approximately ⅔ of carriers are identified through family history-based screening, and while germline mutations are more common in men with metastatic cancer, they are uncommon in the total prostate cancer population. This means that among low- and intermediate-risk patients, 200-300 people must be screened to find one additional carrier, and among high-risk patients, approximately 50 people must be screened to find an additional carrier. Genetic testing costs money and takes up valuable counseling time, so Dr. Bryce argues that testing all patients is not a sensible allocation of resources.
Read MoreAll Men with Prostate Cancer and All Patients with Advanced Disease Should Undergo Germline Testing
Brian T. Helfand, MD, PhD, Chief of the Division of Urology and the Ronald L. Chez Family and Richard Melman Family Endowed Chair at NorthShore University HealthSystem in Evanston, Illinois, takes the pro side in a point-counterpoint debate on the merits of germline testing for all patients with prostate cancer, from the screening stage to the advanced treatment stage. Dr. Helfand argues that germline testing is beneficial during screening since the identification of rare pathogenic mutations can indicate which patients are at high risk for more aggressive prostate cancer. Germline testing for patients with localized disease is also useful since if a patient has a genetic variant it is more advisable to proceed to definitive treatment with surgery or radiation as opposed to putting them on active surveillance. Dr. Helfand concludes by observing that it can be particularly useful for patients with advanced disease to undergo germline testing since some genetic variants are associated with increased response to certain treatments, such as PARP inhibitors and platinum-based therapies for men with DNA damage repair mutations and immunotherapies for DNA mismatch repair mutations.
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Trials in Neoadjuvant Therapy for Patients with High-Risk Localized Prostate Cancer
Rana R. McKay, MD, Associate Professor of Medicine at the University of California, San Diego, and Co-Leader of the Genitourinary Oncology Disease Team at the Moores Cancer Center, discusses neoadjuvant hormonal therapy for patients with high-risk localized prostate cancer. Neoadjuvant therapy has been shown to be beneficial to patients with breast, rectal, bladder, and other cancers, but historic neoadjuvant trials in prostate cancer have had limited long-term follow-up and have failed to systematically evaluate pathologic response. More recent trials are seeking to remedy these gaps, and results from a recent phase 2 trial indicate that a subset of high-risk patients do benefit greatly from intense neoadjuvant hormonal therapy. Dr. McKay explains that the phase 3 PROTEUS trial, which is currently recruiting, will hopefully allow researchers to better define exceptional responders and non-responders, identify intermediate pathologic endpoints, and figure out how best to integrate imaging and tissue biomarkers to guide neoadjuvant therapy selection for prostate cancer patients.
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Germline Testing for Active Surveillance
Brian T. Helfand, MD, PhD, Chief of the Division of Urology at NorthShore University HealthSystem in Evanston, Illinois, discusses the growing role of genetic assessment in prostate cancer screening, emphasizing the benefits of finding patients’ single nucleotide polymorphism (SNP)-based polygenic risk score (PRS). He acknowledges the roles of family history and testing for rare pathogenic mutations like BRCA2, ATM, and CHEK2, but observes that the former can change over time and be difficult to accurately obtain, while the latter is only relevant to a small percentage of patients. PRS, or genetic risk score, is a number calculated based on the cumulative variation across multiple SNPs, which is then used to provide an easily interpreted estimate of disease risk that is more informative than family history, improves predictive performance, and is significantly associated with both prostate cancer incidence and mortality. Dr. Helfand concludes by noting that there are currently no agreed upon guidelines for timing and frequency of PSA testing, but genetic assessment, and particularly PRS, could clarify who would benefit from early screening.
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