Topic: Biomarkers

Integrated Multi-Modality Diagnostic Evaluation of Prostate Cancer

Sanoj Punnen, MD, MAS, Associate Professor of Clinical Urology in the University of Miami Health System, explains how multimodal detection options could improve and personalize prostate cancer diagnosis, specifically the combination of MRI and biomarkers. He reviews the pros and cons of each option, noting incidence and mortality rates. To bolster his points, Dr. Punnen summarizes data from the PRECISION trial and the PROMIS trial. He also looks at a 2018 trial studying MRI and 4Kscore® for significant prostate cancer detection and a 2021 study that developed a 4Kscore®/MRI‐based tool to assist clinicians in biopsy decision‐making and counseling of those at risk for prostate cancer. Dr. Punnen concludes by calling for further research, specifically studies comparing biomarkers head-to-head and trials focusing on PET imaging and quantitative imaging.

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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.

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Liquid Diagnostics and Prostate Cancer

E. David Crawford, MD, Editor-in-Chief of Grand Rounds in Urology and Professor of Urology at the University of California, San Diego, discusses how to use liquid diagnostics in combination with PSA testing to reduce unnecessary prostate biopsies. Dr. Crawford explains that while PSA is a good, inexpensive test of the relative risk of prostate cancer, better guidance is needed for application, especially because 90% of PSA tests are ordered by general practitioners rather than specialists. He suggests that medical practitioners consider a PSA of >1.5 to 4 as the danger zone where further evaluation is indicated. These patients should not be immediately sent for a prostate biopsy, but should instead be evaluated for benign prostatic hyperplasia and then for prostate cancer risk using liquid diagnostics. Dr. Crawford recommends following a diagnostic pathway, like the one at pcmarkers.com, to determine which patients need treatment.

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In My Opinion: Biomarkers for the Diagnosis of Prostate Cancer

Michael A. Gorin, MD, discusses biomarkers for diagnosing prostate cancer, including PSA, mpMRI, and serum and urine tests. He gives an overview of the history of prostate specific antigen (PSA), emphasizing that PSA screening is beneficial even as he acknowledges that PSA’s high sensitivity and low specificity result in many unnecessary biopsies. There are now many serum and urine biomarker tests that can help provide more specificity, including 4KScore, Prostate Health Index, SelectMDx, and ExoDx Prostate IntelliScore (EPI), all of which are endorsed by the NCCN Guidelines. Dr. Gorin notes that, when price is considered, SelectMDx and EPI outperform the other tests. Dr. Gorin concludes the presentation by discussing how multiparametric MRI should be used in prostate cancer diagnosis, noting that while there is little official guidance on this yet, he uses it in his own practice if a patient has a PSA ≥3 and receives an abnormal result from a serum or urine biomarker test.

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Trials in Neoadjuvant Therapy for Patients with High-Risk Localized Prostate Cancer

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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Updates in PARP Inhibition and Germline Testing in Prostate Cancer

Alan H. Bryce, MD, Medical Director of the Genomic Oncology Clinic at Mayo Clinic Arizona in Scottsdale, outlines recent treatment updates for prostate cancer patients, beginning with a brief review of germline testing recommendations. Following this, Dr. Bryce discusses two newly-approved PARP inhibitors that target mutations: rucaparib and olaparib. Dr. Bryce then poses a series of questions and challenges that physicians should consider as ongoing trials for various disease states and combinations (neoadjuvant, metastatic castrate sensitive prostate cancer, firstline metastatic castrate resistance prostate cancner, PARP inhibition + immunotherapy, etc.) continue.

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Panel Discussion: Next Generation Genomics and Prostate Cancer Biomarkers

Leonard G. Gomella, MD, FACS, leads a panel discussion with Gerald L. Andriole, Jr., MD; Alan H. Bryce, MD; Brian F Chapin, MD; E. David Crawford, MD; Steven E. Finkelstein, MD, FACRO; A. Karim Kader, MD, PhD; and Neal D. Shore, MD, FACS on how biomarkers are being used to treat prostate cancer. Biomarkers are used to diagnose PCa and to decide whether or not to biopsy or repeat biopsy. They also discuss how biomarkers are used to treat localized disease and advanced disease. Both tissue and liquid biopsies are used for somatic DNA mutations, with liquid biopsies becoming increasingly important since it gives real-time results. Guidelines for germline testing and counseling are being updated, and germline testing for family members is becoming increasingly important. PARP inhibitors are now approved for detecting BRCA mutations. There is broader approval for the medication olaparib for both germline and somatic testing. They also review the updated biomarker map. They discuss how these changes will shape precision medicine and personalized care. It is essential for the urology community to be familiar with all these aspects of testing and clinical applications. They discuss why the PCA 3 test has been declining. They also discuss the need to send a clear message to primary care physicians.

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Genetics and Biomarkers for Prostate Cancer and Bladder Cancer

Alan H. Bryce, MD, Medical Director of the Genomic Oncology Clinic at Mayo Clinic Arizona in Scottsdale, discusses genetics and biomarkers for prostate cancer and bladder cancer. Genetic testing is now considered part of best practice for the treatment of cancer, but even still the topic can be confusing due to the number of different test types and scenarios. In order to combat this confusion, it is important that urologists continue to educate themselves on the matter. Dr. Bryce discusses the purpose of using either germline or somatic tests and the different information they can tell us. He goes into particular detail about the somatic test and how useful it can be in determining which targeted therapies to use for both prostate and bladder cancer. Finally, he also offers some advice on best practices for utilizing the somatic test including: testing every patient, always using a fresh biopsy, and retesting before each line of systemic therapy.

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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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Kaiser Permanente Prostate Cancer Risk Calculator 1.0

Joseph C. Presti, Jr., MD, FACS, Regional Leader of Urologic Oncology Surgery at Kaiser Permanente Northern California, discusses the development of Kaiser Permanente’s new prostate cancer risk calculator and its merits. Dr. Presti explains that older risk calculators tend to oversimplify variables like race, are based on outdated systematic biopsy schemes, and are often poorly calibrated due to the sampling frame used. Using TRIPOD guidelines (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) and the LASSO (least absolute shrinkage and selection operator) system of selection, Kaiser Permanente researchers determined that the variables that ought to be included in a prostate cancer prediction model are age, race, PSA, body-mass index, family history, number of prior negative biopsies, digital rectal exam (DRE), and prostate volume. They created 3 different models based on this, with the simplest but least accurate including clinical core variables but no DRE and no prostate volume, the second-most accurate including DRE but no prostate volume, and the most accurate including DRE and prostate volume. Dr. Presti notes that all of these models compare favorably to other risk calculators.

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Updates in Screening: Prostate Cancer Guidelines

Gerald L. Andriole, Jr., MD, a Robert K. Royce Distinguished Professor and Chief of Urologic Surgery at Barnes-Jewish Hospital, the Siteman Cancer Center, and Washington University School of Medicine in St. Louis, Missouri, reviews guidelines for prostate cancer screening, including the unchanged 2018 AUA guidelines and the 2020 updates to the NCCN and EAU guidelines. Following this, he explains why he disagrees with a 2020 article that suggests physicians use a PSA level of 10 ng/mL as the threshold when referring PCa patients to urology and thus biopsy. Lastly, he outlines five ways physicians can improve the early detection of prostate cancer.

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Genetic Risk Score for Prostate Cancer Screening

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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