Prostate Cancer Genetic Risk Evaluation and Screening Study

Study Overview
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Brief Summary
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This study aims to define the natural history of men at high genetic risk for prostate cancer on the basis of specific germline genetic mutations or a positive family history and evaluate the utility of prostate MRI as a screening tool. The hypothesis is that this targeted population of men are at elevated risk of developing prostate cancer compared to the general population, and enhanced screening with MRI will enable early detection and diagnosis of potentially aggressive prostate cancer, characterization of the penetrance of specific mutations, and potentially identify new genetic risk mutations.

Detailed Description
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Prostate cancer is the most common malignancy and the second leading cause of cancer-related deaths in American men. Prostate cancer has substantial inherited predisposition and men harboring specific genetic variants or a positive family history have been associated with an increased risk of developing prostate cancer. Men with specific genetic variants, such as pathogenic BRCA2 mutations, are at particularly greater risk of developing aggressive forms of prostate cancer and thus warrant undergoing careful screening for prostate cancer. However, the penetrance of many mutations in prostate cancer risk genes is unknown, and some men have no identifiable mutations in known risk genes despite a strong family history of prostate cancer. Prospectively collected clinical data along with biospecimens from unaffected individuals at high genetic risk for developing prostate cancer will advance the understanding of how specific mutations contribute to the development of prostate cancer and how these prostate cancers might be best detected. The purpose of this study is to prospectively screen men at high risk genetic risk for prostate cancer by prostate exam, PSA, and prostate MRI to characterize the penetrance and cancer-related outcomes of specific mutations, identify potentially novel genetic risk mutations and/or markers for early detection.

Official Title
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Prostate Cancer Genetic Risk Evaluation and Screening Study (PROGRESS)

Conditions
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Prostatic Neoplasm, Prostate Cancer, BRCA2 Mutation, BRCA1 Mutation, ATM Gene Mutation, MMR Mutation, Lynch Syndrome, Genetic Predisposition to Disease

Intervention / Treatment
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* Diagnostic Test: Prostate cancer screening


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men 35-74 years old No known diagnosis of prostate cancer Life expectancy >10 years Meet either cohort A or B criteria Cohort A: Documented pathogenic or likely pathogenic germline genetic mutation in a prostate cancer risk gene from a CLIA-certified laboratory (ATM, ATR, BRCA1, BRCA2, BRIP1, CHEK2, EPCAM, FANCA, GEN1, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51C, RAD51D, TP53) Cohort B: A strong family history suggestive of high genetic risk for prostate cancer with negative clinical genetic testing Exclusion Criteria: Prior diagnosis or treatment of prostate cancer Inability to undergo prostate MRI Inability to receive MRI contrast agent

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort A<br>Documented germline known pathogenic or likely pathogenic mutation in a prostate cancer related risk gene | Diagnostic Test: Prostate cancer screening<br>* Physical exam (digital rectal exam), prostate-specific antigen (PSA) and PSA derivatives, and multiparametric MRI of the prostate<br>|
| Cohort B<br>Family history suggestive of high genetic risk for prostate cancer with clinical genetic testing negative for known pathogenic or likely pathogenic mutations in prostate cancer-related risk genes | Diagnostic Test: Prostate cancer screening<br>* Physical exam (digital rectal exam), prostate-specific antigen (PSA) and PSA derivatives, and multiparametric MRI of the prostate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnosis of prostate cancer | Diagnosis of prostate cancer stratified by NCCN clinical risk category incorporating clinical stage, grade, and PSA at diagnosis. | From date of enrollment until date of diagnosis of prostate cancer or age of 75 reached, which ever came first, assessed up to 20 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive predictive value of multiparametric MRI for detection of prostate cancer | Positive predictive value of multiparametric prostate MRI for detecting clinically significant prostate cancer in men at high genetic risk for prostate cancer with a positive MRI (PI-RADS score of 3 or higher) | From date of enrollment until date of diagnosis of prostate cancer or age of 75 reached, which ever came first, assessed up to 20 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BRCA2, BRCA1, Mismatch Repair Deficiency, Lynch Syndrome, HOXB13, Family History of Prostate Cancer