Men at High Genetic Risk for Prostate Cancer

Study Overview
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Brief Summary
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Background: Research studies have shown that genetic changes and family history may increase a man s risk for prostate cancer. Researchers want to follow the prostate health of men who have specific genetic changes associated with prostate cancer to help them learn more about which men are at higher risk for prostate cancer. Objectives: To study men with specific genetic changes and determine who is at higher risk for getting prostate cancer. To study if certain genetic changes and family history can be used to help prevent or treat prostate cancer. Eligibility: Persons assigned male at birth ages 30-75 who have one or more specific genetic changes but without prostate cancer. Design: This study does not perform genetic testing. All participants must have documented genetic changes and able to provide a copy of the report. Before enrollment, participants will provide a copy of documented genetic changes and go through a telephone interview to determine eligibility for the study. On enrollment, participants will have medical and family history review, medication review, physical exam, blood collection for clinical and research testing, and MRI (magnetic resonance imaging) of the prostate. Every year, participants will repeat the physical exam, medical history, family history, medication review, routine blood tests, including PSA and testosterone. Every 2 years, participants will repeat all the above plus prostate MRI and blood tests for research. If, at any time, the physical exam, blood tests or MRI are abnormal, participants may be asked to do a biopsy. If the biopsy results in prostate cancer, participants will be given counseling on next steps, general treatment recommendations, and then followed with a phone call each year. Participants may ask to speak with a genetic counselor.

Detailed Description
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Background: 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 certain genetic variants that are associated with an increased risk of prostate cancer. An evolving approach to prostate cancer screening is to target populations at risk of developing prostate cancer based on their genetic predisposition. Objective: To follow the natural history of men with known germline variants or likely pathogenic variants in genes that put them at risk for developing prostate cancer. Eligibility: Persons assigned male at birth who are between ages 30-75 years old. Documented germline pathogenic or likely pathogenic variants in prostate cancer-related risk gene: BRCA 1 and 2, DNA Mismatch Repair (MMR) genes associated with Lynch syndrome (MLH1, MSH2, MSH6, PMS2, and EPCAM), HOXB13, ATM, NBN, TP53, CHEK2, PALB2, RAD51C, RAD51D, BRIP1, or FANC (FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, and FANCM). Must be able and willing to provide informed consent. Design: Up to 500 subjects will be enrolled. Participants will undergo sampling of blood for prostate-specific antigen. Based on these results and age, participants will be considered for biopsy and/or continued monitoring if feasible upon clinical discretion. Participants will undergo a baseline MRI evaluation with follow-up scans every 2 years as clinically indicated. Following initial evaluation, participants will be followed as clinically indicated, usually at 12 month intervals, to determine their PSA level, prostate cancer treatment (if relevant) and/or disease/survival status until death.

Official Title
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Natural History Study of Men at High Genetic Risk for Prostate Cancer

Conditions
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Prostatic Neoplasms

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Persons assigned male at birth between the ages of 30-75 years. Documented germline variant (i.e. pathogenic/likely pathogenic variant) in prostate cancer risk-related gene from a CLIA certified laboratory: BRCA1 and BRCA2, MMR genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) associated with Lynch syndrome, as well as HOXB13, ATM, NBN, TP53, CHEK2, PALB2, RAD51C, RAD51D, BRIP1, or FANC (FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, and FANCM). Prognosis of >5 years survival if affected by another cancer Ability of subject to understand and the willingness to sign a written informed consent document Exclusion Criteria: Prior diagnosis or treatment for prostate cancer Known contraindication to MRI: Participants unable to fit through MRI scanner (radiologist discretion) Allergy to MR contrast agent Participants with pacemakers, cerebral aneurysm clips, shrapnel injury, or implantable electronic device Active concomitant medical or psychological illnesses that may increase the risk to the subject or inability to obtain informed consent, at the discretion of the principal investigator.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 75 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 1<br>Participants with germline pathogenic or likely pathogenic variants in prostate cancer-related risk genes | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Natural history of high genetic risk for prostate cancer | To follow the natural history of men with known germline variants or likely pathogenic variants in genes that put them at high risk for developing prostate cancer | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| mpMRI feasibility | test the feasibility and accuracy of multi parametric magnetic resonance imaging (mpMRI) for the localization and detection of local prostate cancer | baseline and every two years until death or when criteria for removal from study is met | 
| role of mpMRI | role of mpMRI in monitoring participants on active surveillance and as a follow up tool for monitoring local disease progression | baseline and every two years until death or when criteria for removal from study is met | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BRCA 1, BRCA 2, MMR genes, Lynch Syndrome, Natural History