Heart and Blood Diseases

All Conditions

Nutritional and Metabolic Diseases

Gland and Hormone Related Diseases

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Digestive System Diseases

Coronary Artery Disease

Diabetes Mellitus, Type 2

Prostatic Neoplasms

Diabetes Mellitus

Breast Neoplasms

Atrial Fibrillation

Coronary Disease

Myocardial Ischemia

Colorectal Neoplasms

Ischemia

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Metabolic Diseases

Glucose Metabolism Disorders

Endocrine System Diseases

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Arrhythmias, Cardiac

Heart Diseases

Arteriosclerosis

Arterial Occlusive Diseases

Vascular Diseases

Patient-participants in the PRS-high arm and their providers will receive their high-PRS results at baseline, along with educational resources about the results.

Patient-participants in the UC-high arm and their providers will receive their high-PRS results after a 24-month observation period, along with educational resources about the results.

Patient-participants in the PRS-average arm and their providers will receive their average-PRS results at baseline, along with educational resources about the results.

Patient-participants in the UC-average arm and their providers will receive their average-PRS results after a 24-month observation period, along with educational resources about the results..

Polygenic risk score report from a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory for coronary artery disease, atrial fibrillation, type 2 diabetes, colorectal cancer, breast cancer (for women only), and prostate cancer (for men only), delivered along with patient- and provider-level educational material.

Polygenic risk score (PRS)

Jason L. Vassy, MD, MPH, SM

This trial will determine the clinical effectiveness of polygenic risk score testing among patients at high genetic risk for at least one of six diseases (coronary artery disease, atrial fibrillation, type 2 diabetes mellitus, colorectal cancer, breast cancer, or prostate cancer), measured by time-to-diagnosis of prevalent or incident disease over 24 months.

One of the most pressing controversies in genomics today is the clinical utility of polygenic risk scores (PRS). Broadening the scope of genomic risk testing beyond monogenic diseases, PRS combine information from hundreds or even millions of genetic loci, each with a very small effect size on the risk of common complex disease. The result is a continuous quantitative risk factor for susceptibility to conditions such as coronary artery disease (CAD), type 2 diabetes (T2D), and breast cancer. Compared to rarer monogenic disease variants, PRS have greater transformative potential for public health and healthcare in their ability to identify much larger proportions of the population at significantly elevated risk for disease, facilitating evidence-based prevention and management. Moreover, their prediction ability has vastly improved compared to earlier PRS that included only a limited number of genetic variants. However, while the associations between PRS and a wide range of common diseases are well established (clinical validity), the potential impact of this information on patient health outcomes (clinical utility) remains contested and understudied.

This study will examine the effectiveness and implementation outcomes from the use of PRS for 6 common diseases that are screened for by PCPs and have established prevention strategies: CAD, AFib, T2D, colorectal cancer, prostate cancer, and breast cancer. This trial has two aims:

Aim 1: Conduct a randomized controlled trial (RCT) to determine the clinical effectiveness of PRS among patients at high genetic risk for at least one disease, measured by changes in clinical management (process outcomes) and time to diagnosis of prevalent or incident disease (clinical outcome) over 24 months.

Aim 2: Measure high-priority genomic medicine implementation outcomes, including primary care provider (PCP) knowledge and beliefs about PRS, patient activation in healthcare, medication adherence, and costs.

Randomized clinical trial comparing polygenic risk score (PRS) testing and reporting to delayed reporting

Participants are randomized to have them and their primary care providers receive their PRS results at baseline (PRS) or after 24 months (usual care, UC). Randomization is stratified by PRS results: A high-risk stratum consists of all participants with at least one PRS indicating high risk, while the remaining participants comprise the average-risk stratum. Participants who do not receive their results at baseline are blinded to whether they have all average-risk PRS results or any high-risk PRS results. Outcomes assessors and data analysts will be blinded to randomization and PRS results status.

The Genomic Medicine at VA Study

Pragmatic Randomized Trial of Polygenic Risk Scoring for Common Diseases in Primary Care

We will share de-identified individual-level trial data through a data repository housed on a secure VA server and accessible only to outside investigators with Institutional Review Board (IRB).

Semi-structured interviews will collect qualitative data on participating providers' understanding of and perceived utility of the PRS risk information.

The most recent systolic and diastolic blood pressure values recorded in the medical record prior to or on the date of enrollment and prior to or on the date 24 months after enrollment.

The most recent BMI values recorded in the medical record prior to or on the date of enrollment and prior to or on the date 24 months after enrollment.

Self-reported use of prescription or over-the-counter aspirin will be assessed on the baseline and end-of-study surveys.

Self-reported physical will be assessed on the baseline and end-of-study surveys using the Rapid Assessment of Physical Activity.

Self-reported alcohol will be assessed on the baseline and end-of-study surveys using measures from the Behavioral Risk Factor Surveillance System, recorded as an ordinal 5-item Likert response (from "Never" to "Very often").

Self-reported processed meat intake assessed on the baseline and end-of-study surveys using a food frequency question from National Cancer Institute Eating Habits Questionnaire, recorded as an ordinal 5-item Likert response (from "Never" to "Very often").

The most recent LDL-C values recorded in the medical record prior to or on the date of enrollment and prior to or on the date 24 months after enrollment.

Self-reported smoking status will be assessed on the baseline and end-of-study surveys using measures from the Behavioral Risk Factor Surveillance System.

Relevant prescription medication changes during 24-month observation period, including antihypertensives, cholesterol-lowering medications, anticoagulants, antiplatelet medications, 5-alpha reductase inhibitors, selective estrogen receptor modulators, aromatase inhibitors, as abstracted from medical record review.

As determined by data collected from the baseline survey (VR-12)

The primary outcome of the study is time-to-diagnosis both of undiagnosed prevalent cases of the 6 target conditions and incident cases during the study period. This composite outcome will only include clinically significant diagnoses, as adjudicated by expert clinical chart review.

Any evidence that the patient-participant underwent additional diagnostic testing for the six target diseases since enrollment: coronary artery disease (stress testing, cardiac CT for coronary artery calcium (CAC), coronary angiography), atrial fibrillation (ECG, heart rhythm monitoring), type 2 diabetes (hemoglobin A1c, blood glucose), colorectal cancer (colonoscopy, sigmoidoscopy, fecal blood testing, CT colonography), breast cancer (mammography, breast MRI, breast ultrasound, breast biopsy), and prostate cancer (PSA testing, prostate biopsy).

Self-reported understanding, competence, and willingness to participate health care decisions and processes assessed on the baseline and end-of-study surveys, using the 13-item short form of the Patient Activation Measure (Hibbard, Health Services Research 2005).

A combination of administrative data and microcosting approaches will be used to estimate the costs of the intervention and the subsequent patient-level healthcare costs over the 24 months after enrollment. Estimates of the infrastructure and personnel needed to deliver the intervention will be derived empirically from the study. Healthcare costs will be abstracted from billing and administrative data.

Self-report of taking medications as prescribed assessed on the baseline and end-of-study surveys, using the 3-item Voils Medication Adherence Survey (Voils, Medical Care, 2012).

VA Boston Healthcare System

Boston VA Research Institute, Inc.

Principal Investigator

Genetic Risk Score

Genetic Predisposition to Disease

Disease Susceptibility

Disease Attributes

Participants are placed into their arm after appropriate genetic testing has been conducted to determine their risk.

Participants will be put into PRS cohorts based on their genetic data.

All participants enrolled into the study will receive a PSA screening test and an mpMRI, regardless of their polygenic risk score.

Polygenic Risk Score (PRS)

Adam S Kibel, MD, MHCM

Daniella Furtado

Pamela Coleman, MD

Tamaro S Hudson, PhD, MPH

Peter A Pinto, MD

Ismail B Turkbey, MD

Peter L Choyke, MD, FACR

Gregory T Chesnut, MD

Peter Pinto, MD

The goal of this clinical trial is to evaluate a screening method to detect clinically relevant prostate cancer. This clinical trial is using genetic data to determine a man's risk of cancer, together with multiparametric magnetic resonance imaging (mpMRI) to identify men with higher grade cancer.

The main questions it aims to answer are:

* If genetic data related to prostate cancer used with MRI can identify higher-grade, potentially fatal prostate cancer
* What age a MRI is useful clinically for prostate cancer screening
* If deep learning methods used with MRI when the genetic risk of the man is known can more accurately predict significant cancers

Participants will:

* Get a prostate specific antigen (PSA) blood test
* Get an mpMRI
* Get the results of their genetic data to determine if they are considered high-, intermediate-, or low-risk for prostate cancer based on the trials genetic testing
* Follow-up for this trial based on the participants risk and findings from the PSA test and mpMRI

Background:

* Prostate cancer is the most commonly diagnosed cancer among men in the United States
* Prostate cancer screening using the marker prostate-specific antigen (PSA) is controversial
* PSA based screening is less effective, at least in part, because it rests on screening the entire population
* Polygenic risk scores stratify men based on their prostate cancer genetic predisposition and may improve population level screening programs by focusing on men with higher risk of disease and sparing low risk men
* It is critical that studies aiming to translate the development of an early-detection strategy are conducted within a diverse patient population to address prostate cancer mortality disparities

Study Design:

* Plan to accrue 1,500 participants from both established biobanks and primary care offices
* Participants will get an initial PSA screening blood test and an mpMRI
* Participants will have their polygenic risk score determined from genome-wide association study (GWAS) data
* Participant follow-up will be determined by PRS results, as well as if there are abnormal findings on their PSA screening and/or mpMRI

Objectives:

* To evaluate a screening algorithm to detect clinically relevant prostate cancer (Gleason score ≥7) using genetic data (PRS) to determine risk of cancer and mpMRI to identify men with higher grade cancer
* To determine optimal age to begin screening using PRS and mpMRI
* To determine if rare variants in DNA repair enzymes could help refine screening
* To determine if deep learning methods applied to mpMRI and informed by genetic risk can more accurately predict significant cancers

Prostate cancer screening using prostate specific antigen (PSA) is controversial. On the one hand, there is a reduction in prostate cancer mortality associated with screening. On the other, there is clear evidence that widespread and indiscriminate PSA based screening has led to over diagnosis and over treatment of prostate cancer. In part this is due to indiscriminate screening of all men, not just those at risk. Development and implementation of a screening strategy specifically targeting men at risk for potentially harmful prostate cancer, while sparing low risk men the burdens of screening, is urgently needed.

The investigators believe that integration of genetic testing and multiparametric MRI (mpMRI) will dramatically improve screening. Polygenic risk scores (PRS) have been developed to determine an individual's risk of prostate cancer and attempts have been made to create risk scores for clinically relevant disease. mpMRI has been established as an aid in differentiating clinically relevant from indolent prostate cancer.

Our scientific premise is that an integrated approach which leverages the strengths of both genetics and mpMRI will do more than simply risk stratify men into those at risk for and not at risk for prostate cancer; the investigators will stratify a population of men into those with and those without clinically relevant prostate cancer. The investigators hypothesize that genetic testing to first identify patients at risk of prostate cancer followed by mpMRI to determine who likely has clinically relevant disease represents an optimal strategy.

This study will determine if a polygenic risk score can be used in conjunction with mpMRI to identify Gleason score ≥7 cancer.

Polygenic Risk Stratification Combined With mpMRI to Identify Clinically Relevant Prostate Cancer

The ratio between men with high PRS and intermediate PRS in each of the three age groups (40-54, 55-64, 65-69) regardless of their ethnicity.

The ratio between men with high PRS and intermediate PRS in each of the six age groups (40-44, 45-49, 50-54, 55-59, 60-64, 65-69) regardless of their ethnicity.

Examine the extent to which the addition of rare variants to the PRS involves risk prediction. The weighting procedure will be implemented to account for oversampling of high risk cases.

National Cancer Institute (NCI)

Adam S. Kibel, MD

Chair, Department of Urology, Brigham Health & Dana-Farber Cancer Institute; DiNovi Family Distinguished Chair in Urology, Brigham and Women's Hospital; Elliott Carr Cutler Professor of Surgery, Harvard Medical School

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Genomic Medicine at VA Study	NCT04331535	Coronary Artery... Atrial Fibrilla... Type 2 Diabetes Colorectal Canc... Breast Cancer Prostate Cancer	Polygenic risk ...	50 Years - 70 Years	Boston VA Research Institute, Inc.
The Genomic Medicine at VA Study	NCT04331535	Coronary Artery... Atrial Fibrilla... Type 2 Diabetes Colorectal Canc... Breast Cancer Prostate Cancer	Polygenic risk ...	50 Years - 70 Years	Boston VA Research Institute, Inc.
Polygenic Risk Stratification Combined With mpMRI to Identify Clinically Relevant Prostate Cancer	NCT06398639	Prostate Cancer Polygenic Risk ...	Polygenic Risk ...	40 Years - 69 Years	Brigham and Women's Hospital

Spots Global Cancer Trial Database for polygenic risk score (prs)