The Active Surveillance Study

Study Overview
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Brief Summary
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The Active Surveillance study is a prospective study developed to look at the association of biomarkers with PrCa presentation and progression among men on Active Surveillance and stratify it by their genetic risk. This study will also investigate the incidence and progression by differing genetic risks.

Detailed Description
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This prospective study will look at the association of biomarkers with PrCa presentation and progression among men on Active Surveillance and stratify it by their genetic risk. This study will also investigate the incidence and progression by differing genetic risks. The study will review the serial PSA and imaging data for men in AS comparing and contrasting the men of known higher genetic risk for PrCa with those without. Additionally, the study aims to collect samples to investigate the profile of plasma, serum, urine, stool and saliva biomarkers in men at a higher genetic risk of PrCa, who have been diagnosed with low risk PrCa and are undergoing Active Surveillance. It will also review the association of specific genetic profiles and biomarkers (biological samples - plasma, serum, urine, stool and saliva). These markers will be compared and contrasted with samples from men with no known increased genetic risk for PrCa. The study aims to recruit a total of 200 men with low grade PrCa, aged ≥18 into two cohorts (i.e. men on AS who are known to be at higher genetic risk and those on AS with no known increased genetic risk of PrCa. Patients will be identified through the urology clinics at the Royal Marsden Hospital. These will be men who are already registered at the Royal Marsden Hospital and undergoing active surveillance (as determined by the MDT).

Official Title
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Active Surveillance Study for Prostate Cancer Management for Men at Higher Genetic Risk Compared With Men at No Known Higher Genetic Risk.

Conditions
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Prostate Cancer

Intervention / Treatment
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* Other: Active Surveillance


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men ≥18 years old under the care of the Active Surveillance clinic in the Royal Marsden Hospital (RMH). Known diagnosis of PrCa, deemed suitable for Active surveillance at multi-disciplinary meeting (MDT). Men at genetically higher PrCa risk who are either: Men of European ancestry with a positive family history of PrCa defined as: Having a first degree relative (or second degree if through female line) with histologically or death certificate proven PrCa diagnosed at <70 years Having two relatives on the same side of the family with histologically or death certificate proven PrCa where at least one is diagnosed at <70 years Having three relatives on the same side of the family with histologically or death certificate proven PrCa diagnosed at any age Or (2) Men of black African or Caribbean ancestry defined as: - Both parents and all 4 grandparents from that origin Or (3) Men with a pathogenic mutation in a gene thought to cause a higher risk of prostate cancer: (including BRCA1, BRCA2, ATM, PALB2, MLH1, MSH2, MSH6, CHEK2 and other DNA repair gene mutations as listed in appendix A) Or (4) Men with a high genetic risk (common and/or rare variants) for PrCa resulting in a RR of ≥2 of PrCa Men with no known high risk genetic factors who have been diagnosed with low grade PrCa and deemed suitable for Active Surveillance at multi-disciplinary meeting (control group) as defined in the 4 criteria above. Who performance status 0-2 (see Appendix B) Absence of any psychological, familial, sociological, or geographical situation potentially hampering compliance with the study protocol and follow-up schedule. Exclusion Criteria: No PrCa diagnosis PrCa diagnosis that is not deemed suitable for active surveillance at multi-disciplinary meeting Any significant psychological conditions that may be worsened or exacerbated by participation in the study

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Control Arm<br>Men diagnosed with low-grade PrCa undergoing Active Surveillance and are not known to have an increased genetic risk for PrCa e.g. Men without high-risk mutations or high polygenic risk score (PRS). Men diagnosed with PrCa suitable for Active Surveillance who wish to continue follow up at The Royal Marsden Hospital (RMH) will be offered enrolment in collection and monitoring of various biological samples. These men will act as a control group, as they do not have a known higher genetic risk of PrCa. The control group will have genetic analysis carried out on provided saliva samples. Their family history will be captured. They will be genotyped using the latest technology and at a minimum have PRS testing done. Men may be moved out of the control arm and into the high-risk arm, if identified at a higher genetic risk or as having a strong family history of PrCa for the purposes of the analysis. Any clinically significant genetic results will be discussed with the participants. | Other: Active Surveillance<br>* Active surveillance (AS) is an accepted management strategy for men diagnosed with low risk PrCa, generally defined as PSA <10ng/ml and Gleason score of ≤6 and clinical stage T1 to T2a. Occasionally, a minority of men with Gleason 3+4 disease are included, though majority of those included in AS studies have Gleason 3+3 disease or less. Men in AS studies have repeated biopsies based on various criteria including PSA velocity, repeat biopsy at set time points and change noted on digital rectal examination (DRE), biopsy or MRI imaging. Progression of disease has been defined in various ways in different studies, generally, using criteria of Gleason upgrade to greater than Gleason 3+3, evidence of Gleason 4 or Gleason 5 disease, >50% involvement of any one biopsy core, and greater than 2 cores positive on repeat biopsy. Percentages of men on AS who have upgrade on repeat biopsy have been found to be 19-34%; this may differ in our cohort of men with increased genetic risk for PrCa.<br>|
| High-risk Arm<br>Men who have been diagnosed with low grade PrCa and are undergoing active surveillance who are at genetically higher risk of PrCa defined as: Men of European ancestry with a family history defined as at least one first degree (or second degree if through the female line) relative with PrCa diagnosed at <70 years (diagnosis verified). Men of Black African or Caribbean ancestry irrespective of family history Men of any ethnicity known to carry a mutation in a high-risk gene (Appendix A). Men with a high genetic risk (common and/or rare variants) defined as those with a RR of ≥2. | Other: Active Surveillance<br>* Active surveillance (AS) is an accepted management strategy for men diagnosed with low risk PrCa, generally defined as PSA <10ng/ml and Gleason score of ≤6 and clinical stage T1 to T2a. Occasionally, a minority of men with Gleason 3+4 disease are included, though majority of those included in AS studies have Gleason 3+3 disease or less. Men in AS studies have repeated biopsies based on various criteria including PSA velocity, repeat biopsy at set time points and change noted on digital rectal examination (DRE), biopsy or MRI imaging. Progression of disease has been defined in various ways in different studies, generally, using criteria of Gleason upgrade to greater than Gleason 3+3, evidence of Gleason 4 or Gleason 5 disease, >50% involvement of any one biopsy core, and greater than 2 cores positive on repeat biopsy. Percentages of men on AS who have upgrade on repeat biopsy have been found to be 19-34%; this may differ in our cohort of men with increased genetic risk for PrCa.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the incidence of disease progression of PrCa in the cohorts studied. | Descriptive statistics will be used to determine and compare the characteristics of cancers in each cohort at recruitment. Disease progression will be classified as a Y/N indicator in order to look at the proportion of those progressing in each cohort, using logistic regression to adjust for covariates of interest, such as age at diagnosis, tumour-node-metastasis stage, and Gleason score. Rate ratios for the cumulative incidence of disease progression for any disease, compared between the two cohorts, will be calculated using Poisson regression offset by person-years of follow-up, adjusting for covariates of interest. | The full analysis being completed within one year of date of completion of 5 year follow-up of the last participant. | 
| To determine the incidence of aggressiveness of PrCa in the cohorts studied. | Participants will be defined as experiencing disease progression if they have an upstaging or progression of their disease on MRI or biopsy. i.e., change in MRI or change in Gleason. Rate ratios for the cumulative incidence of aggressive disease (defined as progression on MRI or biopsy that results in the need for active treatment within one year of starting AS), compared between the two cohorts, will be calculated using Poisson regression offset by person-years of follow-up, adjusting for covariates of interest. | The full analysis being completed within one year of date of completion of 5 year follow-up of the last participant. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To investigate the role of biomarker profiles in men undergoing active surveillance who are also at genetically higher risk for PrCa. | We will focus on DW-MRI at diagnosis, again using descriptive statistics and time-to-event analyses to break down the incidence of disease progression in each cohort and determine the association and interaction between higher genetic risk and DW-MRI. | 5 years | 
| To investigate the role of biomarker profiles in men undergoing active surveillance who are also at genetically higher risk for PrCa. | We will focus on metabolites using descriptive statistics and time-to-event analyses to break down the incidence of disease progression in each cohort and determine the association and interaction between higher genetic risk and metabolite levels. | 5 years |