The PROFILE Study: Germline Genetic Profiling: Correlation With Targeted Prostate Cancer Screening and Treatment
The PROFILE Study: Germline Genetic Profiling: Correlation With Targeted Prostate Cancer Screening and Treatment
Prostate cancer is the most common cancer in men in the United Kingdom (UK) with over 40,000
 men diagnosed each year. Prostate cancer (PrCa) can run in some families and research studies
 have identified several genetic changes that are thought to increase the risk of developing
 prostate cancer. This study aims to look at the potential risk of these changes in targeted
 screening. Some of these changes may cause a very slight increase in prostate cancer risk
 while others may cause a much larger increase in risk of developing prostate cancer. The
 investigators will invite men with a family history of prostate cancer for targeted prostate
 screening (Prostate Specific Antigen (PSA) testing and a biopsy of the prostate gland) and
 genetic profiling. This research will help us to determine what the risk of cancer is for men
 who have inherited these genetic changes and also increase our knowledge about the role of
 genetics in developing prostate cancer targeted screening. Some of these changes may cause a
 very slight increase in prostate cancer risk while others may cause a much larger increase in
 risk of developing prostate cancer.

 The investigators will invite men with a family history of prostate cancer for targeted
 prostate screening (PSA testing and a biopsy of the prostate gland) and genetic profiling.
 This research will help us to determine what the risk of cancer is for men who have inherited
 these genetic changes and also increase our knowledge about the role of genetics in
 developing prostate cancer.
Purpose and Design

 The aim of the PROFILE study is to investigate the role of targeted prostate cancer screening
 in men with a family history of the disease and with the role of specific genetic profiles
 and biomarkers (both biological samples and DWMRI). This study has been designed using an
 observational approach to look at the correlation of cancer incidence (on biopsy) with
 genetic profile. The aim is to evaluate targeted screening for prostate cancer in men with a
 family history of the disease, to estimate the incidence of prostate cancer and the
 sensitivity and specificity of PSA screening in these populations and correlate this with
 single nucleotide polymorphism (SNP) profiles and biological endpoints.

 Two cohorts will be recruited:

 1. Men with family history of prostate cancer.

 2. Men of AfroCaribbean descent.

 Men with no prior screening will be offered immediate biopsy and genetic profiling. This will
 provide data on genetic profiling and correlation with biopsy irrespective of PSA in men who
 have not had any previous screening.

 A PSA screening algorithm was considered as an alternative to biopsy but there is great
 controversy over the PSA threshold that should be used as a cut-off. Recent data have shown
 that a considerable percentage of men with a PSA within normal range have cancer at biopsy.
 Therefore it has been decided by the Steering Committee that all participants should be
 offered a biopsy within this study. This will tell us the acceptability of this approach.

 Some men may opt not to have biopsy. These men will be followed up six monthly PSA and biopsy
 performed if PSA is above or equal to 1.0ng/ml if the man is aged under 50 years, or where
 PSA is above or equal to 2.0ng/ml if the man is aged fifty years or over.

 Eligibility and Recruitment

 Men with either:

 1. A positive family history of PrCa defined as:

 -  Men with a first degree relative (or second degree if through female line) with
 histologically or death certificate proven PrCa diagnosed at <70 years

 -  Men with 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

 -  Men with three relatives on the same side of the family with histologically or
 death certificate proven PrCa diagnosed at any age

 2. Of African or Caribbean ancestry defined as:

 Both parents and all 4 grandparents from that origin

 -  Age 40- 69 years

 -  WHO performance status 02 (see Appendix A)

 -  Absence of any psychological, familial, sociological or geographical situation
 potentially hampering compliance with the study protocol and follow up schedule.

 Exclusion criteria

 -  Previous cancer with a life expectancy of less than five years.

 -  Previous PrCa

 -  Negative biopsy within one year before recruitment

 -  Comorbidities making prostate biopsy risk unacceptable (Warfarin or Clopidogrel).

 -  Contraindications to having an MRI (pacemakers, aneurysm clips, claustrophobia)

 Subject Withdrawal

 o Subjects may withdraw from the study at any time if they so wish without giving a reason.
 No further data will be collected about that individual, and any unused samples will be
 destroyed. Data collected up to that point will be retained for audit purposes.

 Cancer cases Men who are found to have prostate cancer at biopsy will be referred to their
 local urologist for treatment according to local policy. Men will be followed up for 10 years
 in order to evaluate the different treatment regimens.

 Genetic Profiling All men will have genetic profiling to correlate with disease status and
 men will be given the results of this test. It will be emphasised that these are research
 results and written information will be provided as a reference guide.

 Informed Consent All subjects will be informed of the aims of the study, the possible adverse
 events, the procedures and possible hazards to which he will be exposed, and the mechanism of
 treatment allocation if prostate cancer was to be diagnosed. He will be informed as to the
 strict confidentiality of his patient data, but that his medical records may be reviewed for
 trial purposes by authorised individuals other than their treating physician.

 It will be emphasised that the participation is voluntary and that the subject is allowed to
 refuse further participation in the protocol whenever he wants. This will not prejudice the
 subject's subsequent care. Documented informed consent will be obtained, according to the
 principals of good clinical practice (GCP), for all subjects included in the study before
 they are registered onto the study.

 Risks, burdens, benefits There is a risk of complications from having a prostate biopsy, and
 these complications are detailed in the patient information sheet, together with likelihood
 of incidence. Complications are rare and standard procedures will be followed at all sites to
 minimise their occurrence. The benefit of taking part may be that prostate cancer may be
 diagnosed in men previously unaware that they had the disease. While there is the potential
 for overdiagnosis of indolent disease, there is also the potential for detecting and treating
 clinically significant disease.

 Provision of results from the genetic profiling One further consideration is the occurrence
 of anxiety as a result of taking part in the study, particularly in receiving research
 genetic test results. There is considerable uncertainty about how genetic profile relates to
 predicted risk of prostate cancer. For this reason individualised written information will be
 provided to each participant putting the research results in the context of the current
 population risks. It will be stressed that these are research results only and that the
 investigators do not fully understand the meaning of the results.

 A psychosocial study is being run concurrently and will explore these issues in more depth
 and the participant's experience of receiving these results will be an important component of
 the evaluation of this study.

 Confidentiality All information which is collected will be accessible only to the immediate
 study team. Any data that is shared will be de-identified and any published data will be
 anonymised so that no participant is recognisable from the results.

 Medical records and the data collected for the study may be looked at by authorised persons
 from the Institute of Cancer Research, by regulatory authorities and by authorised people to
 check that the study is being carried out correctly. All will have a duty of confidentiality
 to participants.

 End of Study Follow-up After the participant has completed the study they will be advised
 about any ongoing screening or follow-up that is required. This will be organised through the
 participants general practitioner (GP).

 Use of samples in future research The informed consent process will explain that samples are
 donated as a "gift". If any of the samples collected are to be considered for use in future
 research projects this would have to be approved by the Ethics Committee first.
Inclusion Criteria:

 Men with either:

 1. A positive family history of PrCa defined as:

 -  Men with a first degree relative (or second degree if through female line) with
 histologically or death certificate proven PrCa diagnosed at <70 years

 -  Men with 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

 -  Men with three relatives on the same side of the family with histologically or
 death certificate proven PrCa diagnosed at any age

 2. Of African or Caribbean ancestry defined as:

 Both parents and all 4 grandparents from that origin

 -  Age 40- 69 years

 -  WHO performance status 02 (see Appendix A)

 -  Absence of any psychological, familial, sociological or geographical situation
 potentially hampering compliance with the study protocol and follow up schedule.

 Exclusion Criteria:

 -  Previous cancer with a life expectancy of less than five years.

 -  Previous PrCa

 -  Negative biopsy within one year before recruitment

 -  Comorbidities making prostate biopsy risk unacceptable (Warfarin or Clopidogrel).

 -  Contraindications to having an MRI (pacemakers, aneurysm clips, claustrophobia)