Clinical trial NCT00261456: The IMPACT Study - Identification of Men With a Genetic Predisposition to ProstAte Cancer
Official title: The IMPACT Study - Identification of Men With a Genetic Predisposition to ProstAte Cancer: Targeted Screening in Men at Higher Genetic Risk and Controls
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Prostate Cancer
BRCA Mutation
Mismatch Repair Gene Mutation
Genetic Predisposition to Disease
Keywords: Prostate cancer
BRCA1
BRCA2
prostate screening
PSA
prostate biopsy
Lynch Syndrome
Mismatch Repair Genes
MLH1
MSH2
MSH6
Lead sponsor: Institute of Cancer Research, United Kingdom
Sponsor class: OTHER
Collaborators: name: Cancer Research UK
name: Royal Marsden NHS Foundation Trust
name: Ronald and Rita McAulay Foundation
name: BRCA Research and Cure Alliance
First posted: 2005-12-05
Enrollment: 3500
Sex: MALE
Minimum age (years): 40
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Any patient that meets the eligibility criteria and maybe attending a genetics clinic at a number of international centres that have gone through ethical approval.

Brief summary: The IMPACT study is an international targeted prostate screening study of men at increased prostate cancer risk due to the presence of known pathogenic mutations in BRCA1 and BRCA2 genes and Mis-Match Repair genes (MLH1, MSH6, MSH2).

There are only approximately 150 men with a known BRCA1 or BRCA2 mutation in the UK. Research has shown that these men are at an increased risk of developing prostate cancer but more information is needed about the pathogenesis of prostate cancer in this defined group and the role of screening in these men. The study will offer annual PSA screening to these men to determine the incidence of prostate cancer in this group. The study will also look at new markers of early prostate cancer in this cohort.

The power calculations for this study are 850 carriers and 850 controls (age-matched men without BRCA1/2. Mis match repair mutations). It is therefore essential to gain international collaboration to meet the target of recruiting 850 men with these known mutations and a control group of 850 men who have tested negative for a known familial mutation.

Detailed description: Prostate cancer is a significant public health problem. In the EU approximately 200,000 men are diagnosed annually with prostate cancer. There are 24,000 cases per year in England and Wales and 10,000 deaths. The incidence is increasing, even when screen-detected cancers are considered, and within the next few years it will become the most common cancer in UK men.

that an alteration in the breast cancer predisposition genes BRCA1 and BRCA2, may predispose to prostate cancer (PC) and this study will increase this evidence-base. There is some evidence, at least in BRCA2 carriers, that the prostate cancer in these men may be more aggressive and so earlier detection could theoretically reduce mortality. It has been reported that unaffected individuals from families with multiple cases of PC show an increased percentage of raised PSA levels, but the use of PSA level and its predictive value in healthy males with BRCA1/2 mutations has not been studied. If PSA were to be used as a screening tool in BRCA1/2 mutation carriers, we would need to gain a better understanding of the pathogenesis of PC in these men and determine whether they have a different baseline PSA profile compared with controls.

The high prevalence of hormone-dependent/secreting tumours such as breast, ovary and prostate in BRCA1/2 carriers suggests an important role of hormones and their receptors in the development of cancer. Androgens and androgen receptors are considered crucial elements in PC pathogenesis. Therefore male sex hormones will be measured to determine the hormone profile in BRCA1/2 carriers compared with a control group. There is strong evidence that BRCA1/2 play an important role in DNA repair and cell cycling. Therefore, we will investigate abnormalities of the metabolic processes in individuals with a BRCA1/2 mutation where cell cycling may be abnormal. Analysis of proteins (proteomics) and metabolites (metabonomics) are powerful approaches to identifying proteins and metabolites involved in cancer formation. The analysis of the proteins and metabolites will enable us to investigate the effect of the presence of a BRCA1/2 mutation and aid in the identification of new biomarkers for prostate cancer.

The target population is a group of 850 males who carry a known pathogenic mutation in the BRCA1/2 genes (500 BRCA1 and 350 BRCA2). These men will be recruited through genetics clinics across the UK and the world. A control group of men who have tested negative for a known pathogenic mutation that is running in their family will also be recruited through the genetics clinics.

All participants will be invited to attend annually for 5 years for an appointment lasting approximately 30 minutes during which they will discuss the study in detail before giving their written consent agreeing to participate. They will have a 50ml blood sample taken and be asked to provide a urine sample every year. They will also be required to complete a short family and medical history questionnaire. These appointments will either take place at the centre they are registered at, at the Royal Marsden Hospital, or in their own home depending on the arrangements made with the collaborating consultant and patient preference.

The PSA level of all participants will be measured locally. If PSA is \>3.0ng/ml, a ten core prostatic biopsy will be offered, carried out by a consultant urologist. Ten biopsies will be used for diagnostic purposes, with two extra biopsy samples taken for research analysis with the patients fully informed written consent prior to the procedure being carried out. If any of the ten cores identify the presence of prostate cancer, they will receive treatment for this as advised by their local centre. The PSA will be quality controlled by batch testing at a reference lab. If the value locally was \<3.0ng/ml but is \>3ng/ml in the reference lab it will be remeasured locally.

If high grade Prostatic Intraepithelial Neoplasia (PIN) is detected or if the sample is inconclusive then a sextant biopsy repeated after 6 weeks will be recommended, in accordance with the ERSPC protocol. If atypical acini are detected then immediate biopsy will be undertaken.

Eligibility criteria: Inclusion Criteria:

* Male carriers of a known pathogenic BRCA1/2 or Mismatch Repair gene mutations (MSH2, MSH6, MLH1) or men testing negative for a known BRCA1/2/ Mismatch repair mutation (MSH2, MSH6, MLH1) in their family
* Aged between 40-69 years old
* WHO performance status 0-2
* No previous history of prostate cancer
* No previous prostate biopsy for raised PSA
* Absence of any psychological, familial, sociological or geographical situation potentially hampering compliance with the study protocol and follow-up schedule
* Fully informed, written consent according to ICH/EU GCP and national/local regulations before subject registration.

Exclusion Criteria:

* Previous cancer with terminal prognosis of less than 5 years
* Previous prostate cancer

Primary outcomes:
measure: Primary Endpoint (BRCA)
timeFrame: Through study completion, a minimum of 10 years follow up in participants.
measure: Primary Endpoint (Mismatch Repair/Lynch Cohort)
timeFrame: Through study completion, a minimum of 10 years follow up in participants.
Secondary outcomes:
measure: PSA threshold for prostate cancer detection
timeFrame: Through study completion, a minimum of 10 years follow up in participants.
measure: Positive Predictive value of PSA level for prostate cancer detection
timeFrame: Through study completion, a minimum of 10 years follow up in participants.
measure: Cancer Pathology (BRCA)
timeFrame: Through study completion, a minimum of 10 years follow up in participants.
measure: Cancer Pathology (Mismatch Repair/Lynch Cohort)
timeFrame: Through study completion, a minimum of 10 years follow up in participants.
Other outcomes:
Locations:
city: Sutton
country: United Kingdom
facility: Cancer Genetics Unit, Royal Marsden Hospital
state: Surrey
Study officials:
affiliation: Institute of Cancer Research and Royal Marsden Hospital
name: Rosalind A Eeles, FRCP FRCR
role: PRINCIPAL_INVESTIGATOR
References:
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