Trial Information

The IMPACT Study - Identification of Men With a Genetic Predisposition to ProstAte Cancer: Targeted Screening in BRCA1/2 Mutation Carriers & Controls

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.