The IMPACT Study - Identification of Men With a Genetic Predisposition to ProstAte Cancer

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. 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 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.

Inclusion Criteria

• Male carriers of a known pathogenic BRCA1/2 mutations or men testing negative for a known BRCA1/2 mutation 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

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.

Trial Phase Phase NA

Trial Type Not provided by clinicaltrials.gov

Lead Organization
Institute of Cancer Research - Sutton

• Primary ID 05/MRE07/25
• Secondary IDs NCI-2022-01165, CCR2598
• Clinicaltrials.gov ID NCT00261456