ObjectiveIncreased risk of prostate cancer (PCa) is observed in men with BRCA1/BRCA2 mutations. Sex and gender are key determinants of health and disease although unequal care exists between the sexes. Stereotypical male attitudes are shown to lead to poor health outcomes. MethodsMen with BRCA1/2 mutations and diagnosed with PCa were identified and invited to participate in a qualitative interview study. Data were analysed using a framework approach. Masculinity theory was used to report the impact of having both a BRCA1/2 mutation and PCa. ResultsEleven of 15 eligible men were interviewed. The umbrella concept of Ambiguity in a Masculine World was evident. Men's responses often matched those of women in a genetic context. Men's BRCA experience was described, as on the back burner but a bonus enabling familial detection and early diagnosis of PCa. Embodiment of PCa took precedence as men revealed stereotypical ideal masculine responses such as stoicism and control while creating new masculinities when faced with the vicissitudes of having 2 gendered conditions. ConclusionHealth workers are urged to take a reflexive approach, void of masculine ideals, a belief in which obfuscates men's experience. Research is required regarding men's support needs in the name of equality of care.

Aims: This study has tested the hypothesis that, in a matched series of prostate cancers, either with or without BRCA1 or BRCA2 mutations, RAD51 protein expression is enhanced in association with BRCA mutation genotypes. Methods and Results: RAD51 expression identified immunohistochemically was compared between prostate cancers occurring in BRCA1 or BRCA2 mutation-carriers and controls. RAD51 protein expression in the cytoplasm and nuclei of the benign tissues was significantly less than in the malignant tissues (p<0.001). In all cancers, cytoplasmic expression of RAD51 was more prevalent and associated with higher Gleason score (p < 0.05) irrespective of BRCA mutation status, than its expression in benign tissues (p < 0.001). Although nuclear staining was not observed in BRCAassociated cancers with Gleason score ≤ 7, it was significantly increased in all other groups of prostate cancers when compared to benign tissues (p < 0.001). Conclusions: RAD51 protein is strongly expressed in high-grade prostate cancers, whether sporadic or associated with BRCA germline mutations. Distinct localisation of RAD51 between cytoplasm and nucleus, particularly in cancers of Gleason score ≤ 7, reflects distinct levels of RAD51 regulatory activity, from transcription to DNA repair. This biomarker may be of value in identifying patients requiring urgent treatment at diagnosis as well as in analysing biological mechanisms underlying aggressive phenotype of human prostate cancer.

Background A novel oncogenetic clinic was established in 2002 at the Royal Marsden NHS Foundation Trust offering advice and specialist follow-up for families with a germline mutation in BRCA1 or BRCA2. The remit of this multidisciplinary clinic, staffed by individuals in both oncology and genetics, is to provide individualised screening recommendations, support in decision making, risk reducing strategies, cascade testing, and an extensive research portfolio.Methods A retrospective analysis was performed to evaluate uptake of genetic testing, risk reducing surgery and cancer prevalence in 346 BRCA1/BRCA2 families seen between January 1996 and December 2006.Results 661 individuals attended the clinic and 406 mutation carriers were identified; 85.8% mutation carriers have chosen to attend for annual follow-up. 70% of mutation carriers elected for risk reducing bilateral salpingo-oophorectomy (RRBSO). 32% of unaffected women chose risk reducing bilateral mastectomy. 32% of women with breast cancer chose contralateral risk reducing mastectomy at time of diagnosis. Some women took over 8 years to decide to have surgery. 91% of individuals approached agreed to participate in research programmes.Interpretation A novel specialist clinic for BRCA1/2 mutation carriers has been successfully established. The number of mutation positive families is increasing. This, and the high demand for RRBSO in women over 40, is inevitably going to place an increasing demand on existing health resources. Our clinic model has subsequently been adopted in other centres and this will greatly facilitate translational studies and provide a healthcare structure for management and follow-up of such people who are at a high cancer risk.

We have shown that prostate cancer occurring in men with germline BRCA1 and BRCA2 mutations is more aggressive.In an attempt to identify an associated immunohistochemical phenotype, we have studied TP53 immunostaining in prostate cancers in mutation carriers versus prostate cancers occurring in a control group of men.There was a significantly higher expression of TP53 protein in prostate cancer with a higher Gleason score (p< 0.001).Twenty four per cent of prostate cancer occurring in BRCA1/2 mutation carriers and 19% of those from controls stained positively for the TP53 protein; this difference was not significant.Cases and controls were combined and matched for benign and malignant disease within the same individual.There were 152 men who had a sample of each within the tissue samples.Thirty one (20%) stained positively within the malignant tissue alone; none had positive staining in benign tissue, p<0.001.Over expression of TP53 cannot distinguish prostate cancer on a background of BRCA1/2 mutation, but it is associated with prostate cancer malignant tissue per se, in particular aggressive disease.

There are no standardised guidelines for the role of adjuvant radiotherapy post-prostatectomy. Evidence that may shed light into its appropriate usage is marred by the difficulty in defining adjuvant radiotherapy and failure of some studies to adequately distinguish it from salvage radiotherapy. The ability to identify which prostate cancers are likely to benefit from immediate post-operative radiotherapy would enable the judicious use of this modality and minimise the unnecessary exposure to its side-effects. This review outlines the pre- and post-surgical clinical considerations that form the discussion around the requirement for adjuvant therapy; radiotherapy, androgen deprivation therapy and chemotherapy. Principles for the use of local and systemic therapies are discussed.

There is a high and rising prevalence of prostate cancer (PRCA) within the male population of the United Kingdom. Although the relative risk of PRCA is higher in male BRCA2 and BRCA1 mutation carriers, the histological characteristics of this malignancy in these groups have not been clearly defined. We present the histopathological findings in the first UK series of BRCA1 and BRCA2 mutation carriers with PRCA. The archived histopathological tissue sections of 20 BRCA1/2 mutation carriers with PRCA were collected from histopathology laboratories in England, Ireland and Scotland. The cases were matched to a control group by age, stage and serum PSA level of PRCA cases diagnosed in the general population. Following histopathological evaluation and re-grading according to current conventional criteria, Gleason scores of PRCA developed by BRCA1/2 mutation carriers were identified to be significantly higher ( Gleason scores 8, 9 or 10, P = 0.012) than those in the control group. Since BRCA1/2 mutation carrier status is associated with more aggressive disease, it is a prognostic factor for PRCA outcome. Targeting screening to this population may detect disease at an earlier clinical stage which may therefore be beneficial.

IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international collaboration investigating the utility of targeted prostate-specific antigen (PSA) screening for men at increased risk of prostate cancer due to inherited predisposition. Although the majority of prostate cancer occurs sporadically, it is recognized that family history plays a role in a significant number of cases: a family history either of prostate cancer alone [1], or of other cancers including breast and ovarian cancer [2]. Evidence of the link between single genes and prostate cancer risk is strongest for the BRCA1 and BRCA2 genes [3-5], with BRCA2 in particular thought to lead to a relative risk of 4.65 (95% CI 3.48-6.22). This relative risk may be as high as 7.33 in men under the age of 65 years. Population prostate cancer screening remains controversial because of the potential for detection of clinically insignificant disease in young men and the risk of over-treatment. There is increasing interest and concern in European countries about whether prostate cancer screening should be offered to the general population and whether this would lead to a reduction in mortality from prostate cancer. IMPACT raises the hypothesis that targeting screening at the men in the population who are known to have an increased risk of the disease might improve the effectiveness of prostate cancer screening. Beginning with a pilot of 100 patients, the IMPACT study ultimately aims to recruit a total of 850 carriers of mutations in BRCA1 and BRCA2 and 850 controls (men shown not to carry familial BRCA1/2 mutations by predictive genetic testing). Recruitment will be open for five years, followed by five years of follow-up. In 2005, a project known as AIDIT (Advancing International co-operation and Developing Infrastructure for Targeted screening of prostate cancer in men with genetic predisposition) was awarded funding through the EC Framework 6 Programme as part of an endeavour to reduce research fragmentation and duplication, and to facilitate research collaboration across Europe. IMPACT currently includes collaborators from 24 countries. AIDIT's aim is to expand the IMPACT consortium within the associated candidate countries (ACCs) and new member states of the EU. The expansion of IMPACT is likely to benefit both the study and the research teams: a higher number of collaborating centres will allow access to a larger number of men at risk, making it possible to recruit as many carriers as are needed for the study, particularly in populations likely to harbour founder mutations; and for all collaborators - both new and existing - it is hoped that participation in AIDIT and IMPACT will foster an environment of ongoing interaction and learning.

Aims: The relative risk of prostate cancer is 1.07 in BRCA1 carriers (1.8 in men under the age of 65 years) and 4.65 in BRCA2 carriers. The results of 2 general population screening studies from Europe and the US are awaited, but no reduction in mortality has been achieved so far. It is likely that only a subset of high risk men will benefit from screening. IMPACT aims to establish a prostate cancer screening programme in men with BRCA1 and BRCA2 mutations to determine the incidence and pathology of prostate cancer and the sensitivity and specificity of PSA testing in this group.

AIDIT (Advancing International Co-operation and Developing Infrastructure for Targeted Screening of Prostate Cancer in Men with Genetic Predisposition) is a project funded by the Sixth Framework Programme of the European Community which is endeavouring to facilitate co-operation between European countries in the field of cancer research. The project also aims to raise awareness of familial prostate cancer among health professionals and the public within the associated candidate countries (ACCs) and new member states of the European Union (EU). AIDIT will focus on linking clinical and research teams in the ACCs and new member states with the IMPACT Consortium (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), an international team investigating screening and diagnosis for men with a genetic risk of prostate cancer predisposition genes BRCA1 or BRCA2). Cancer research has been targeted as a high priority for the European Community; however, research is most successful when centralised and well coordinated, avoiding the duplication and fragmentation associated with smaller, isolated studies. AIDIT will consolidate the current IMPACT consortium and allow research partners from across the world to benefit from shared knowledge and experience. To date, the AIDIT team has established a website to facilitate communication between project collaborators (www.impact-study.co.uk), has been represented at several international meetings and has facilitated a conference for the IMPACT study to bring together international research teams, clinicians and policy makers.