Anita V. Mitra

Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype

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.

The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine.

Background Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. Methodology/Principal Findings MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate. Conclusions These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring.

Overexpression of RAD51 occurs in aggressive prostatic cancer.

Aims:  To test the hypothesis that, in a matched series of prostatic cancers, either with or without BRCA1 or BRCA2 mutations, RAD51 protein expression is enhanced in association with BRCA mutation genotypes.

Clinical and immunological assessment of Mycobacterium vaccae (SRL172) with chemotherapy in patients with malignant mesothelioma

The objectives of this study were to determine the toxicity of intratumoural/intrapleural SRL172 in addition to intradermal SRL172 and standard chemotherapy (mitomycin-C, vinblastine and cisplatin) in patients with malignant mesothelioma. Patients received chemotherapy (mitomycin-C: 8 mg m−2, vinblastine: 6 mg m−2, cisplatin 50 mg m−2) on a 3-weekly basis for up to six courses. IP SRL172 injections were given 3-weekly prior to chemotherapy and escalated in groups of three patients from 1 μg to 1 mg bacilli in 10-fold increments. Patients were also given ID SRL172 at a dose of 1 mg bacilli 4-weekly. Patients were assessed for toxicity after each course of chemotherapy and for response by CT imaging. Immuno-haematological parameters were analyzed pre-treatment and 1 month after completion of treatment. There was no dose limiting toxicity with IP SRL172 although there was greater toxicity at the highest dose (n=13). There were six out of 16 partial responses (37.5%). Haemato-immunological parameters, measured in seven patients pre and post-therapy, revealed that response rate correlated with a decrease in platelet count and there was an increase in activation of natural killer cells and a decrease in the percentage of IL-4 producing T cells in all tested patients post-treatment. SRL172 can be given safely into tumour deposits and the pleural cavity in patients with malignant mesothelioma and we have established the dose for phase II testing.

A review of targeted screening for prostate cancer: introducing the IMPACT Study

The scope of this review does not cover those men with Afro-Caribbean ancestry; it focuses instead on studies primarily of men with a positive family history. We aim to give a brief overview of current screening practices and highlight the genetic evidence for prostate cancer. A review of targeted screening practices leads to an introduction of our study, the Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening for BRCA1 and BRCA2 carriers and controls ; the IMPACT study. This is the first international study to target PSA screening based upon known genotype.

The carrier clinic: an evaluation of a novel clinic dedicated to the follow-up of BRCA1 and BRCA2 carriers—implications for oncogenetics practice

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.

The Effect of Dutasteride on Magnetic Resonance Imaging Defined Prostate Cancer: MAPPED—A Randomized, Placebo Controlled, Double-Blind Clinical Trial

Purpose: Dutasteride, which is licensed for symptomatic benign prostatic hyperplasia, has been associated with a lower progression rate of low risk prostate cancer. We evaluated the effect of dutasteride on prostate cancer volume as assessed by T2‐weighted magnetic resonance imaging. Materials and Methods: In this randomized, double‐blind, placebo controlled trial, men with biopsy proven, low‐intermediate risk prostate cancer (up to Gleason 3 + 4 and PSA up to 15 ng/ml) who had visible lesion of 0.2 ml or greater on T2‐weighted magnetic resonance imaging sequences were randomized to daily dutasteride 0.5 mg or placebo for 6 months. Lesion volume was assessed at baseline, and 3 and 6 months with image guided biopsy to the lesion at study exit. The primary end point was the percent reduction in lesion volume over 6 months. This trial was registered with the European Clinical Trials register (EudraCT 2009–102405–18). Results: A total of 42 men were recruited between June 2010 and January 2012. In the dutasteride group, the average volumes at baseline and 6 months were 0.55 and 0.38 ml, respectively and the average reduction was 36%. In the placebo group, the average volumes at baseline and 6 months were 0.65 and 0.76 ml, respectively, and the average reduction was −12%. The difference in percent reductions between the groups was 48% (95% CI 27.4–68.3, p <0.0001). The most common adverse event was deterioration in erectile function, which was 25% in men randomized to dutasteride and 16% in men randomized to placebo. Conclusions: Dutasteride was associated with a significant reduction in prostate cancer volume on T2‐weighted magnetic resonance imaging compared to placebo.

Ambiguity in a masculine world: Being a BRCA1/2 mutation carrier and a man with prostate cancer.

Increased 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.

Overexpression of TP53 is Associated with Aggressive Prostate Cancer butdoes not Distinguish Disease in BRCA1 or BRCA2 Mutation Carriers froma Control Group

We have shown that prostate cancer occurring in men with germline BRCA1 and BRCA2 mutations is more ag- gressive. 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.

Short report. The AIDIT and IMPACT conference 2006: Outcomes and future directions.

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. AIDITs 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.