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

OBJECTIVE: 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. METHODS: Men 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. RESULTS: Eleven 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. CONCLUSION: Health 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.

Genetic predisposition to prostate cancer.

INTRODUCTION: Prostate cancer (PrCa) is the commonest non-cutaneous cancer in men in the UK. Epidemiological evidence as well as twin studies points towards a genetic component contributing to aetiology. SOURCES OF DATA: Key recently published literature. AREAS OF AGREEMENT: A family history of PrCa doubles the risk of disease development in first-degree relatives. Linkage and genetic sequencing studies identified rare moderate-high-risk gene loci, which predispose to PrCa development when altered by mutation. Genome-wide association studies have identified common single-nucleotide polypmorphisms (SNPs), which confer a cumulative risk of PrCa development with increasing number of risk alleles. There are emerging data that castrate-resistant disease is associated with mutations in DNA repair genes. AREAS OF CONTROVERSY: Linkage studies investigating possible high-risk loci leading to PrCa development identified possible loci on several chromosomes, but most have not been consistently replicated by subsequent studies. Germline SNPs related to prostate specific antigen (PSA) levels and to normal tissue radiosensitivity have also been identified though not all have been validated in subsequent studies. GROWING POINTS: Utilizing germline SNP profiles as well as identifying high-risk genetic variants could target screening to high-risk groups, avoiding the drawbacks of PSA screening. AREAS TIMELY FOR DEVELOPING RESEARCH: Incorporating genetics into PrCa screening is being investigated currently using both common SNP profiles and higher risk rare variants. Knowledge of germline genetic defects will allow the development of targeted screening programs, preventive strategies and the personalized treatment of PrCa.

Selective organ preservation with neo-adjuvant chemotherapy for the treatment of muscle invasive transitional cell carcinoma of the bladder.

BACKGROUND: Radiotherapy for muscle invasive bladder cancer (MIBC) aims to offer organ preservation without oncological compromise. Neo-adjuvant chemotherapy provides survival advantage; response may guide patient selection for bladder preservation and identify those most likely to have favourable result with radiotherapy. METHODS: Ninety-four successive patients with T2-T4aN0M0 bladder cancer treated between January 2000 and June 2011 were analysed at the Royal Marsden Hospital. Patients received platinum-based chemotherapy following transurethral resection of bladder tumour; repeat cystoscopy (± biopsy) was performed to guide subsequent management. Responders were treated with radiotherapy. Poor responders were recommended radical cystectomy. Progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS) were estimated using Kaplan-Meier method; univariate and multivariate analyses were performed using the Cox proportional hazard regression model. RESULTS: Response assessment was performed in 89 patients. Seventy-eight (88%) demonstrated response; 53 (60%) achieved complete response (CR); 74 responders had radiotherapy; 4 opted for cystectomy. Eleven (12%) demonstrated poor response, 10 received cystectomy. Median survival for CR was 90 months (95% CI 64.7, 115.9) compared with 16 months (95% CI 5.4, 27.4; P < 0.001) poor responders. On multivariate analysis, only response was associated with significantly improved PFS, OS and DSS. After a median follow-up of 39 months (range 4-127 months), 14 patients (16%) required salvage cystectomy (8 for non-muscle invasive disease, 5 for invasive recurrence, 1 for radiotherapy related toxicity). In all, 82% had an intact bladder at last follow-up after radiotherapy; 67% had an intact bladder at last follow-up or death. Our study is limited by its retrospective nature. CONCLUSIONS: Response to neo-adjuvant chemotherapy is a favourable prognostic indicator and can be used to select patients for radiotherapy allowing bladder preservation in >80% of the selected patients.

High burden of copy number alterations and c-MYC amplification in prostate cancer from BRCA2 germline mutation carriers.

BACKGROUND: Germline BRCA2 mutations are associated with poorer outcome prostate cancer (PCa) compared with sporadic tumours but this association remains to be characterised. In this study, we aim to assess if there is a signature set of copy number alterations (CNA) that could aid to the identification of BRCA2-mutated tumours and would assist us to understand their aggressive clinical behaviour. METHODS: High-resolution array comparative genomic hybridisation profiling of DNA from PCa and matched morphologically normal prostate samples from 9 BRCA2 germline mutation carriers and 16 non-carriers in combination with unsupervised analysis was used to define copy number features. RESULTS: PCa from BRCA2 germline mutation carriers (B2T) harbour significantly more CNA than non-carrier tumours (NCTs) (P = 14 × 10(-6)). A hundred and sixteen regions had a significantly different distribution with both false discovery rate (FDR) and P value <0.01, including CNA in the genomic region containing c-MYC that was present in 89% B2T versus 12.5% NCT (P = 3 × 10(-4)). Loss of heterozygosity (LOH) at the BRCA2 locus was observed in 67% of B2T. Elevated CNA are already present in 50% of the morphologically normal prostate tissue from BRCA2 carriers. CONCLUSION: The relative high amount of CNAs in morphologically normal prostate tissue of BRCA2 carriers implies a field effect and together with the observed LOH could be used as a marker of PCa risk in these men. Several features previously associated with poor PCa outcome have been found to be significantly more common in BRCA2-mutated PCa than in sporadic tumours and may help to explain their adverse prognosis and be of relevance for targeted therapies.

Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes.

BACKGROUND: A rare recurrent missense variant in HOXB13 (rs138213197/G84E) was recently reported to be associated with hereditary prostate cancer. Population-based studies have established that, since the frequency of this single-nucleotide polymorphism (SNP) varies between geographic regions, the associated proportion of prostate cancer (PrCa) risk contribution is also highly variable by country. PATIENTS AND METHODS: This is the largest comprehensive case-control study assessing the prevalence of the HOXB13 G84E variant to date and is the first in the UK population. We genotyped 8652 men diagnosed with PrCa within the UK Genetic Prostate Cancer Study (UKGPCS) and 5252 healthy men from the UK ProtecT study. RESULTS: HOXB13 G84E was identified in 0.5% of the healthy controls and 1.5% of the PrCa cases, and it was associated with a 2.93-fold increased risk of PrCa [95% confidence interval (CI) 1.94-4.59; P = 6.27 × 10(-8)]. The risk was even higher among men with family history of PrCa [odds ratio (OR) = 4.53, 95% CI 2.86-7.34; P = 3.1 × 10(-8)] and in young-onset PrCa (diagnosed up to the age of 55 years; OR = 3.11, 95% CI 1.98-5.00; P = 6.1 × 10(-7)). There was no significant association between Gleason Score, presenting prostate specific antigen, tumour-node-metastasis (TNM) stage or NCCN risk group and carrier status. HOXB13 G84E was not associated with overall or cancer-specific survival. We found that the polygenic PrCa risk score (PR score), calculated using the 71 known single-nucleotide polymorphisms (SNPs) associated with PrCa and the HOXB13 G84E variant act multiplicatively on PrCa risk. Based on the estimated prevalence and risk, this rare variant explains ∼1% of the familial risk of PrCa in the UK population. CONCLUSIONS: The clinical importance of HOXB13 G84E in PrCa management has not been established. This variant was found to have no effect on prognostic implications but could be used for stratifying screening, by identifying men at high risk. CLINICAL TRIALS NUMBERS: Prostate Testing for Cancer and Treatment (ProtecT): NCT02044172. UK GENETIC PROSTATE CANCER STUDY: Epidemiology and Molecular Genetics Studies (UKGPCS): NCT01737242.

Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.

Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease.

BACKGROUND: Prostate cancer (PrCa) is one of the most common diseases to affect men worldwide and among the leading causes of cancer-related death. The purpose of this study was to use second-generation sequencing technology to assess the frequency of deleterious mutations in 22 tumour suppressor genes in familial PrCa and estimate the relative risk of PrCa if these genes are mutated. METHODS: Germline DNA samples from 191 men with 3 or more cases of PrCa in their family were sequenced for 22 tumour suppressor genes using Agilent target enrichment and Illumina technology. Analysis for genetic variation was carried out by using a pipeline consisting of BWA, Genome Analysis Toolkit (GATK) and ANNOVAR. Clinical features were correlated with mutation status using standard statistical tests. Modified segregation analysis was used to determine the relative risk of PrCa conferred by the putative loss-of-function (LoF) mutations identified. RESULTS: We discovered 14 putative LoF mutations in 191 samples (7.3%) and these mutations were more frequently associated with nodal involvement, metastasis or T4 tumour stage (P=0.00164). Segregation analysis of probands with European ancestry estimated that LoF mutations in any of the studied genes confer a relative risk of PrCa of 1.94 (95% CI: 1.56-2.42). CONCLUSIONS: These findings show that LoF mutations in DNA repair pathway genes predispose to familial PrCa and advanced disease and therefore warrants further investigation. The clinical utility of these findings will become increasingly important as targeted screening and therapies become more widespread.

Spontaneous antibodies against Engrailed-2 (EN2) protein in patients with prostate cancer.

We reported the expression of the homeodomain-containing transcription factor Engrailed-2 (EN2) in prostate cancer and showed that the presence of EN2 protein in the urine was highly predictive of prostate cancer. This study aimed to determine whether patients with prostate cancer have EN2 autoantibodies, what the prevalence of these antibodies is and whether they are associated with disease stage. The spontaneous immunoglobulin (Ig)G immune response against EN2 and for comparison the tumour antigen New York Esophageal Squamous Cell Carcinoma 1 (NY-ESO-1), were tested by enzyme-linked immunosorbent assay (ELISA) in three different cohorts of prostate cancer patients as well as a group of men genetically predisposed to prostate cancer. Thirty-two of 353 (9·1%) of the SUN cohort representing all stages of prostate cancer demonstrated EN2 IgG responses, 12 of 107 patients (11·2%) in the advanced prostate cancer patients showed responses, while only four of 121 patients (3·3%) with castrate-resistant prostate cancer showed EN2 autoantibodies. No significant responses were found in the predisposed group. Anti-EN2 IgG responses were significantly higher in patients with prostate cancer compared to healthy control males and similarly prevalent to anti-NY-ESO-1 responses. While EN2 autoantibodies are not a useful diagnostic or monitoring tool, EN2 immunogenicity provides the rationale to pursue studies using EN2 as an immunotherapeutic target.

Randomised pilot study of dose escalation using conformal radiotherapy in prostate cancer: long-term follow-up.

BACKGROUND: Radical three-dimensional conformal radiotherapy (CFRT) with initial androgen suppression (AS) is a standard management for localised prostate cancer (PC). This pilot study evaluated the role of dose escalation and appropriate target volume margin. Here, we report long-term follow-up. METHODS: Eligible patients had T1b-T3b N0 M0 PC. After neoadjuvant AS, they were randomised to CFRT, giving (a) 64 Gy with either a 1.0- or 1.5-cm margin and (b) ±10 Gy boost to the prostate alone. RESULTS: One hundred and twenty-six men were randomised and treated. Median follow-up was 13.7 years. The median age was 66.6 years at randomisation. Median presenting prostate-specific antigen (PSA) was 14 ng ml(-1). Sixty-four out of 126 patients developed PSA failure. Forty-nine out of 126 patients restarted AS, 34 out of 126 developed metastases and 28 out of 126 developed castrate-resistant prostate cancer (CRPC). Fifty-one out of 126 patients died; 19 out of 51 died of PC. Median overall survival (OS) was 14.4 years. Although escalated dose results were favourable, no statistically significant differences were seen between the randomised groups; PSA control (hazard ratio (HR): 0.77 (95% confidence interval (CI): 0.47-1.26)), development of CRPC (HR: 0.81 (95% CI: 0.40-1.65)), PC-specific survival (HR: 0.59 (95% CI:0.23-1.49)) and OS (HR: 0.81 (95% CI: 0.47-1.40)). There was no evidence of a difference in PSA control according to margin size (HR: 1.01 (95% CI: 0.61-1.66)). INTERPRETATION: Long-term follow-up of this small pilot study is compatible with a benefit from dose escalation, but confirmation from larger trials is required. There was no obvious detriment using the smaller radiotherapy margin.

Reproductive decision-making in young female carriers of a BRCA mutation.

STUDY QUESTION: How do young women, who were identified as carrying a BRCA gene mutation before they had children, approach reproductive decision-making and what are their attitudes towards reproductive genetic testing? SUMMARY ANSWER: Reproductive decision-making within the context of cancer risk is complex and influenced by personal experiences of cancer. Younger women were not concerned with reproductive decision-making at the time of their genetic test; however, the impact on subsequent reproductive decision-making was considerable and left them with unanticipated dilemmas, such as having children who would be at risk of inheriting cancer predisposition, timing risk-reducing surgery and changing perceptions of responsibility. WHAT IS KNOWN ALREADY: Individuals carrying gene mutations predisposing to hereditary breast/ovarian cancer have concerns about passing on the gene mutation to children. STUDY DESIGN, SIZE, DURATION: Qualitative methodology and thematic analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were collected through semi-structured interviews with 25 women aged 18-45 who had received a positive result for a BRCA1 or BRCA2 gene mutation while childless. MAIN RESULTS AND THE ROLE OF CHANCE: Analysis revealed four central themes: (i) the impact of cancer on reproductive decision-making; (ii) motivation for genetic testing; (iii) risk management and timing of planning children; and (iv) optimism for future medical advancements. LIMITATIONS, REASONS FOR CAUTION: This study explores the views of female BRCA carriers. Further research should explore the views of couples, men, and include samples with greater ethnic and social diversity. WIDER IMPLICATIONS OF THE FINDINGS: This evidence highlights the need for reproductive decision-making to be addressed at the time of pretest genetic counselling. More information should be provided on reproductive options as well as counselling/support to guide women's reproductive decision-making and prenatal testing options at the time they undertake genetic testing. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by Cancer Research UK (Number C1226 A7920) and NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and RMH. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus.

A locus for familial melanoma, MLM, has been mapped within the same interval on chromosome 9p21 as the gene for a putative cell cycle regulator, p16INK4 (CDKN2) MTS1. This gene is homozygously deleted from many tumour cell lines including melanomas, suggesting that CDKN2 is a good candidate for MLM. We have analysed CDKN2 coding sequences in pedigrees segregating 9p melanoma susceptibility and 38 other melanoma-prone families. In only two families were potential predisposing mutations identified. No evidence was found for heterozygous deletions of CDKN2 in the germline of melanoma-prone individuals. The low frequency of potential predisposing mutations detected suggests that either the majority of mutations fall outside the CDKN2 coding sequence or that CDKN2 is not MLM.

A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome.

Breast cancer in men is rare--among the risk factors that have been identified are a family history of breast cancer and evidence of androgen insufficiency. We report a family in which two brothers who both developed breast cancer had clinical and endocrinological evidence of androgen resistance. Sequence analysis revealed a mutation in the androgen receptor gene on the X chromosome, within the region encoding the DNA binding domain. This is the first report of a germline mutation in a member of the steroid/thyroid hormone receptor superfamily associated with the development of cancer.

Localization of the gene for Cowden disease to chromosome 10q22-23.

Cowden disease (CD) (MIM 158350), or multiple hamartoma syndrome, is a rare autosomal dominant familial cancer syndrome with a high risk of breast cancer. Its clinical features include a wide array of abnormalities but the main characteristics are hamartomas of the skin, breast, thyroid, oral mucosa and intestinal epithelium. The pathognomonic hamartomatous features of CD include multiple smooth facial papules, acral keratosis and multiple oral papillomas. The pathological hallmark of the facial papules are multiple trichilemmomas. Expression of the disease is variable and penetrance of the dermatological lesions is assumed to be virtually complete by the age of twenty. Central nervous system manifestations of CD were emphasized only recently and include megalencephaly, epilepsy and dysplastic gangliocytomas of the cerebellum (Lhermitte-Duclos disease, LDD). Early diagnosis is important since female patients with CD are at risk of developing breast cancer. Other lesions include benign and malignant disease of the thyroid, intestinal polyps and genitourinary abnormalities. To localize the gene for CD, an autosomal genome scan was performed. A total of 12 families were examined, resulting in a maximum lod score of 8.92 at theta = 0.02 with the marker D10S573 located on chromosome 10q22-23.

Germline BRCA1 mutations increase prostate cancer risk.

BACKGROUND: Prostate cancer (PrCa) is one of the most common cancers affecting men but its aetiology is poorly understood. Family history of PrCa, particularly at a young age, is a strong risk factor. There have been previous reports of increased PrCa risk in male BRCA1 mutation carriers in female breast cancer families, but there is a controversy as to whether this risk is substantiated. We sought to evaluate the role of germline BRCA1 mutations in PrCa predisposition by performing a candidate gene study in a large UK population sample set. METHODS: We screened 913 cases aged 36­86 years for germline BRCA1 mutation, with the study enriched for cases with an early age of onset. We analysed the entire coding region of the BRCA1 gene using Sanger sequencing. Multiplex ligation-dependent probe amplification was also used to assess the frequency of large rearrangements in 460 cases. RESULTS: We identified 4 deleterious mutations and 45 unclassified variants (UV). The frequency of deleterious BRCA1 mutation in this study is 0.45%; three of the mutation carriers were affected at age 65 years and one developed PrCa at 69 years. Using previously estimated population carrier frequencies, deleterious BRCA1 mutations confer a relative risk of PrCa of ~3.75-fold, (95% confidence interval 1.02­9.6) translating to a 8.6% cumulative risk by age 65. CONCLUSION: This study shows evidence for an increased risk of PrCa in men who harbour germline mutations in BRCA1. This could have a significant impact on possible screening strategies and targeted treatments.

Genetic variants associated with predisposition to prostate cancer and potential clinical implications.

Prostate cancer is the commonest cancer in the developed world. There is an inherited component to this disease as shown in familial and twin studies. However, the discovery of these variants has been difficult. The emergence of genome-wide association studies has led to the identification of over 46 susceptibility loci. Their clinical utility to predict risk, response to treatment, or treatment toxicity, remains undefined. Large consortia are needed to achieve adequate statistical power to answer these genetic-clinical and genetic-epidemiological questions. International collaborations are currently underway to link genetic with clinical/epidemiological data to develop risk prediction models, which could direct screening and treatment programs.

Polygenic susceptibility to prostate and breast cancer: implications for personalised screening.

BACKGROUND: We modelled the efficiency of a personalised approach to screening for prostate and breast cancer based on age and polygenic risk-profile compared with the standard approach based on age alone. METHODS: We compared the number of cases potentially detectable by screening in a population undergoing personalised screening with a population undergoing screening based on age alone. Polygenic disease risk was assumed to have a log-normal relative risk distribution predicted for the currently known prostate or breast cancer susceptibility variants (N=31 and N=18, respectively). RESULTS: Compared with screening men based on age alone (aged 55-79: 10-year absolute risk ≥2%), personalised screening of men age 45-79 at the same risk threshold would result in 16% fewer men being eligible for screening at a cost of 3% fewer screen-detectable cases, but with added benefit of detecting additional cases in younger men at high risk. Similarly, compared with screening women based on age alone (aged 47-79: 10-year absolute risk ≥2.5%), personalised screening of women age 35-79 at the same risk threshold would result in 24% fewer women being eligible for screening at a cost of 14% fewer screen-detectable cases. CONCLUSION: Personalised screening approach could improve the efficiency of screening programmes. This has potential implications on informing public health policy on cancer screening.

Psychological impact and acceptability of magnetic resonance imaging and X-ray mammography: the MARIBS Study.

BACKGROUND: As part of the Magnetic Resonance Imaging for Breast Screening (MARIBS), Study women with a family history of breast cancer were assessed psychologically to determine the relative psychological impact and acceptability of annual screening using magnetic resonance imaging (MRI) and conventional X-ray mammography (XRM). METHODS: Women were assessed psychologically at baseline (4 weeks before MRI and XRM), immediately before, and immediately after, both MRI and XRM, and at follow-up (6 weeks after the scans). RESULTS: Overall, both procedures were found to be acceptable with high levels of satisfaction (MRI, 96.3% and XRM, 97.7%; NS) and low levels of psychological morbidity throughout, particularly at 6-week follow-up. Low levels of self-reported distress were reported for both procedures (MRI, 13.5% and XRM, 7.8%), although MRI was more distressing (P=0.005). Similarly, higher anticipatory anxiety was reported before MRI than before XRM (P=0.003). Relative to XRM, MRI-related distress was more likely to persist at 6 weeks after the scans in the form of intrusive MRI-related thoughts (P=0.006) and total MRI-related distress (P=0.014). More women stated that they intended to return for XRM (96.3%) than for MRI (88%; P<0.0005). These effects were most marked for the first year of screening, although they were also statistically significant in subsequent years. CONCLUSION: Given the proven benefits of MRI in screening for breast cancer in this population, these data point to the urgent need to provide timely information and support to women undergoing MRI.

BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients.

BACKGROUND: A family history of prostate cancer (PrCa) is a strong risk factor for the disease, indicating that inherited factors are important in this disease. We previously estimated that about 2% of PrCa cases diagnosed ≤ 55 years harbour a BRCA2 mutation and PrCa among BRCA2 carriers has been shown to be more aggressive, with poorer survival. METHODS: To further evaluate the role of BRCA2 in PrCa predisposition, we screened 1864 men with PrCa aged between 36 and 88 years. We analysed the BRCA2 gene using a novel high-throughput multiplex fluorescence heteroduplex detection system developed for the ABI3130xl genetic analyzer. RESULTS: We identified 19 protein-truncating mutations, 3 in-frame deletions and 69 missense variants of uncertain significance (UV) in our sample set. All the carriers of truncating mutations developed PrCa at ≤ 65 years, with a prevalence of BRCA2 mutation of 1.20% for cases in this age group. CONCLUSION: Based on the estimated frequency of BRCA2 mutations in the United Kingdom we estimate that germline mutations in the BRCA2 gene confer an ∼ 8.6-fold increased risk of PrCa by age 65, corresponding to an absolute risk of ∼ 15% by age 65. These results suggest that routine testing of early onset PrCa cases for germline BRCA2 mutations will further help to refine the prevalence and risk associated with BRCA2 mutations and may be useful for guiding management options.