Prostate Cancer Prevention Clinic for Men With Risk of Familial Prostate Cancer
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 300
- 主要终点
- Number and kind of Genetic Alterations and correlation with clinical and pathologic features
研究概览
简要总结
Secondary prevention of prostate cancer (PCa) is not standardized and high-risk groups at the time of diagnosis are not well defined. Hereditary susceptibility which is reported in about 10% of men is one important risk factor for PCa development but the absolute risk and clinical importance is fairly unknown. The population risk for developing PCa is estimated to be 11%. If men carry a mutation in BRCA2 or HOXB13, the lifetime risk is 2 to 10-fold increased. "ProFam-Risk" is a prospective cohort analysis not only to validate the known genetic risk scores but also to establish recommendations for follow of high risk populations based on a combination of clinical parameters, imaging (magnetic resonance imaging of the prostate), and genetic profile. Aim of this individualized recommendation is on the one hand to early detect PCa before developing of advanced disease and on the other hand to counsel men at low risk in order to prevent overdiagnosis and overtreatment. Overall, "ProFam-Risk" aims to create a best possible counseling and clinical care for men with familial risk to develop PCa. In this pilot study, about 100 men per year will be included for a total period of 3 years. In addition to the registration of clinical, imaging, and genetic information, liquids and tissue (if available) will be sampled for analysis in the above mentioned research questions.
详细描述
Prostate cancer (PCA) is common in men. If men carry a mutation in BRCA2 or HOXB13, the lifetime risk is 2 to 10-fold increased. Germline testing is used for individualized risk prediction. In the context of the precision medicine era, different multigene panels are used for hereditary cancer syndromes, including hereditary breast and ovarian cancer (HBOC), Lynch syndrome and hereditary prostate cancer . In addition, targeted therapy with e.g. PARP inhibitors and immunotherapeutic drugs is based on the presence of mutations in DNA repair genes such as BRCA1 and BRCA2, ATM or mismatch repair genes . Furthermore, polygenic risk scores (PRS) are associated with the risk to develop prostate cancer in European and multi-ethnic ancestries with HRs of 1.6 to 5 . Trans-ancestry genome-wide association studies have revealed 269 risk variants from tissue related to prostate cancer including known tumor-related genes like TP53 and CHEK2 .
To more precisely tailor screening for prostate cancer, risk groups with a higher prevalence of clinically significant PCA (csPCA) need to be defined.
Current NCCN guidelines recommend e. g. genetic testing for men with a positive family history of PCA. The prevalence of germline variants in these men diagnosed with PCA at age 60 was 17.2% of which about 30% were BRCA1 or BRCA2 mutations and 4.5% were HOXB13. The absolute risk to develop PCA up to the age of 80 years in BRCA2 carriers is supposed to be 27% - 60%.
Limited data are available concerning the mutational landscape of PCA and somatic oncogenic drivers. To date, studies predominantly focused on known tumor genes with potential clinical actionability and their underlying pathways to guide clinical management in advanced tumor diseases. Systematic mutational profiling in different stages of tumor disease and correlation with germline findings are urgently needed for an in depth understanding of the prostate cancer pathogenesis and identifying promising drug candidates as well as early detection of driver mutations for lethal cancers.
First attempts to combine clinical and genetic data are currently tested in the PROFILE and BARCODE 1 studies. Men with a positive family history of PCA at age 40-69 years were recommended to undergo prostate biopsy regardless of prostate specific antigen (PSA) levels and 25% of those had PCA. The succeeding BARCODE 1 trial is currently recruiting men at ages 55-69 years who are offered genotyping by 130 germline PCA risk single nucleotide polymorphisms (SNPs) from saliva. After calculating a polygenic risk score (PRS), participants above the 90% percentile are offered screening by magnetic resonance imaging (MRI) followed by prostate biopsy. Prostate cancer detection was about 40% of all men screened within the pilot study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Healthy men with familial risk ( ≥ 2 first-degree relatives with PCA diagnosed at any age oder ≥ 1 first-degree relative with PCA diagnosed at the age <60)
- •healthy men with genetic risk (BRCA1/2 Germline mutation)
- •Men with PCA and genetic oder familial risk (familial risk = ≥ 2 first-degree relatives with PCA diagnosed at any age oder ≥ 1 first-degree relative with PCA diagnosed at the age <60; genetic risk= BRCA1/2 Germline mutation)
排除标准
- •<18 years
- •no consent
结局指标
主要结局
Number and kind of Genetic Alterations and correlation with clinical and pathologic features
时间窗: 3-4 years
mutation database for germline mutations and tumor mutations in familial PCA: Besides the mutation positive men (group 2), all will receive multigene panel analysis( ATM, BRCA1, BRCA2, EPCAM, HOXB13, MLH1, MSH2, MSH6, PMS2, TP53) and if negative, whole exome sequencing (WES), whole genome sequencing and transcriptome analyses The aim is to systematically and prospektively review genotype-phenotype correlations in the established candidate genes and to systematically correlate the clinical and pathologic features with the identified underlying genetic alterations. DNA for WES, WGS and RNA will be prepared by standard procedures, e.g. the FlexiGene DNA Kit (Qiagen) and PAXgene Blood RNA Kit (Qiagen)
Reduction in PCA-specific anxiety
时间窗: 3-4 years
Assessment if men after risk assessment and genetic counseling will have a reduction in cancer-specific anxiety --\>Follow-ups with 3 measurement points (before, during, after counseling (T0, T1, T2)) The reduction in cancer-specific anxiety and improvement of personal risk perception and of personal control are tested by using a of variance- analytical model with repeated measures (T0, T1, T2) and the group factor "risk group" (high vs. intermediate vs. low) Quantitative questionnaire: • Prostate Cancer-specific anxiety (MAX-PC, modified scale 'prostate cancer anxiety', Lehmann 2006)
次要结局
- Improvement of PCA-specific personal risk perception(3-4 years)
研究者
Jale Lakes
senior doctor at the department of urology
Heinrich-Heine University, Duesseldorf