Dataset Information

Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

ABSTRACT:

Background

Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations.

Objective

To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3?yr of screening, by BRCA status.

Design, setting, and participants

Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3?yr, and if PSA?>?3.0?ng/ml, men were offered prostate biopsy.

Outcome measurements and statistical analysis

PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians.

Results and limitations

A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3?yr of screening, 527 men had PSA?>?3.0?ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p?=? 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64?yr; p?=? 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p?=? 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC]?=?0.73) for clinically significant cancer at biopsy than PSA alone (AUC?=?0.65).

Conclusions

After 3?yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers.

Patient summary

We demonstrate that after 3?yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening.

SUBMITTER: Page EC

PROVIDER: S-EPMC6880781 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

Page Elizabeth C EC Bancroft Elizabeth K EK Brook Mark N MN Assel Melissa M Hassan Al Battat Mona M Thomas Sarah S Taylor Natalie N Chamberlain Anthony A Pope Jennifer J Raghallaigh Holly Ni HN Evans D Gareth DG Rothwell Jeanette J Maehle Lovise L Grindedal Eli Marie EM James Paul P Mascarenhas Lyon L McKinley Joanne J Side Lucy L Thomas Tessy T van Asperen Christi C Vasen Hans H Kiemeney Lambertus A LA Ringelberg Janneke J Jensen Thomas Dyrsø TD Osther Palle J S PJS Helfand Brian T BT Genova Elena E Oldenburg Rogier A RA Cybulski Cezary C Wokolorczyk Dominika D Ong Kai-Ren KR Huber Camilla C Lam Jimmy J Taylor Louise L Salinas Monica M Feliubadaló Lidia L Oosterwijk Jan C JC van Zelst-Stams Wendy W Cook Jackie J Rosario Derek J DJ Domchek Susan S Powers Jacquelyn J Buys Saundra S O'Toole Karen K Ausems Margreet G E M MGEM Schmutzler Rita K RK Rhiem Kerstin K Izatt Louise L Tripathi Vishakha V Teixeira Manuel R MR Cardoso Marta M Foulkes William D WD Aprikian Armen A van Randeraad Heleen H Davidson Rosemarie R Longmuir Mark M Ruijs Mariëlle W G MWG Helderman van den Enden Apollonia T J M ATJM Adank Muriel M Williams Rachel R Andrews Lesley L Murphy Declan G DG Halliday Dorothy D Walker Lisa L Liljegren Annelie A Carlsson Stefan S Azzabi Ashraf A Jobson Irene I Morton Catherine C Shackleton Kylie K Snape Katie K Hanson Helen H Harris Marion M Tischkowitz Marc M Taylor Amy A Kirk Judy J Susman Rachel R Chen-Shtoyerman Rakefet R Spigelman Allan A Pachter Nicholas N Ahmed Munaza M Ramon Y Cajal Teresa T Zgajnar Janez J Brewer Carole C Gadea Neus N Brady Angela F AF van Os Theo T Gallagher David D Johannsson Oskar O Donaldson Alan A Barwell Julian J Nicolai Nicola N Friedman Eitan E Obeid Elias E Greenhalgh Lynn L Murthy Vedang V Copakova Lucia L Saya Sibel S McGrath John J Cooke Peter P Rønlund Karina K Richardson Kate K Henderson Alex A Teo Soo H SH Arun Banu B Kast Karin K Dias Alexander A Aaronson Neil K NK Ardern-Jones Audrey A Bangma Chris H CH Castro Elena E Dearnaley David D Eccles Diana M DM Tricker Karen K Eyfjord Jorunn J Falconer Alison A Foster Christopher C Gronberg Henrik H Hamdy Freddie C FC Stefansdottir Vigdis V Khoo Vincent V Lindeman Geoffrey J GJ Lubinski Jan J Axcrona Karol K Mikropoulos Christos C Mitra Anita A Moynihan Clare C Rennert Gadi G Suri Mohnish M Wilson Penny P Dudderidge Tim T Offman Judith J Kote-Jarai Zsofia Z Vickers Andrew A Lilja Hans H Eeles Rosalind A RA

European urology 20190916 6

<h4>Background</h4>Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations.<h4>Objective</h4>To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status.<h4>Design, setting, and participants</h4>Men aged 40-69 yr with a germline p ...[more]

PMID: 31537406

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Project description:BackgroundMen with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations.ObjectiveTo report the first year's screening results for all men at enrollment in the study.Design, setting and participantsWe recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrollment, and those men with PSA >3 ng/ml were offered prostate biopsy.Outcome measurements and statistical analysisPSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types.Results and limitationsWe recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups.ConclusionsThe IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease.Patient summaryIn this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment.

Project description:Patients with germline BRCA2 gene mutations (BRCA2mut) have more aggressive prostate cancer. Analysis of all reported germline BRCA2mut prostate cancer cases allows better understanding of the clinicopathologic features and survival outcomes of these men.A systematic review was performed with the MEDLINE database to capture articles evaluating clinicopathologic characteristics of men with BRCA2mut associated prostate cancer. Inclusion criteria were at least five subjects, confirmation of BRCA2mut status, and data for at least 2 clinical parameters of disease. Meta-analysis was performed on outcomes data. Chi-squared tests were used to compare disease features among men undergoing formal versus ad hoc screening, as well as an age of diagnosis less than versus greater than 65 years. Rates of metastatic disease among BRCA2mut cases were compared to rates among non-carrier control subjects and the general population using the SEER database.Twelve out of 289 studies met our inclusion criteria, representing 261 BRCA2mut men. Among carriers, the median age at diagnosis was 62 years and median PSA was 15?ng/dl with 95% of men having a PSA>3. Over 40% of BRCA2mut patients had T3/T4 disease and over 25% were metastatic at presentation. Survival was worse in BRCA2mut men with prostate cancer when compared to non-BRCA2mut subjects. BRCA2mut carriers had significantly higher rates of metastatic disease (18%) versus non-carrier controls (8%) and the SEER population (4%).BRCA2mut carriers are more likely to have poor risk of prostate cancer at presentation and exhibit worse oncologic outcomes relative to non-carriers, including a fourfold increase in metastatic disease. Younger men and those undergoing formal screening present with less advanced disease which supports a need for earlier identification and screening protocols. Additionally, this population may benefit from alternative therapeutic paradigms. Prostate 76:1135-1145, 2016. © 2016 Wiley Periodicals, Inc.

Project description:BACKGROUND:BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies. OBJECTIVE:To estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location. DESIGN, SETTING, AND PARTICIPANTS:This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3?yr, respectively). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods. RESULTS AND LIMITATIONS:Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99-6.61) and absolute PCa risk of 27% (95% CI 17-41%) and 60% (95% CI 43-78%) by ages 75 and 85?yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43-3.88); the corresponding SIR at age <65?yr was 3.57 (95% CI 1.68-7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99-2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07-5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14-0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ?7 (SIR 5.07, 95% CI 3.20-8.02) than Gleason score ?6 PCa (SIR 3.03, 95% CI 1.24-7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44-10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses. CONCLUSIONS:The results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers. PATIENT SUMMARY:In this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene.

Project description:OBJECTIVES:To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS:Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS:A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION:This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening.

Dataset Information

Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

Background

Objective

Design, setting, and participants

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Patient summary

Publications

Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

Similar Datasets

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