Publications by authors named "Freddie C Hamdy"

258 Publications

Intermediate-risk Prostate Cancer-A Sheep in Wolf's Clothing?

Eur Urol Oncol 2021 Jul 22. Epub 2021 Jul 22.

Sorbonne Université, Urology Department, Hôpital Pitié-Salpêtrière, Paris, France.

This case-based discussion describes a 65-year-old man newly diagnosed with International Society of Urological Pathology (ISUP) grade 2 prostate cancer (PCa). According to the European Association of Urology classification system, the patient harbors an intermediate-risk cancer. In step-by step discussion, we elaborate guideline-based treatment modalities for intermediate-risk PCa focused on debating active surveillance versus active treatment. Thereby, we discuss the importance of patient characteristics, including age, hereditary factors, life expectancy and comorbidity status, findings of multiparametric magnetic resonance imaging, as well as prostate-specific antigen (PSA) density and PSA kinetics, in predicting the clinical course of the disease. In addition, we focus on cribriform pathology as a predictor of adverse outcomes and critically discuss its relevance in patient management. Lastly, we outline genomic stratification in ISUP 2 cancer as a future tool to predict PCa aggressiveness. PATIENT SUMMARY: Based on current guidelines, patients with intermediate-risk prostate cancer are treated actively or can alternatively undergo an active surveillance approach when favorable risk factors are present. One major issue is to discriminate between patients who benefit from an active therapy approach and those who benefit from a deferred treatment. Therefore, reliable biomarkers and early predictors of disease progression are needed urgently.
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http://dx.doi.org/10.1016/j.euo.2021.07.004DOI Listing
July 2021

Tumour irradiation combined with vascular-targeted photodynamic therapy enhances antitumour effects in pre-clinical prostate cancer.

Br J Cancer 2021 Jun 21. Epub 2021 Jun 21.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.

Background: There is a need to improve the treatment of prostate cancer (PCa) and reduce treatment side effects. Vascular-targeted photodynamic therapy (VTP) is a focal therapy for low-risk low-volume localised PCa, which rapidly disrupts targeted tumour vessels. There is interest in expanding the use of VTP to higher-risk disease. Tumour vasculature is characterised by vessel immaturity, increased permeability, aberrant branching and inefficient flow. FRT alters the tumour microenvironment and promotes transient 'vascular normalisation'. We hypothesised that multimodality therapy combining fractionated radiotherapy (FRT) and VTP could improve PCa tumour control compared against monotherapy with FRT or VTP.

Methods: We investigated whether sequential delivery of FRT followed by VTP 7 days later improves flank TRAMP-C1 PCa tumour allograft control compared to monotherapy with FRT or VTP.

Results: FRT induced 'vascular normalisation' changes in PCa flank tumour allografts, improving vascular function as demonstrated using dynamic contrast-enhanced magnetic resonance imaging. FRT followed by VTP significantly delayed tumour growth in flank PCa allograft pre-clinical models, compared with monotherapy with FRT or VTP, and improved overall survival.

Conclusion: Combining FRT and VTP may be a promising multimodal approach in PCa therapy. This provides proof-of-concept for this multimodality treatment to inform early phase clinical trials.
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http://dx.doi.org/10.1038/s41416-021-01450-6DOI Listing
June 2021

A Systematic Review of Prostate Cancer Heterogeneity: Understanding the Clonal Ancestry of Multifocal Disease.

Eur Urol Oncol 2021 Jun 20;4(3):358-369. Epub 2021 Apr 20.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Department of Urology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Oxford NIHR Biomedical Research Centre, University of Oxford, UK. Electronic address:

Context: Studies characterising genomic changes in prostate cancer (PCa) during natural progression have greatly increased our understanding of the disease. A better understanding of the evolutionary history of PCa would allow advances in diagnostics, prognostication, and novel therapies that together will improve patient outcomes.

Objective: To review the molecular heterogeneity of PCa and assess recent efforts to profile intratumoural heterogeneity and clonal evolution.

Evidence Acquisition: We screened a total of 1313 abstracts from PubMed published between 2009 and 2020, of which we reviewed 84 full-text articles. We excluded 49, resulting in 35 studies for qualitative analysis.

Evidence Synthesis: In studies of primary disease (16 studies, 4793 specimens), there is a lack of consensus regarding the monoclonal or polyclonal origin of primary PCa. There is no consistent mutation giving rise to primary PCa. Detailed clonal analysis of primary PCa has been limited by current techniques. By contrast, clonal relationships between PCa metastases and a potentiating clone have been consistently identified (19 studies, 732 specimens). Metastatic specimens demonstrate consistent truncal genomic aberrations that suggest monoclonal metastatic progenitors.

Conclusions: The relationship between the clonal dynamics of PCa and clinical outcomes needs further investigation. It is likely that this will provide a biological rationale for whether radical treatment of the primary tumour benefits patients with oligometastatic PCa. Future studies on the mutational burden in primary disease at single-cell resolution should permit the identification of clonal patterns underpinning the origin of lethal PCa.

Patient Summary: Prostate cancers arise in different parts of the prostate because of DNA mutations that occur by chance at different times. These cancer cells and their origin can be tracked by DNA mapping. In this review we summarise the state of the art and outline what further science is needed to provide the missing answers.
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http://dx.doi.org/10.1016/j.euo.2021.02.008DOI Listing
June 2021

Positron Emission Tomography and Whole-body Magnetic Resonance Imaging for Metastasis-directed Therapy in Hormone-sensitive Oligometastatic Prostate Cancer After Primary Radical Treatment: A Systematic Review.

Eur Urol Oncol 2021 Mar 6. Epub 2021 Mar 6.

Nuclear Medicine Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna, Italy.

Context: Next-generation imaging includes positron emission tomography (PET) imaging and whole-body magnetic resonance imaging (wbMRI) including diffusion-weighted imaging. Accurate quantification of oligometastatic disease using next-generation imaging is important to define the role and value of metastasis-directed therapy (MDT).

Objective: To perform a review of next-generation imaging modalities in the detection of recurrent oligometastatic hormone-sensitive prostate cancer in men who received prior radical treatment for localized disease.

Evidence Acquisition: MEDLINE, Scopus, Cochrane Libraries, and Web of Science databases were systematically searched for studies reporting next-generation imaging and oncological outcomes. An expert panel of urologists, radiation oncologists, radiologists, and nuclear medicine physicians performed a nonsystematic review of strengths and limitations of currently available imaging options for detecting the presence and extent of recurrent oligometastatic disease.

Evidence Synthesis: From 370 articles identified, three clinical trials and 21 observational studies met the following inclusion criteria: metachronous oligometastatic recurrence after radical treatment for prostate cancer, MDT, and hormone-sensitive patients. Androgen deprivation therapy (ADT) was allowed before MDT. Next-generation imaging modalities included PET/computed tomography and/or PET/MRI with the following tracers: choline (n = 1), NaF (n = 1), and prostate-specific membrane antigen (PSMA; n = 1) for clinical trials; choline (n = 7) or PSMA (n = 11) or both (n = 3) for observational studies. The number of metastases ranged from two to five lesions in most studies. In PSMA-based studies, progression-free survival ranged from 19% to 100%, whereas in studies employing choline, progression-free survival ranged from 16% to 93%. Overall, ADT-free survival ranged from 48% to 79%, while local control was reported as 75-100% and prostate-specific antigen response as 23-94%. Among the different PET tracers and wbMRI, PSMA PET is emerging as the most accurate imaging technique in defining the oligometastatic status.

Conclusions: PSMA and choline PET contribute to guiding MDT in men with hormone-sensitive oligometastatic prostate cancer. Further studies are warranted to ascertain their role and optimize the timing of imaging for such patients.

Patient Summary: We looked at the evidence regarding the use of modern imaging techniques to direct additional treatments in men with early spread of prostate cancer after they receive their initial radical treatment. We found that next-generation imaging, in particular prostate-specific membrane antigen and choline positron emission tomography, can successfully guide metastasis-directed therapies, and further trials should evaluate which modalities are best suited to improve outcomes for our patients.
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http://dx.doi.org/10.1016/j.euo.2021.02.003DOI Listing
March 2021

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Nat Commun 2021 02 23;12(1):1236. Epub 2021 Feb 23.

Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS (PHS, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10). Comparing the 80/20 PHS percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
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http://dx.doi.org/10.1038/s41467-021-21287-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902617PMC
February 2021

Use of intraoperative fluorescence to enhance robot-assisted radical prostatectomy.

Future Oncol 2021 Mar 16;17(9):1083-1095. Epub 2021 Feb 16.

Department of Urology, Churchill Hospital Cancer Centre, Oxford University Hospitals NHS Foundation Trust, OX3 7LE, UK.

Robot-assisted radical prostatectomy has become the standard of care for the removal of localized prostate cancer. Positive outcomes depend upon the precise removal of the prostate and associated tissue without damage to nearby structures. This process can be aided by fluorescence-guided surgery to enhance the visual contrast between different structures. Here the authors have conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify ten investigations into the use of fluorescence-guided surgery in robot-assisted radical prostatectomy. These studies used fluorescent tracers to identify structures, including the prostate, neurovascular bundle and lymph nodes. These studies demonstrate the safe and effective use of fluorescence-guided surgery in robot-assisted radical prostatectomy and pave the way for further developments in this field.
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http://dx.doi.org/10.2217/fon-2020-0370DOI Listing
March 2021

Identification of a serum biomarker signature associated with metastatic prostate cancer.

Proteomics Clin Appl 2021 May 4;15(2-3):e2000025. Epub 2021 May 4.

Department of Immunotechnology and CREATE Health Translational Cancer Center, Lund University, Lund, Sweden.

Purpose: Improved early diagnosis and determination of aggressiveness of prostate cancer (PC) is important to select suitable treatment options and to decrease over-treatment. The conventional marker is total prostate specific antigen (PSA) levels in blood, but lacks specificity and ability to accurately discriminate indolent from aggressive disease.

Experimental Design: In this study, we sought to identify a serum biomarker signature associated with metastatic PC. We measured 157 analytes in 363 serum samples from healthy subjects, patients with non-metastatic PC and patients with metastatic PC, using a recombinant antibody microarray.

Results: A signature consisting of 69 proteins differentiating metastatic PC patients from healthy controls was identified.

Conclusions And Clinical Relevance: The clinical value of this biomarker signature requires validation in larger independent patient cohorts before providing a new prospect for detection of metastatic PC.
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http://dx.doi.org/10.1002/prca.202000025DOI Listing
May 2021

Local anaesthetic transperineal (LATP) prostate biopsy using a probe-mounted transperineal access system: a multicentre prospective outcome analysis.

BJU Int 2021 Jan 15. Epub 2021 Jan 15.

Churchill Hospital Cancer Centre, Oxford, UK.

Objectives: To assess the feasibility of local anaesthetic transperineal (LATP) technique using a single-freehand transperineal (TP) access device, and report initial prostate cancer (PCa) detection, infection rates, and tolerability.

Patients And Methods: Observational study of a multicentre prospective cohort, including all consecutive cases. LATP was performed in three settings: (i) first biopsy in suspected PCa, (ii) confirmatory biopsies for active surveillance, and (iii) repeat biopsy in suspected PCa. All patients received pre-procedure antibiotics according to local hospital guidelines. Local anaesthesia was achieved by perineal skin infiltration and periprostatic nerve block without sedation. Ginsburg protocol principles were followed for systematic biopsies including cognitive magnetic resonance imaging-targeted biopsies when needed using the PrecisionPoint™ TP access device. Procedure-related complications and oncological outcomes were prospectively and consecutively collected. A validated questionnaire was used in a subset of centres to collect data on patient-reported outcome measures (PROMs).

Results: Some 1218 patients underwent LATP biopsies at 10 centres: 55%, 24%, and 21% for each of the three settings, respectively. Any grade PCa was diagnosed in 816 patients (67%), of which 634 (52% of total) had clinically significant disease. Two cases of sepsis were documented (0.16%) and urinary retention was observed in 19 patients (1.6%). PROMs were distributed to 419 patients, with a 56% response rate (n = 234). In these men, pain during the biopsy was described as either 'not at all' or 'a little' painful by 64% of patients. Haematuria was the most common reported symptom (77%). When exploring attitude to re-biopsy, 48% said it would be 'not a problem' and in contrast 8.1% would consider it a 'major problem'. Most of the patients (81%) described the biopsy as a 'minor or moderate procedure tolerable under local anaesthesia', while 5.6% perceived it as a 'major procedure that requires general anaesthesia'.

Conclusion: Our data suggest that LATP biopsy using a TP access system mounted to the ultrasound probe achieves excellent PCa detection, with a very low sepsis rate, and is safe and well tolerated. We believe a randomised controlled trial comparing LATP with transrectal ultrasound-guided biopsy (TRUS) to investigate the relative trade-offs between each biopsy technique would be helpful. Patient summary What is the paper about? Several hospitals around the world collaborated to report their initial experience with local anaesthetic transperineal (LATP) prostate biopsy. In this technique, biopsy needles pass through the skin below the scrotum rather than the bowel lining via the back passage. The procedure used to require general anaesthetic but can now be performed under local anaesthetic. The paper presents the cancer detection and complication rates found, and the acceptability of the LATP procedure to men undergoing prostate biopsy. What does it mean for patients? In over a thousand biopsies from ten hospitals, cancer detection rates were high and there was a very low risk of infection or difficulty passing urine after the LATP procedure. Most men reported it to be acceptable under local anaesthetic, but a small number considered it painful and would have preferred general anaesthesia. Further research is planned.
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http://dx.doi.org/10.1111/bju.15337DOI Listing
January 2021

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Prostate Cancer Prostatic Dis 2021 Jun 8;24(2):532-541. Epub 2021 Jan 8.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).

Materials And Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
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http://dx.doi.org/10.1038/s41391-020-00311-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157993PMC
June 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

A new Editorial Team for the BJU International….

Authors:
Freddie C Hamdy

BJU Int 2020 08;126(2):213-214

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http://dx.doi.org/10.1111/bju.15180DOI Listing
August 2020

Active monitoring, radical prostatectomy and radical radiotherapy in PSA-detected clinically localised prostate cancer: the ProtecT three-arm RCT.

Health Technol Assess 2020 08;24(37):1-176

Department of Urology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Background: Prostate cancer is the most common cancer among men in the UK. Prostate-specific antigen testing followed by biopsy leads to overdetection, overtreatment as well as undertreatment of the disease. Evidence of treatment effectiveness has lacked because of the paucity of randomised controlled trials comparing conventional treatments.

Objectives: To evaluate the effectiveness of conventional treatments for localised prostate cancer (active monitoring, radical prostatectomy and radical radiotherapy) in men aged 50-69 years.

Design: A prospective, multicentre prostate-specific antigen testing programme followed by a randomised trial of treatment, with a comprehensive cohort follow-up.

Setting: Prostate-specific antigen testing in primary care and treatment in nine urology departments in the UK.

Participants: Between 2001 and 2009, 228,966 men aged 50-69 years received an invitation to attend an appointment for information about the Prostate testing for cancer and Treatment (ProtecT) study and a prostate-specific antigen test; 82,429 men were tested, 2664 were diagnosed with localised prostate cancer, 1643 agreed to randomisation to active monitoring ( = 545), radical prostatectomy ( = 553) or radical radiotherapy ( = 545) and 997 chose a treatment.

Interventions: The interventions were active monitoring, radical prostatectomy and radical radiotherapy.

Trial Primary Outcome Measure: Definite or probable disease-specific mortality at the 10-year median follow-up in randomised participants.

Secondary Outcome Measures: Overall mortality, metastases, disease progression, treatment complications, resource utilisation and patient-reported outcomes.

Results: There were no statistically significant differences between the groups for 17 prostate cancer-specific ( = 0.48) and 169 all-cause ( = 0.87) deaths. Eight men died of prostate cancer in the active monitoring group (1.5 per 1000 person-years, 95% confidence interval 0.7 to 3.0); five died of prostate cancer in the radical prostatectomy group (0.9 per 1000 person-years, 95% confidence interval 0.4 to 2.2 per 1000 person years) and four died of prostate cancer in the radical radiotherapy group (0.7 per 1000 person-years, 95% confidence interval 0.3 to 2.0 per 1000 person years). More men developed metastases in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring,  = 33 (6.3 per 1000 person-years, 95% confidence interval 4.5 to 8.8); radical prostatectomy,  = 13 (2.4 per 1000 person-years, 95% confidence interval 1.4 to 4.2 per 1000 person years); and radical radiotherapy,  = 16 (3.0 per 1000 person-years, 95% confidence interval 1.9 to 4.9 per 1000 person-years;  = 0.004). There were higher rates of disease progression in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring ( = 112; 22.9 per 1000 person-years, 95% confidence interval 19.0 to 27.5 per 1000 person years); radical prostatectomy ( = 46; 8.9 per 1000 person-years, 95% confidence interval 6.7 to 11.9 per 1000 person-years); and radical radiotherapy ( = 46; 9.0 per 1000 person-years, 95% confidence interval 6.7 to 12.0 per 1000 person years;  < 0.001). Radical prostatectomy had the greatest impact on sexual function/urinary continence and remained worse than radical radiotherapy and active monitoring. Radical radiotherapy's impact on sexual function was greatest at 6 months, but recovered somewhat in the majority of participants. Sexual and urinary function gradually declined in the active monitoring group. Bowel function was worse with radical radiotherapy at 6 months, but it recovered with the exception of bloody stools. Urinary voiding and nocturia worsened in the radical radiotherapy group at 6 months but recovered. Condition-specific quality-of-life effects mirrored functional changes. No differences in anxiety/depression or generic or cancer-related quality of life were found. At the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year, the probabilities that each arm was the most cost-effective option were 58% (radical radiotherapy), 32% (active monitoring) and 10% (radical prostatectomy).

Limitations: A single prostate-specific antigen test and transrectal ultrasound biopsies were used. There were very few non-white men in the trial. The majority of men had low- and intermediate-risk disease. Longer follow-up is needed.

Conclusions: At a median follow-up point of 10 years, prostate cancer-specific mortality was low, irrespective of the assigned treatment. Radical prostatectomy and radical radiotherapy reduced disease progression and metastases, but with side effects. Further work is needed to follow up participants at a median of 15 years.

Trial Registration: Current Controlled Trials ISRCTN20141297.

Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 37. See the National Institute for Health Research Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443739PMC
August 2020

Glutamine deprivation alters the origin and function of cancer cell exosomes.

EMBO J 2020 08 28;39(16):e103009. Epub 2020 Jul 28.

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.

Exosomes are secreted extracellular vesicles carrying diverse molecular cargos, which can modulate recipient cell behaviour. They are thought to derive from intraluminal vesicles formed in late endosomal multivesicular bodies (MVBs). An alternate exosome formation mechanism, which is conserved from fly to human, is described here, with exosomes carrying unique cargos, including the GTPase Rab11, generated in Rab11-positive recycling endosomal MVBs. Release of Rab11-positive exosomes from cancer cells is increased relative to late endosomal exosomes by reducing growth regulatory Akt/mechanistic Target of Rapamycin Complex 1 (mTORC1) signalling or depleting the key metabolic substrate glutamine, which diverts membrane flux through recycling endosomes. Vesicles produced under these conditions promote tumour cell proliferation and turnover and modulate blood vessel networks in xenograft mouse models in vivo. Their growth-promoting activity, which is also observed in vitro, is Rab11a-dependent, involves ERK-MAPK-signalling and is inhibited by antibodies against amphiregulin, an EGFR ligand concentrated on these vesicles. Therefore, glutamine depletion or mTORC1 inhibition stimulates release from Rab11a compartments of exosomes with pro-tumorigenic functions, which we propose promote stress-induced tumour adaptation.
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http://dx.doi.org/10.15252/embj.2019103009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429491PMC
August 2020

The ProtecT randomised trial cost-effectiveness analysis comparing active monitoring, surgery, or radiotherapy for prostate cancer.

Br J Cancer 2020 09 16;123(7):1063-1070. Epub 2020 Jul 16.

Bristol Medical School, University of Bristol, Bristol, UK.

Background: There is limited evidence relating to the cost-effectiveness of treatments for localised prostate cancer.

Methods: The cost-effectiveness of active monitoring, surgery, and radiotherapy was evaluated within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial from a UK NHS perspective at 10 years' median follow-up. Prostate cancer resource-use collected from hospital records and trial participants was valued using UK reference-costs. QALYs (quality-adjusted-life-years) were calculated from patient-reported EQ-5D-3L measurements. Adjusted mean costs, QALYs, and incremental cost-effectiveness ratios were calculated; cost-effectiveness acceptability curves and sensitivity analyses addressed uncertainty; subgroup analyses considered age and disease-risk.

Results: Adjusted mean QALYs were similar between groups: 6.89 (active monitoring), 7.09 (radiotherapy), and 6.91 (surgery). Active monitoring had lower adjusted mean costs (£5913) than radiotherapy (£7361) and surgery (£7519). Radiotherapy was the most likely (58% probability) cost-effective option at the UK NICE willingness-to-pay threshold (£20,000 per QALY). Subgroup analyses confirmed radiotherapy was cost-effective for older men and intermediate/high-risk disease groups; active monitoring was more likely to be the cost-effective option for younger men and low-risk groups.

Conclusions: Longer follow-up and modelling are required to determine the most cost-effective treatment for localised prostate cancer over a man's lifetime.

Trial Registration: Current Controlled Trials number, ISRCTN20141297: http://isrctn.org (14/10/2002); ClinicalTrials.gov number, NCT02044172: http://www.clinicaltrials.gov (23/01/2014).
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http://dx.doi.org/10.1038/s41416-020-0978-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524753PMC
September 2020

Impacts of combining anti-PD-L1 immunotherapy and radiotherapy on the tumour immune microenvironment in a murine prostate cancer model.

Br J Cancer 2020 09 9;123(7):1089-1100. Epub 2020 Jul 9.

Department of Oncology, University of Oxford, Oxford, UK.

Background: Radiotherapy enhances innate and adaptive anti-tumour immunity. It is unclear whether this effect may be harnessed by combining immunotherapy with radiotherapy fractions used to treat prostate cancer. We investigated tumour immune microenvironment responses of pre-clinical prostate cancer models to radiotherapy. Having defined this landscape, we tested whether radiotherapy-induced tumour growth delay could be enhanced with anti-PD-L1.

Methods: Hypofractionated radiotherapy was delivered to TRAMP-C1 and MyC-CaP flank allografts. Tumour growth delay, tumour immune microenvironment flow-cytometry, and immune gene expression were analysed. TRAMP-C1 allografts were then treated with 3 × 5 Gy ± anti-PD-L1.

Results: 3 × 5 Gy caused tumour growth delay in TRAMP-C1 and MyC-CaP. Tumour immune microenvironment changes in TRAMP-C1 at 7 days post-radiotherapy included increased tumour-associated macrophages and dendritic cells and upregulation of PD-1/PD-L1, CD8 T-cell, dendritic cell, and regulatory T-cell genes. At tumour regrowth post-3 × 5 Gy the tumour immune microenvironment flow-cytometry was similar to control tumours, however CD8, natural killer and dendritic cell gene transcripts were reduced. PD-L1 inhibition plus 3 × 5 Gy in TRAMP-C1 did not enhance tumour growth delay versus monotherapy.

Conclusion: 3 × 5 Gy hypofractionated radiotherapy can result in tumour growth delay and immune cell changes in allograft prostate cancer models. Adjuncts beyond immunomodulation may be necessary to improve the radiotherapy-induced anti-tumour response.
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http://dx.doi.org/10.1038/s41416-020-0956-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525450PMC
September 2020

A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data.

Cancer Epidemiol Biomarkers Prev 2020 09 24;29(9):1731-1738. Epub 2020 Jun 24.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.

Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.

Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.

Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.

Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483627PMC
September 2020

The effect of sample size on polygenic hazard models for prostate cancer.

Eur J Hum Genet 2020 10 8;28(10):1467-1475. Epub 2020 Jun 8.

Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076, Tuebingen, Germany.

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.
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http://dx.doi.org/10.1038/s41431-020-0664-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608255PMC
October 2020

Negative Predictive Value of Multiparametric Magnetic Resonance Imaging in the Detection of Clinically Significant Prostate Cancer in the Prostate Imaging Reporting and Data System Era: A Systematic Review and Meta-analysis.

Eur Urol 2020 09 20;78(3):402-414. Epub 2020 May 20.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.

Context: Prebiopsy multiparametric magnetic resonance imaging (mpMRI) is increasingly used in prostate cancer diagnosis. The reported negative predictive value (NPV) of mpMRI is used by some clinicians to aid in decision making about whether or not to proceed to biopsy.

Objective: We aim to perform a contemporary systematic review that reflects the latest literature on optimal mpMRI techniques and scoring systems to update the NPV of mpMRI for clinically significant prostate cancer (csPCa).

Evidence Acquisition: We conducted a systematic literature search and included studies from 2016 to September 4, 2019, which assessed the NPV of mpMRI for csPCa, using biopsy or clinical follow-up as the reference standard. To ensure that studies included in this analysis reflect contemporary practice, we only included studies in which mpMRI findings were interpreted according to the Prostate Imaging Reporting and Data System (PIRADS) or similar Likert grading system. We define negative mpMRI as either (1) PIRADS/Likert 1-2 or (2) PIRADS/Likert 1-3; csPCa was defined as either (1) Gleason grade group ≥2 or (2) Gleason grade group ≥3. We calculated NPV separately for each combination of negative mpMRI and csPCa.

Evidence Synthesis: A total of 42 studies with 7321 patients met our inclusion criteria and were included for analysis. Using definition (1) for negative mpMRI and csPCa, the pooled NPV for biopsy-naïve men was 90.8% (95% confidence interval [CI] 88.1-93.1%). When defining csPCa using definition (2), the NPV for csPCa was 97.1% (95% CI 94.9-98.7%). Calculation of the pooled NPV using definition (2) for negative mpMRI and definition (1) for csPCa yielded the following: 86.8% (95% CI 80.1-92.4%). Using definition (2) for both negative mpMRI and csPCa, the pooled NPV from two studies was 96.1% (95% CI 93.4-98.2%).

Conclusions: Multiparametric MRI of the prostate is generally an accurate test for ruling out csPCa. However, we observed heterogeneity in the NPV estimates, and local institutional data should form the basis of decision making if available.

Patient Summary: The negative predictive values should assist in decision making for clinicians considering not proceeding to biopsy in men with elevated age-specific prostate-specific antigen and multiparametric magnetic resonance imaging reported as negative (or equivocal) on Prostate Imaging Reporting and Data System/Likert scoring. Some 7-10% of men, depending on the setting, will miss a diagnosis of clinically significant cancer if they do not proceed to biopsy. Given the institutional variation in results, it is of upmost importance to base decision making on local data if available.
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http://dx.doi.org/10.1016/j.eururo.2020.03.048DOI Listing
September 2020

Transcriptomic and Functional Screens Reveal MicroRNAs That Modulate Prostate Cancer Metastasis.

Front Oncol 2020 13;10:292. Epub 2020 Mar 13.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.

Identifying new mechanisms that underlie the complex process of metastasis is vital to combat this fatal step in prostate cancer (PCa) progression. Small non-coding RNAs are emerging as important regulators of tumor cell biology. Here we take an integrative approach to elucidate the contribution of microRNAs to metastatic progression, combining transcriptomic analysis with functional screens for migration and morphology. We developed high-content microscopy, high-throughput functional screens for migration and morphology in PCa cells using a microRNA library. RNA-Seq analysis of paired epithelial and mesenchymal PCa cells identified differential expression of 200 microRNAs. Data integration identified two microRNAs that inhibited migration, induced an epithelial-like morphology and were increased in epithelial PCa cells. An overrepresentation of the AAGUGC seed sequence was detected in all three datasets. Analysis of published datasets of patients with PCa identified microRNAs of clinical relevance. The integration of high-throughput functional and expression analyses identifies microRNAs with clinical significance that modulate metastatic behavior in PCa.
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http://dx.doi.org/10.3389/fonc.2020.00292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082744PMC
March 2020

Detailed Molecular and Immune Marker Profiling of Archival Prostate Cancer Samples Reveals an Inverse Association between TMPRSS2:ERG Fusion Status and Immune Cell Infiltration.

J Mol Diagn 2020 05 27;22(5):652-669. Epub 2020 Mar 27.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom; Oxford National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom; Department of Cellular Pathology, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom. Electronic address:

Prostate cancer is a significant global health issue, and limitations to current patient management pathways often result in overtreatment or undertreatment. New ways to stratify patients are urgently needed. We conducted a feasibility study of such novel assessments, looking for associations between genomic changes and lymphocyte infiltration. An innovative workflow using an in-house targeted sequencing panel, immune cell profiling using an image analysis pipeline, RNA sequencing, and exome sequencing in select cases was tested. Gene fusions were profiled by RNA sequencing in 27 of 27 cases, and a significantly higher tumor-infiltrating lymphocyte (TIL) count was noted in tumors without a TMPRSS2:ERG fusion compared with those with the fusion (P = 0.01). Although this finding was not replicated in a larger validation set (n = 436) of The Cancer Genome Atlas images, there was a trend in the same direction. Differential expression analysis of TIL-high and TIL-low tumors revealed the enrichment of both innate and adaptive immune response pathways. Mutations in mismatch repair genes (MLH1 and MSH6 mutations in 1 of 27 cases) were identified. We describe a potential immune escape mechanism in TMPRSS2:ERG fusion-positive tumors. Detailed profiling, as shown herein, can provide novel insights into tumor biology. Likely differences with findings with other cohorts are related to methods used to define region of interest, but this warrants further study in a larger cohort.
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http://dx.doi.org/10.1016/j.jmoldx.2020.02.012DOI Listing
May 2020

Systematic review and meta-analysis of the associations between body mass index, prostate cancer, advanced prostate cancer, and prostate-specific antigen.

Cancer Causes Control 2020 May 11;31(5):431-449. Epub 2020 Mar 11.

Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England.

Purpose: The relationship between body mass index (BMI) and prostate cancer remains unclear. However, there is an inverse association between BMI and prostate-specific antigen (PSA), used for prostate cancer screening. We conducted this review to estimate the associations between BMI and (1) prostate cancer, (2) advanced prostate cancer, and (3) PSA.

Methods: We searched PubMed and Embase for studies until 02 October 2017 and obtained individual participant data from four studies. In total, 78 studies were identified for the association between BMI and prostate cancer, 21 for BMI and advanced prostate cancer, and 35 for BMI and PSA. We performed random-effects meta-analysis of linear associations of log-PSA and prostate cancer with BMI and, to examine potential non-linearity, of associations between categories of BMI and each outcome.

Results: In the meta-analyses with continuous BMI, a 5 kg/m increase in BMI was associated with a percentage change in PSA of - 5.88% (95% CI - 6.87 to - 4.87). Using BMI categories, compared to normal weight men the PSA levels of overweight men were 3.43% lower (95% CI - 5.57 to - 1.23), and obese men were 12.9% lower (95% CI - 15.2 to - 10.7). Prostate cancer and advanced prostate cancer analyses showed little or no evidence associations.

Conclusion: There is little or no evidence of an association between BMI and risk of prostate cancer or advanced prostate cancer, and strong evidence of an inverse and non-linear association between BMI and PSA. The association between BMI and prostate cancer is likely biased if missed diagnoses are not considered.
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http://dx.doi.org/10.1007/s10552-020-01291-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105428PMC
May 2020

The ProtecT trial: analysis of the patient cohort, baseline risk stratification and disease progression.

BJU Int 2020 04 12;125(4):506-514. Epub 2020 Feb 12.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.

Objective: To test the hypothesis that the baseline clinico-pathological features of the men with localized prostate cancer (PCa) included in the ProtecT (Prostate Testing for Cancer and Treatment) trial who progressed (n = 198) at a 10-year median follow-up were different from those of men with stable disease (n = 1409).

Patients And Methods: We stratified the study participants at baseline according to risk of progression using clinical disease stage, pathological grade and PSA level, using Cox proportional hazard models.

Results: The findings showed that 34% of participants (n = 505) had intermediate- or high-risk PCa, and 66% (n = 973) had low-risk PCa. Of 198 participants who progressed, 101 (51%) had baseline International Society of Urological Pathology Grade Group 1, 59 (30%) Grade Group 2, and 38 (19%) Grade Group 3 PCa, compared with 79%, 17% and 5%, respectively, for 1409 participants without progression (P < 0.001). In participants with progression, 38% and 62% had baseline low- and intermediate-/high-risk disease, compared with 69% and 31% of participants with stable disease (P < 0.001). Treatment received, age (65-69 vs 50-64 years), PSA level, Grade Group, clinical stage, risk group, number of positive cores, tumour length and perineural invasion were associated with time to progression (P ≤ 0.005). Men progressing after surgery (n = 19) were more likely to have a higher Grade Group and pathological stage at surgery, larger tumours, lymph node involvement and positive margins.

Conclusions: We demonstrate that one-third of the ProtecT cohort consists of people with intermediate-/high-risk disease, and the outcomes data at an average of 10 years' follow-up are generalizable beyond men with low-risk PCa.
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http://dx.doi.org/10.1111/bju.14987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187290PMC
April 2020

Ten-year Mortality, Disease Progression, and Treatment-related Side Effects in Men with Localised Prostate Cancer from the ProtecT Randomised Controlled Trial According to Treatment Received.

Eur Urol 2020 03 24;77(3):320-330. Epub 2019 Nov 24.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.

Background: The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer (PCa) randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy.

Objective: To determine report outcomes according to treatment received in men in randomised and treatment choice cohorts.

Design, Setting, And Participants: This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy.

Intervention: Two cohorts included 1643 men who agreed to be randomised; 997 declined randomisation and chose treatment.

Outcome Measurements And Statistical Analysis: Health-related quality of life impacts on urinary, bowel, and sexual function were assessed using patient-reported outcome measures. Analysis was carried out based on treatment received for each cohort and on pooled estimates using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores.

Results And Limitations: According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p=0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p=0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6mo) and urinary incontinence (55% at 6mo) after surgery, and of sexual dysfunction (88% at 6mo) and bowel dysfunction (5% at 6mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and outdating of the interventions being evaluated during the lengthy follow-up required in trials of screen-detected PCa.

Conclusions: Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group.

Patient Summary: More than 90 out of every 100 men with localised prostate cancer do not die of prostate cancer within 10yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are much better after active monitoring, but the risks of spreading of prostate cancer are more common.
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http://dx.doi.org/10.1016/j.eururo.2019.10.030DOI Listing
March 2020

Mating induces switch from hormone-dependent to hormone-independent steroid receptor-mediated growth in Drosophila secondary cells.

PLoS Biol 2019 10 7;17(10):e3000145. Epub 2019 Oct 7.

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.

Male reproductive glands like the mammalian prostate and the paired Drosophila melanogaster accessory glands secrete seminal fluid components that enhance fecundity. In humans, the prostate, stimulated by environmentally regulated endocrine and local androgens, grows throughout adult life. We previously showed that in fly accessory glands, secondary cells (SCs) and their nuclei also grow in adults, a process enhanced by mating and controlled by bone morphogenetic protein (BMP) signalling. Here, we demonstrate that BMP-mediated SC growth is dependent on the receptor for the developmental steroid ecdysone, whose concentration is reported to reflect sociosexual experience in adults. BMP signalling appears to regulate ecdysone receptor (EcR) levels via one or more mechanisms involving the EcR's N terminus or the RNA sequence that encodes it. Nuclear growth in virgin males is dependent on ecdysone, some of which is synthesised in SCs. However, mating induces additional BMP-mediated nuclear growth via a cell type-specific form of hormone-independent EcR signalling, which drives genome endoreplication in a subset of adult SCs. Switching to hormone-independent endoreplication after mating allows growth and secretion to be hyperactivated independently of ecdysone levels in SCs, permitting more rapid replenishment of the accessory gland luminal contents. Our data suggest mechanistic parallels between this physiological, behaviour-induced signalling switch and altered pathological signalling associated with prostate cancer progression.
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http://dx.doi.org/10.1371/journal.pbio.3000145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797231PMC
October 2019

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

Eur Urol 2019 12 16;76(6):831-842. Epub 2019 Sep 16.

International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.

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.
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http://dx.doi.org/10.1016/j.eururo.2019.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880781PMC
December 2019

Factors associated with trial recruitment, preferences, and treatments received were elucidated in a comprehensive cohort study.

J Clin Epidemiol 2019 09 3;113:200-213. Epub 2019 Jun 3.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.

Objectives: Recruitment to pragmatic trials is often difficult, and little is known about factors associated with key participation and treatment decisions. These were explored in the Prostate cancer testing and Treatment (ProtecT) study.

Study Design And Setting: Baseline sociodemographic, patient-reported outcome, clinical history, and prostate cancer biopsy data were collected for all patients eligible to take part in the ProtecT trial, in a comprehensive cohort design. Men who rejected randomization specified a preferred option and were followed up identically to the randomized cohort. Factors associated with participation decisions, patient preferences, and reasons for changing treatment were explored.

Results: Of 2,664 men with clinically localized prostate cancer, 997 (37%) rejected randomization. Their treatment preferences and subsequent treatment choices/changes in both randomized and treatment choice cohorts were strongly associated with prostate cancer risk features: toward active monitoring for low-risk disease and toward radical options with higher risk prostate cancer. Among many factors measured, only a small number of weak associations were found for occupation groups and some patient symptoms. Similar percentages changed from the random allocation and initially stated preference.

Conclusion: The comprehensive cohort design provided new insights into trial recruitment and participation decisions. Opportunities to improve recruitment by supporting recruiters with equipoise and patient preferences were identified.
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http://dx.doi.org/10.1016/j.jclinepi.2019.05.036DOI Listing
September 2019
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