Title: Integrating genetic testing into the prostate cancer pathway to more precisely guide care, treatment and accelerate clinical trials
Funder: Department of Health and Social Care

Abstract: Research question: How can the integration of genetic testing within the prostate cancer (PrCa) screening, diagnostic and management pathway improve patient care and be cost efficient for the NHS? Background: PrCa affects 1-in-8 UK men, has a high mortality rate; considerable morbidity; and is estimated to cost the UK &pound;160m/year. Early detection of men who will develop aggressive cancers, whilst avoiding over-diagnosis of indolent disease, remains a significant challenge. We have developed and validated a genetic test that detects both common and rare genetic variants. This programme will inform the implementation of that test into the UK National Genomic Test Directory (NGTD) and demonstrate its utility in the PrCa screening and treatment pathway. Aims and objectives: To demonstrate germline genetic testing in the PrCa care pathway to improve and inform patient management Methods: Five work packages (WP) will integrate findings from several interlinked projects applying genetic testing within PrCa screening and management. WP1 is a large prospective cohort-study using a gene panel test in a population of men to identify: (i) those at high-risk; (ii) those at risk of aggressive/lethal PrCa. WP2 will offer targeted screening to men - from WP1 - identified with germline mutations in rare genes. For those at higher-risk of aggressive PrCa, we will track clinical outcomes (WP3) and offer clinical trials of therapies that precisely target aggressive PrCa. Qualitative exploration of stakeholder experiences and economic evaluations will consider the impact and benefits of integrating genetics into PrCa screening and management from the perspective of the patient (WP4) and the NHS (WP5). WP4 will determine the information/support requirements of men going through the testing process. WP5 will evaluate whether a programme of genetic testing, in combination with targeted PrCa screening in unaffected men, will have health benefits for men and whether this would be cost-effective or cost-saving for the NHS. Timelines for delivery If successful, this research will alter the PrCa screening and treatment pathway within ten years. We aim to generate evidence to support NGTD adoption of the genetic panel test by the programme end. The economic evaluation will be available at the end of the programme. The digital educational resource will be developed and launched by the end of the programme. Anticipated impact and dissemination By programme completion: 1.Adoption of genetic testing into the NGTD for men with PrCa and guidelines for whom/when to test. 2.Identification of men with genetic variants for targeted treatment, forging pathways into clinical trials, thus speeding up translation of novel therapies. 3.Development of a digital, patient-facing, educational resource package to support implementation. 4.Health economic analysis assessing whether integration of genetic testing into the screening and treatment pathway is cost-effective and where/ when any cost savings could occur in the pathway. Longer-term Outputs: 1.Precise estimates of each specific PrCa variant and long-term clinical outcomes. 2.National Screening Committee adoption of targeted PrCa screening for unaffected men at higher genetic risk. 3.Report to NICE/the Royal Colleges, Prostate Cancer UK (PCUK), Cancer Research UK (CRUK) on role of targeted therapies guiding management.

Lay abstract: Prostate cancer affects 1-in-8 men in the UK and kills almost 12,000 annually. Half the cases occur due to genetic factors and patients are often concerned for it developing in family members, particularly those who decline fast due to aggressive forms. In the last two decades there has been huge progress in our knowledge of human genes. Gene testing now helps guide treatment for other cancers (e.g., breast and colon). Our research group has found gene changes that can lead to prostate cancer. This could be used to improve the chances of identifying people who may develop prostate cancer and those likely to develop more aggressive forms of the disease. We are a world-leading group of medical and health researchers with strong professional links that could shape the use of gene testing. Our programme aims to generate the evidence needed to introduce the testing into the NHS. If successful, it will lead to earlier diagnosis and more personalised treatment with the potential to save many lives. Through this research, we will offer gene testing to: (a) 1,000 men at risk of prostate cancer, and (b) 1,000 men known to have prostate cancer. We can also use gene testing data already collected from a group of 1,160 men without prostate cancer and no family history (study funded by Cancer Research UK). Comparing these three groups will allow us to check the gene test accurately identifies men s risk status. Men identified to be at risk of aggressive prostate cancer types will be offered routine screening (scans and blood tests), if they do not already have cancer. Men with a diagnosis of prostate cancer will be offered opportunities to join clinical trials of promising treatments (funded by the European Research Council). We will track all men at risk of the most aggressive types for up to 5 years to assess the impact of testing. For men identified to be at risk of cancer we will offer routine prostate cancer screening through studies funded by Prostate Cancer UK and the European Research Council. We will also collect information to assess whether gene testing offers the NHS good value for money. In addition, we will interview men to capture their experience of gene testing. This information will help us develop resources for men undergoing gene testing in the future. To ensure our gene testing can fit into routine NHS practice, we will talk to patients and the public. We will also closely consult healthcare staff. This includes those who decide healthcare spending, those who look after NHS gene testing services, and those concerned with medical training. We will also work with major charities, such as Cancer Research UK and Prostate Cancer UK

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS