Title: Improvement in risk prediction, early detection and prevention of breast cancer
Funder: Department of Health (England)

Abstract: Aims: The overarching aims of the programme are to improve methods for prediction of risk of breast cancer (BC) in order to develop risk adapted mammographic screening and targeted preventive strategies. We aim to improve the precision of prediction of BC risk in women in the NHS Breast Screening Programme (BSP) and women with a family history by combining risk factors into existing programmes and investigating new genetic modifiers of risk. We will assess the viability of two main preventive interventions based on risk assessment a) to assess the uptake of chemoprevention (tamoxifen, anastrazole) b) to assess lifestyle interventions, their uptake and behaviour modification. We will also assess the viability of reducing or increasing screening intervals in the BSPbased on risk algorithms Background: BC is diagnosed in 44,000 and causes 12,000 deaths per year in the U.K. Although BC deaths have decreased in many Western countries, the incidence of the disease is continuing to rise. In particular, countries with historically low incidence, BC rates are rising rapidly making it the world’s most prevalent cancer. The increase in incidence is almost certainly related to dietary and reproductive patterns associated with Western lifestyles. Indeed there is evidence from genetic studies in the US, Iceland and UK of a 3-fold increased incidence in the general population and also in those at the highest level of risk with BRCA1/2 mutations in the past 80 years. Understandably there is increasing interest in disease prevention to spare women the trauma of diagnosis and increasingly aggressive treatment. There is a need, not only to predict which women will develop the disease, but also to apply drug and lifestyle measures in order to prevent the disease. Current risk prediction models based on combinations of risk factors have good overall predictive power, but are still weak at predicting which particular women will develop the disease (discriminatory power) Research plan:New risk prediction methods will be developed from examination of a range of SNPs for high-risk as well as those associated with lower risks. This will be married in a prediction program with other known risk factors to provide greatly improve discriminatory power and the accuracy of individual risk prediction. We will include information on mammographic density which is not yet part of a risk prediction model despite being a greater risk factor than most factors currently included. Risk assessment of women in the BSP will determine appropriate screening intervals or if they are at sufficient risk for BSP screening with huge potential savings to the NHS from more focussed use of resources. We anticipate the development of highly predictive algorithms for risk prediction within 5 years and to have developed validated prevention programmes appropriately targeted at risk. Research team: The team brings together a senior NHS clinician with a track record of innovation and delivery of health service research for patient benefit with experts in breast screening, radiology, biostatistics, health economics, delivery and evaluation of diet and exercise interventions, quality of life, NHS service management and women at risk. We have previously successfully completed and published studies which have altered practice nationally. The team has over 1,000 peer reviewed publications (PI >300) and more than £21m of peer reviewed grants currently active. Our multidisciplinary team allows us to focus on several key aspects of breast cancer risk assessment and prevention. Environment: Largest FHC and screening population. The programme is based in a new £12m BC treatment and prevention centre at the University Hospital of South Manchester and builds on development work from ouselves. Dissemination to the network will be through our links to Greater Manchester NCRN and BSP. Outputs:Circulation of patient groups will enable dissemination of results into the patient population. We will use the highly effective communication network within the BSP and publication. Public involvement: Consumer involvement across several groups of women at risk has been fundamental to the development of the research questions. The programme includes public fora/focus groups to inform output and for dissemination. Ethical implications: Ethics approval is being sought for the two intervention studies in project 3/4. This is already in place for project 1/2. Justification of resources: We require personnel for data collection and analysis. Individual researchers are necessary to run the different projects and we need an overall co-ordinator. Large scale statistical support is also necessary with a genetic epidemiologist and staistician based between London and Manchester


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS