Title: Providing breast cancer risk information as part of national breast cancer screening programme: building an evidence base on benefits and harms to inform a decision to implement.
Funder: Department of Health and Social Care

Abstract: Breast cancer is the most common overall UK cancer, despite rarity in men, causing 15% of female cancer deaths. The National-Health-Service-Breast-Screening-Programme (NHSBSP) aims at early detection, but only 32% of cancers are detected by this route. It has been repeatedly argued that the NHSBSP causes considerable harms due to false positive test results, and produces comparatively few benefits in terms of lives saved. NICE have recommended that women at high-risk (&ge;8% ten-year-risk) of breast cancer should have more frequent screening by mammography and be offered chemopreventative therapy (tamoxifen or raloxifene). Our completed research, the Predicting-Risk-Of-Cancer-At-Screening study (PROCAS-1) showed it was possible to accurately estimate a woman s individual risk of developing breast cancer through self-report questions and information on breast density derived from mammography. To implement this personalised risk-stratified approach as part of the NHSBSP, women need to be aware of their own risk of breast cancer. As part of this research progamme we will define an intervention, BC-Predict, that provides women with their breast cancer risk shortly after receiving a negative NHSBSP- test result, and offer appropriate follow-up care pathways involving chemoprevention and increased frequency of mammography for moderate/high-risk women (&ge;5% ten-year-risk). Before embedding BC-Predict into the existing NHSBSP it must be evaluated to quantify the balance of benefits, harms and NHS costs. A definitive evaluation would require hundreds-of-thousands of women to have sufficient power to detect effects on breast cancer incidence and stage when detected. The present programme of work (PROCAS-2) aims to move towards a definitive study by resolving key uncertainties about the feasibility of (1)-embedding BC-Predict into the NHSBSP, and (2)-conducting a definitive evaluation study. The approach taken is in line with the MRC Framework for Developing and Evaluating Complex Interventions. PROCAS-2 has five workpackages: 1.-developing online systems that can automatically estimate breast cancer risk from questionnaires completed online and mammographic density scores, and generate appropriate letters to be sent to individual women after they receive negative screening test results. 2.-defining the precise content of the intervention (BC-Predict) by (a)-developing risk letters and leaflets that do not produce adverse effects (b)-producing care pathways that are acceptable to staff in the NHSBSP, general practice and Family History Clinics (FHC) (c)-ensuring that the overall BC-Predict package is acceptable to women, including ethnic minority and low-SES women. 3.-evaluating the effects of BC-Predict using a fully counterbalanced study design. Over a period of eight-months, women in Greater Manchester (Withington/Oldham) will be offered BC-Predict and women in East Cheshire/East Lancashire offered usual NHSBSP. In the subsequent 8-months, the study sites will then switch to offer BC-Predict or current NHSBSP. In total, n=18700 women will be offered each treatment. The primary outcome will be uptake of FHC appointments (from FHC-records) followed by additional screening and chemoprevention. A sub-sample of women (n=2152 randomly sampled) will be asked to complete surveys comprising secondary outcome measures (anxiety, future screening intentions, informed decision making, health status and capability) and questions to determine NHS resource use. Semi-strucured interviews with samples of women invited for BC-Predict and staff (from FHC, screening programme and general practice) will explore acceptability of the intervention. 4.-using trial -based and model-based economic analyses to identify the drivers of relative cost-effectiveness of embedding BC-Predict into NHSBSP by identifying the relative healthcare costs and patient benefits. This includes using a structured approach to quantify the extent of existing uncertainty and need for more research. 5.-using nominal group technique in a series of three meetings, key stakeholders (key members of National Screening Committee and NHSBSP, representatives of devolved nations, NICE, trial methodologists, commissioners of services, GPs, representatives of CCGs and FHCs, radiologists, and patient representatives) will be provided with information from WP1-4 to appraise the need for a further definitive evaluation of BC-Predict. Meeting one will assess the degree of feasibility of BC-Predict in practice and whether it produces safe and sufficient uptake to FHC and additional screening and it is plausible to be a cost-effective use of NHS resources. Assuming feasibility, meeting two will focus on how BC-Predict should best be implemented, to optimise benefits and minimise harms. Meeting three will identify the key criteria to include in a definitive evaluation study to assess whether BC-Predict is clinically effective and cost-effective when routinely implemented. This programme will (a)-precisely define BC-Predict using input from users and providers (b)-implement BC-Predict in four locations (c)-evaluate benefits in terms of uptake of FHC clinics, additional screening and chemoprevention, (d)-evaluate the potential for harm (e)-identify the likely relative cost-effectiveness and major sources of uncertainty (f)- elicit key stakeholders views on whether to implement BC-Predict and in what form, and how best to evaluate it as part of implementation. BC-Predict may realise measureable patient benefits by reducing the number of breast cancers due to chemoprevention, and mortality by mammography detecting more breast cancers, and at an earlier stage.

Lay abstract: Background: The National Institute for Health and Care Excellence (NICE) recently stated that women at high-risk of breast cancer should have more frequent breast mammography (x-ray) screening and be offered risk-reducing treatment with the medicines tamoxifen or raloxifene. However, high risk women in the breast screening programme cannot be offered prevention drugs or extra screening as the screening programme does not currently estimate or inform women of their risk. We have completed the Predicting-Risk-Of-Cancer-At-Screening (PROCAS-1) study where, at the time of screening, women s individual risk of developing breast cancer was estimated from a questionnaire about key risk factors (such as lifestyle and family history of cancer, among other questions) and by estimating their breast density (the amount of tissue in the breast that is not fat) from their mammogram. We showed that the most accurate predictions of breast cancer risk are obtained from using the total information collected. In PROCAS-1 over 94% of 58,000 women wished to know their personal risk of breast cancer. Aim: In the study outlined here (PROCAS-2) we wish to examine the effects on women receiving their 10-year breast cancer risk (if they choose to receive it) when they go for breast screening. Method: To do this, considerable work is needed: 1.Automation (via computers) of risk estimation and generation of feedback letters (called BC-Predict ); 2.Discover the best way to give risk information to women; 3.Evaluate benefits and harms of this approach for women; 4.Identify whether adding BC-Predict to the NHSBSP is good value for money. A major part of this research will involve comparisons of women in four sites (East Cheshire/East Lancashire/Oldham/Withington). Women allocated to BC-Predict will attend breast screening as normal, but also complete an online questionnaire, and receive risk information within six weeks of their appointment. Justification: Using the NHSBSP to give risk information may help women at high-risk by increasing uptake of additional breast screening, thereby detecting breast cancers earlier, at a more treatable stage. It may also encourage high-risk women to consider taking a drug for prevention of breast cancer or make changes in their lifestyle, thereby preventing many breast cancers. By contrast, it may increase anxiety, be unacceptable, or costly. Towards the end of PROCAS-2, meetings with key people from NHSBSP, researchers and patient representatives will make decisions on (a) whether estimated benefits are seen as outweighing estimated harms, (b) how best to implement if benefits outweigh harms, and (c) decide on the design of a study to definitively answer whether implementing BC-Predict within NHSBSP results in fewer breast cancers, and cancers being detected at an earlier stage, at an acceptable level of cost. If successful, this study may help women nationally and in other countries where breast screening is used.

Research activity codes: 4.3 INFLUENCES AND IMPACT
Health categories: CANCER AND NEOPLASMS