Personalised prevention of breast cancer in people at moderate or high risk– a new approach to optimising prevention in primary care.

Background: Individuals at moderate-to-high-risk of breast cancer may benefit from preventive interventions such as anti-oestrogen medication or risk-reducing surgery (for those at highest-risk), as recommended by NICE guidelines. However, uptake and adherence to these interventions are often limited by sociodemographic (e.g., age, gender, ethnicity, deprivation, geography) and clinical factors (e.g., side effects, menopause, exogeneous hormones, comorbidities). Concerns about treatment safety, including risks of thrombosis, endometrial cancer, and osteoporosis, further impact decisions. Real-world data (outside of clinical trial settings) on the use and benefits versus harms of these treatments are limited. Additionally, existing decision aids present only illustrative values of breast cancer risk, without consideration for individualised benefit-harm assessments. This highlights an important unmet need for comprehensive tools to support informed decision-making about starting and continuing preventive breast cancer treatments. Aims: This study aims to determine the uptake, adherence, benefits, safety, and cost-effectiveness of pharmacological (tamoxifen, aromatase inhibitors, raloxifene) and surgical interventions to prevent breast cancer, and develop an interactive clinical decision system (CDS) incorporating individualised risk estimates for breast cancer and potential benefits and adverse effects of each treatment, to deliver a personalised approach to decision-making. Methods: We will analyse large healthcare databases representative of the diverse UK population, which contain anonymised, long-term records for millions of individuals (England: QResearch; Wales: SAIL Databank; Scotland: DataLoch; Northern Ireland: Electronic Prescribing Dataset), including GP records (with risk factors, prescriptions, referrals, diagnoses, demographics) linked to hospital, cancer, and mortality registries. Cohorts will include breast cancer-free individuals aged 25-84 years, at moderate-to-high-risk of breast cancer (defined by genetic susceptibility or ≥3% 10-year risk estimated using a risk tool), without prior preventive treatments, who enter the study between 01-Jan-2004 and 31-Dec-2025. For anti-oestrogens and risk-reducing surgery, we will: 1) Describe uptake and discontinuation of treatments, identifying associated sociodemographic and clinical factors; 2) Quantify the potential benefits and adverse effects of each treatment, overall and stratified by sociodemographic and clinical factors; 3) Evaluate cost-effectiveness of these treatments. Results will be pooled across national cohorts, where appropriate. We will complement quantitative analyses with qualitative interviews of patients and clinicians to understand barriers, facilitators, and preferences for decision-making support. Insights gained will inform the development of patient-facing materials, decision aids and the CDS. An important part of this research is patient and public involvement and engagement, which will help shape the design of studies and PhD/DPhil projects, and the co-design and co-production of patient-facing materials and decision aids. Results and Dissemination: This programme of research will stratify analyses by sociodemographic characteristics to ensure generalisability of findings and identify potential disparities. Outputs will include evidence-based decision aids, interactive calculators, patient-facing materials, and policy-relevant knowledge. Findings will be disseminated via medical journals, websites, infographics, and podcasts, as well as through partnerships with patient advocacy and community groups, to influence policy and practice. Impact: This work will address critical knowledge gaps in breast cancer prevention, improve personalised decision-making, and advance policy around equity of care. Developed tools and methodologies will have potential applications for other conditions requiring