Title: Risk-adapted breast radiotherapy
Funder: Department of Health and Social Care

Abstract: Can we: Identify very low risk patients who can safely avoid breast radiotherapy? Exploit physical aspects of radiotherapy to optimise local control/survival with minimal toxicity? Investigate breast radiotherapy pre-surgery to (a) potentially reduce mastectomy/complex surgery (b) improve understanding of radio-resistance/immune modulation and optimise radiation-novel drug combinations? Investigate molecular and spatial patterns of local relapse to optimise patient selection for 'risk-adapted' breast radiotherapy?Background Breast cancer is very common and represents 30% of radiotherapy given. Systemic therapy has evolved to treat distinct molecular subtypes that have very different relapse risks. Radiotherapy has been a 'one size fits all' approach and appropriate patient selection for new techniques based on risk of relapse is needed . Aim Provide breast cancer patients with best chance of cure and least side effects, by linking cutting-edge radiotherapy with world-class breast cancer science to optimise 'risk-adapted' radiotherapy. Methods 1. Can we identify very low risk patients who can safely avoid breast radiotherapy? PRIMETIME, n=2400: Prospective cohort design, biomarker-directed radiotherapy Primary endpoint - ipsilateral local relapse risk at 5 years Planned meta-analysis: Canadian and Australian related studies2. Can we exploit physical aspects of radiotherapy to optimise local control/survival with minimal toxicity? IMPORT HIGH, n=2600: Randomised controlled trial investigating dose-escalated simultaneous integrated boost Primary endpoint - ipsilateral local relapse risk at 5 yearsBreast PBT, n=65: Randomised feasibility study, 2:1 PBT versus optimised photon radiotherapy Primary endpoint - willingness of randomisation Planned meta-analysis: Danish Breast Cancer Group feasibility study3. Can we Investigate breast radiotherapy pre-surgery?Neo-RT, n=43: Single arm feasibility study - pre-operative radiotherapy in patients with borderline conservable breast cancer Primary endpoint -h; feasibility to complete therapy as per protocol Embedded translational study4. Can we investigate molecular and spatial patterns of local relapse to optimise patient selection for 'risk-adapted' breast radiotherapy? IMPORT LOW Clonality, N= 43 paired samples Translational study - shallow whole genome sequencing, targeted deep sequencing of gene panel, RNA profiling Primary endpoint -h; molecular clonality between original tumour and ipsilateral relapse/contralateral new primaryTimelinesWithin 5 years: Complete recruitment for PRIMETIME Publish: 3-year toxicity and 5-year results IMPORT HIGH Feasibility and translational results for Neo-RT IMPORT LOW Clonality Obtain funding and deliver Breast PBT feasibility >5 years: Publish: Primary endpoint results for PRIMETIME and international meta-analysis Breast PBT feasibility study and meta-analysis Develop: International Breast PBT Follow-on Neo-RT study Follow-on IMPORT HIGH clonality study and translational biology PRIMETIME study Anticipated impact and dissemination Likely internationally practice changing: Safe reduction of breast boost radiotherapy to 3 weeks for patients at high risk of relapse Biomarker-directed safe avoidance of breast radiotherapy for patients at very low risk of relapsePotential patient benefits: Avoidance of mastectomy/complex breast conservation following pre-operative radiotherapy Improved target coverage/reduced normal tissue dose with breast PBT Development of radiotherapy-novel drug combinations Optimised selection of risk-adapted breast radiotherapy using molecular classificationPotential benefit for NHS/international health care systems: Low-cost biomarker for safe avoidance of radiotherapy Reduction in/avoidance of radiotherapy Identifying patients likely to benefit from PBT and determining cost utility

Lay abstract: What is the problem? Breast cancer is the commonest cancer in women in the UK and around 55,000 people are diagnosed each year. Breast radiotherapy is important as it reduces the risk of the cancer coming back and can improve survival. Around two-thirds of people with breast cancer have radiotherapy. Breast radiotherapy can cause some side effects, but most are mild and do not last. However, around 30 in 100 women have a change in breast appearance and some notice breast shrinkage, firmness or tenderness. These changes can be permanent and may cause psychological distress. There are also rare, but serious side effects. These include heart damage and new cancers that may not be cured easily. Research shows that breast cancer is made up of several different subtypes, which have different risks of the cancer coming back (recurrence). Different cancer drugs that can be given to different breast cancer subtypes, however, breast radiotherapy tends to be similar even if women have very different risks of recurrence. What is the aim of this research? This research aims to adapt breast radiotherapy according to a patient's risk of recurrence so she has the best chance of cure with least side effects. How will we carry out this research? This research is divided into different parts: 1. Safe avoidance of breast radiotherapy for very low risk-breast cancer We want to find out if there are a group of patients who can avoid radiotherapy completely as the chance of recurrence is very low and risks may outweigh benefits We will use a new research calculation (called IHC4+C) that estimates risk of recurrence2. Radiotherapy for higher-risk breast cancer We will test: Intensity modulated radiotherapy (IMRT) that gives a higher radiotherapy boost to part of the breast where risk of recurrence is highest and lower doses elsewhere If proton beam therapy is safe and acceptable for women at very high-risk of recurrence3. Giving radiotherapy before surgery We will: Test if giving radiotherapy before surgery is feasible Explore how radiotherapy affects the cancer directly and the immune system4. Defining types of recurrence following radiotherapy We will test if recurrences are related to the original cancer (true recurrences) or completely different (new cancers) by comparing their geneticsPossible benefit for patients and NHS Women at very low-risk of recurrence may safely avoid radiotherapy and its side effects Less radiotherapy saves the NHS money that can be spent on other patients Tailored IMRT could reduce breast recurrence, side effects and radiotherapy visits, benefiting patients and NHS We will find out which group of patients may benefit from proton beam therapy and test this further Giving radiotherapy before surgery may shrink the cancer so surgery is less extensive and we will test this further Understanding direct effects of radiotherapy could help us combine radiotherapy with new drugs for very high-risk cancer Understanding whether breast cancer recurrences are related genetically or not could help us select the best radiotherapy techniques for future patientsHow will patients and public be involved? Patients are at the centre of this research: our patients advocates have advised us from the start on: Research questions they feel are important Whether they feel comfortable with the study design and treatmentsPatient advocates have led design of clear patient information and will continue to work with us throughout the lifetime of this research. How will the results be communicated? The results will be presented at national and international medical conferences and published in high quality medical journals. We will work with our patient advocates to produce lay summaries that are available for the general public.

Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS