Breast cancer patients currently receive a one-size-fits-all course of radiotherapy, regardless of their individual risk of relapse. This programme of five linked studies aims to tailor radiotherapy to each patient's molecular profile and tumour biology. The problem is that breast cancer is the most common cancer, accounting for 30% of all radiotherapy delivered in the UK. Systemic treatments are already matched to molecular subtypes, but radiotherapy has not kept pace. This means some patients receive unnecessary radiation—and its side effects—while others may not get enough. If successful, the research could change clinical practice in three concrete ways. A biomarker test could identify very low-risk patients who can safely skip radiotherapy entirely, saving them from side effects and reducing NHS treatment costs. For high-risk patients, a three-week course of dose-escalated radiotherapy could improve local control. Pre-operative radiotherapy might allow some women to avoid mastectomy or complex breast-conserving surgery. The studies also investigate proton beam therapy to spare healthy tissue, and molecular analysis of relapsed tumours to refine patient selection for future risk-adapted treatments.
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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 studies 2. 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 years Breast 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 study 3. 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 - feasibility to complete therapy as per protocol Embedded translational study 4. 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 - molecular clonality between original tumour and ipsilateral relapse/contralateral new primary Timelines Within 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 relapse Potential 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 classification Potential 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
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