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Novel systemic therapies for breast cancer are being rapidly implemented into clinical practice. These drugs often have different mechanisms of action and side-effect profiles compared with traditional chemotherapy. Underpinning practice-changing clinical trials focused on the systemic therapies under investigation, thus there are sparse data available on radiotherapy. Integration of these new systemic therapies with radiotherapy is therefore challenging. Given this rapid, transformative change in breast cancer multimodal management, the multidisciplinary community must unite to ensure optimal, safe, and equitable treatment for all patients. The aim of this collaborative group of radiation, clinical, and medical oncologists, basic and translational scientists, and patient advocates was to: scope, synthesise, and summarise the literature on integrating novel drugs with radiotherapy for breast cancer; produce consensus statements on drug-radiotherapy integration, where specific evidence is lacking; and make best-practice recommendations for recording of radiotherapy data and quality assurance for subsequent studies testing novel drugs., Competing Interests: Declaration of interests IMe declares participation in advisory boards supported by Eli Lilly, Novartis, Pfizer, Pierre Fabre, SeaGen, Daiichi Sankyo, and AstraZeneca. CB declares honoraria from Eli Lilly, and participation in advisory boards supported by Eli Lilly, Novartis, Pfizer, and Amgen. ML received honoraria from or participated in advisory boards for Roche, Novartis, Eli Lilly, Pfizer, AstraZeneca, Daiichi Sankyo, Gilead, SeaGen, Merck Sharp and Dohme, Exact Sciences, Takeda, Ipsen, Sandoz, Libbs, and Knight; received a travel grant from Gilead; and received research support for their institution from Gilead. EdA declares honoraria from or participation in advisory boards for Roche, Genentech, Novartis, SeaGen, Zodiac, Libbs, Pierre Fabre, Eli Lilly, and AstraZeneca. JC declares consulting or advisor roles supported by Roche, Celgene, Cellestia, AstraZeneca, SeaGen, Daiichi Sankyo, Erytech, Athenex, Polyphor, Eli Lilly, Merck Sharp and Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, and Expres2ion Biotechnologies. NH declares honoraria for lectures or consulting from AstraZeneca, Daiichi Sankyo, Gilead, Eli Lilly, Merck Sharp and Dohme, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi, Sandoz, and SeaGen. HSR declares institutional research support from Astellas Pharma, AstraZeneca, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, Gilead Sciences, GSK, Eli Lilly, Merck & Co, Novartis Pharmaceuticals Corporation, OBI Pharma, Pfizer, Pionyr Immunotherapeutics, Sermonix Pharmaceuticals, Taiho Oncology, and Veru. GC reports personal fees for consulting, advisory roles, and speakers’ bureau from Roche, Genentech, Novartis, Pfizer, Eli Lilly, Foundation Medicine, Samsung, and Daiichi Sankyo; honoraria from Ellipses Pharma; and fees for travel and accommodations from Roche, Genentech, and Pfizer. LV declares participation in advisory boards from Daiichi Sankyo and Pfizer. ME declares participation in advisory boards supported by Pfizer and Novartis, and lecture fees supported by AstraZeneca. TS declares participation in advisory boards supported by Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, and Pierre Fabre; and lecture fees supported by Astellas, AstraZeneca, and Bristol Myers Squibb. GM declares consultancy honoraria from Roche, Novartis, AstraZeneca, Pfizer, Jensen, Eli Lilly, and Sanofi. LDM declares consulting fees from Roche, Novartis, Eli Lilly, Merck Sharp and Dohme, Daiichi Sankyo, SeaGen, Gilead, Eisai, Pierre Fabre, AstraZeneca, Stemline Menarini, Exact Sciences, Agendia, GSK, and Pfizer. MM declares consulting fees from Cedilla Therapeutics and PharmEnable, and research support from PharmaMar, Eli Lilly, Pfizer, and Circle Pharma. SP-S declares consulting fees from Pfizer, Novartis, Eli Lilly, AstraZeneca, Gilead, Merck, Sharp and Dohme, and Roche. BP declares consulting fees from Astra Zeneca, SeaGen, Gilead, Eli Lilly, Merck Sharp and Dohme, Daiichi Sankyo, and Pierre Fabre. CS declares consulting fees from AstraZeneca, Daiichi Sankyo, Eisai Europe, Gilead, Novartis, Pharmalex, Pfizer, Phillips Health Works, Pierre Fabre, PintPharma, Puma Biotechnology, Roche Farma, SeaGen, Solti, Synthon Biopharmaceuticals, and Zymeworks. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: IM is a Chief Investigator of the Florence APBI-IMRT phase 3 trial, member of the American Society for Radiation Oncology (ASTRO) taskforce for accelerated partial breast irradiation (APBI) guidelines update, member of the Independent Data Monitoring Committee (IDMC) for PARAPBLE Proton Beam Therapy trial, and received honoraria for advisory role from Eli Lilly, Novartis, Pfizer, Accuray, Seagen, and Gilead outside the submitted work. CEC is a Chief Investigator of the IMPORT Low PBI trial, a member of ASTRO taskforce for APBI guidelines update, member of the writing committee for EBCTCG PBI meta-analysis, Chair of the IDMC for UK PivotalBoost trial, member of the IDMC for TORPEdO Proton Beam Therapy trial, member of the IDMC for European HYPO-G01 breast fractionation trial, member of the IDMC for the UK NIMRAD trial, and member of the International Scientific Advisory Board, Institute Curie; and reports grants to their institution from Radiation Research Network Project Seed Funding Award (MIGRATES), Addenbrooke's Charitable Trust, Lancet Breast Cancer Commission, EME Project: NIHR131120–PARABLE, Radiation Research Network Project Seed Funding Award, NIHR Research Professorship, and Cancer Research UK Radiation Research Unit at the University of Cambridge; outside the submitted work. The views expressed are those of the author and not necessarily those of the NIHR or the Department of Health and Social Care.

High-quality randomised clinical trials testing moderately fractionated breast radiotherapy have clearly shown that local control and survival is at least as effective as with 2 Gy daily fractions with similar or reduced normal tissue toxicity. Fewer treatment visits are welcomed by patients and their families, and reduced fractions produce substantial savings for health-care systems. Implementation of hypofractionation, however, has moved at a slow pace. The oncology community have now reached an inflection point created by new evidence from the FAST-Forward five-fraction randomised trial and catalysed by the need for the global radiation oncology community to unite during the COVID-19 pandemic and rapidly rethink hypofractionation implementation. The aim of this paper is to support equity of access for all patients to receive evidence-based breast external beam radiotherapy and to facilitate the translation of new evidence into routine daily practice. The results from this European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice consensus state that moderately hypofractionated radiotherapy can be offered to any patient for whole breast, chest wall (with or without reconstruction), and nodal volumes. Ultrafractionation (five fractions) can also be offered for non-nodal breast or chest wall (without reconstruction) radiotherapy either as standard of care or within a randomised trial or prospective cohort. The consensus is timely; not only is it a pragmatic framework for radiation oncologists, but it provides a measured proposal for the path forward to influence policy makers and empower patients to ensure equity of access to evidence-based radiotherapy., Competing Interests: Declaration of interests IM received a small fee for occasional attendance at the advisory board supported by Eli Lilly, Novartis, Istituto Gentili, Roche, Pfizer, Ipsen, and Pierre Fabre. MCA received a grant from the Cancer Research UK. ClB declares honoraria from C-RAD and Elekta. PP is a medical adviser of Sordina IORT Technologies. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Several studies have reported associations between radiation toxicity and single nucleotide polymorphisms (SNPs) in candidate genes. Few associations have been tested in independent validation studies. This prospective study aimed to validate reported associations between genotype and radiation toxicity in a large independent dataset., Methods: 92 (of 98 attempted) SNPs in 46 genes were successfully genotyped in 1613 patients: 976 received adjuvant breast radiotherapy in the Cambridge breast IMRT trial (ISRCTN21474421, n=942) or in a prospective study of breast toxicity at the Christie Hospital, Manchester, UK (n=34). A further 637 received radical prostate radiotherapy in the MRC RT01 multicentre trial (ISRCTN47772397, n=224) or in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer (CHHiP) trial (ISRCTN97182923, n=413). Late toxicity was assessed 2 years after radiotherapy with a validated photographic technique (patients with breast cancer only), clinical assessment, and patient questionnaires. Association tests of genotype with overall radiation toxicity score and individual endpoints were undertaken in univariate and multivariable analyses. At a type I error rate adjusted for multiple testing, this study had 99% power to detect a SNP, with minor allele frequency of 0·35, associated with a per allele odds ratio of 2·2., Findings: None of the previously reported associations were confirmed by this study, after adjustment for multiple comparisons. The p value distribution of the SNPs tested against overall toxicity score was not different from that expected by chance., Interpretation: We did not replicate previously reported late toxicity associations, suggesting that we can essentially exclude the hypothesis that published SNPs individually exert a clinically relevant effect. Continued recruitment of patients into studies within the Radiogenomics Consortium is essential so that sufficiently powered studies can be done and methodological challenges addressed., Funding: Cancer Research UK, The Royal College of Radiologists, Addenbrooke's Charitable Trust, Breast Cancer Campaign, Cambridge National Institute of Health Research (NIHR) Biomedical Research Centre, Experimental Cancer Medicine Centre, East Midlands Innovation, the National Cancer Institute, Joseph Mitchell Trust, Royal Marsden NHS Foundation Trust, Institute of Cancer Research NIHR Biomedical Research Centre for Cancer., (Copyright © 2012 Elsevier Ltd. All rights reserved.)