@article{01GSA3GMDASYVE2XAHCDZ94AMD,
  abstract     = {{Background Circadian rhythm impacts broad biological processes, including response to cancer treatment. Evi-dence conflicts on whether treatment time affects risk of radiotherapy side-effects, likely because of differing time analyses and target tissues. We previously showed interactive effects of time and genotypes of circadian genes on late toxicity after breast radiotherapy and aimed to validate those results in a multi-centre cohort.Methods Clinical and genotype data from 1690 REQUITE breast cancer patients were used with erythema (acute; n=340) and breast atrophy (two years post-radiotherapy; n=514) as primary endpoints. Local datetimes per fraction were converted into solar times as predictors. Genetic chronotype markers were included in logistic regressions to identify primary endpoint predictors.Findings Significant predictors for erythema included BMI, radiation dose and PER3 genotype (OR 1.27(95%CI 1.03-1.56); P < 0.03). Effect of treatment time effect on acute toxicity was inconclusive, with no interaction between time and genotype. For late toxicity (breast atrophy), predictors included BMI, radiation dose, surgery type, treatment time and SNPs in CLOCK (OR 0.62 (95%CI 0.4-0.9); P < 0.01), PER3 (OR 0.65 (95%CI 0.44-0.97); P < 0.04) and RASD1 (OR 0.56 (95%CI 0.35-0.89); P < 0.02). There was a statistically significant interaction between time and genotypes of circadian rhythm genes (CLOCK OR 1.13 (95%CI 1.03-1.23), P < 0.01; PER3 OR 1.1 (95%CI 1.01-1.2), P < 0.04; RASD1 OR 1.15 (95%CI 1.04-1.28), P < 0.008), with peak time for toxicity determined by genotype.Interpretation Late atrophy can be mitigated by selecting optimal treatment time according to circadian genotypes (e.g. treat PER3 rs2087947C/C genotypes in mornings; T/T in afternoons). We predict triple-homozygous patients (14%) reduce chance of atrophy from 70% to 33% by treating in mornings as opposed to mid-afternoon. Future clini-cal trials could stratify patients treated at optimal times compared to those scheduled normally.Funding EU-FP7.Copyright (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)}},
  articleno    = {{104269}},
  author       = {{Webb, Adam J. and Harper, Emily and Rattay, Tim and Aguado-Barrera, Miguel E. and Azria, David and Bourgier, Celine and Brengues, Muriel and Briers, Erik and Bultijnck, Renée and Chang-Claude, Jenny and Choudhury, Ananya and Cicchetti, Alessandro and De Ruysscher, Dirk and De Santis, Maria Carmen and Dunning, Alison M. and Elliott, Rebecca M. and Fachal, Laura and Gómez-Caamaño, Antonio and Gutiérrez-Enríquez, Sara and Johnson, Kerstie and Lobato-Busto, Ramón and Kerns, Sarah L. and Post, Giselle and Rancati, Tiziana and Reyes, Victoria and Rosenstein, Barry S. and Seibold, Petra and Seoane, Alejandro and Sosa-Fajardo, Paloma and Sperk, Elena and Taboada-Valladares, Begoña and Valdagni, Riccardo and Vega, Ana and Veldeman, Liv and Ward, Tim and West, Catharine M. and Symonds, R. Paul and Talbot, Christopher J.}},
  issn         = {{2352-3964}},
  journal      = {{EBIOMEDICINE}},
  keywords     = {{General Biochemistry, Genetics and Molecular Biology,General Medicine}},
  language     = {{eng}},
  pages        = {{16}},
  publisher    = {{Elsevier BV}},
  title        = {{Treatment time and circadian genotype interact to influence radiotherapy side-effects : a prospective European validation study using the REQUITE cohort}},
  url          = {{http://doi.org/10.1016/j.ebiom.2022.104269}},
  volume       = {{84}},
  year         = {{2022}},
}

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