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@ARTICLE{Webb:181851,
      author       = {A. J. Webb and E. Harper and T. Rattay and M. E.
                      Aguado-Barrera and D. Azria and C. Bourgier and M. Brengues
                      and E. Briers and R. Bultijnck and J. Chang-Claude$^*$ and
                      A. Choudhury and A. Cicchetti and D. De Ruysscher and M. C.
                      De Santis and A. M. Dunning and R. M. Elliott and L. Fachal
                      and A. Gómez-Caamaño and S. Gutiérrez-Enríquez and K.
                      Johnson and R. Lobato-Busto and S. L. Kerns and G. Post and
                      T. Rancati and V. Reyes and B. S. Rosenstein and P.
                      Seibold$^*$ and A. Seoane and P. Sosa-Fajardo and E. Sperk
                      and B. Taboada-Valladares and R. Valdagni and A. Vega and L.
                      Veldeman and T. Ward and C. M. West and R. P. Symonds and C.
                      J. Talbot},
      collaboration = {R. Consortium},
      title        = {{T}reatment time and circadian genotype interact to
                      influence radiotherapy side-effects. {A} prospective
                      {E}uropean validation study using the {REQUITE} cohort.},
      journal      = {EBioMedicine},
      volume       = {84},
      issn         = {2352-3964},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2022-02266},
      pages        = {104269},
      year         = {2022},
      abstract     = {Circadian rhythm impacts broad biological processes,
                      including response to cancer treatment. Evidence 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.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.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.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 clinical trials could
                      stratify patients treated at optimal times compared to those
                      scheduled normally.EU-FP7.},
      keywords     = {Breast cancer (Other) / Circadian rhythm (Other) / Genetics
                      (Other) / Radiotherapy (Other)},
      cin          = {C020},
      ddc          = {610},
      cid          = {I:(DE-He78)C020-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36130474},
      pmc          = {pmc:PMC9486558},
      doi          = {10.1016/j.ebiom.2022.104269},
      url          = {https://inrepo02.dkfz.de/record/181851},
}