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000181851 0247_ $$2doi$$a10.1016/j.ebiom.2022.104269
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000181851 041__ $$aEnglish
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000181851 1001_ $$aWebb, Adam J$$b0
000181851 245__ $$aTreatment time and circadian genotype interact to influence radiotherapy side-effects. A prospective European validation study using the REQUITE cohort.
000181851 260__ $$aAmsterdam [u.a.]$$bElsevier$$c2022
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000181851 520__ $$aCircadian 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.
000181851 536__ $$0G:(DE-HGF)POF4-313$$a313 - Krebsrisikofaktoren und Prävention (POF4-313)$$cPOF4-313$$fPOF IV$$x0
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000181851 650_7 $$2Other$$aBreast cancer
000181851 650_7 $$2Other$$aCircadian rhythm
000181851 650_7 $$2Other$$aGenetics
000181851 650_7 $$2Other$$aRadiotherapy
000181851 7001_ $$aHarper, Emily$$b1
000181851 7001_ $$aRattay, Tim$$b2
000181851 7001_ $$aAguado-Barrera, Miguel E$$b3
000181851 7001_ $$aAzria, David$$b4
000181851 7001_ $$aBourgier, Celine$$b5
000181851 7001_ $$aBrengues, Muriel$$b6
000181851 7001_ $$aBriers, Erik$$b7
000181851 7001_ $$aBultijnck, Renée$$b8
000181851 7001_ $$0P:(DE-He78)c259d6cc99edf5c7bc7ce22c7f87c253$$aChang-Claude, Jenny$$b9$$udkfz
000181851 7001_ $$aChoudhury, Ananya$$b10
000181851 7001_ $$aCicchetti, Alessandro$$b11
000181851 7001_ $$aDe Ruysscher, Dirk$$b12
000181851 7001_ $$aDe Santis, Maria Carmen$$b13
000181851 7001_ $$aDunning, Alison M$$b14
000181851 7001_ $$aElliott, Rebecca M$$b15
000181851 7001_ $$aFachal, Laura$$b16
000181851 7001_ $$aGómez-Caamaño, Antonio$$b17
000181851 7001_ $$aGutiérrez-Enríquez, Sara$$b18
000181851 7001_ $$aJohnson, Kerstie$$b19
000181851 7001_ $$aLobato-Busto, Ramón$$b20
000181851 7001_ $$aKerns, Sarah L$$b21
000181851 7001_ $$aPost, Giselle$$b22
000181851 7001_ $$aRancati, Tiziana$$b23
000181851 7001_ $$aReyes, Victoria$$b24
000181851 7001_ $$aRosenstein, Barry S$$b25
000181851 7001_ $$0P:(DE-He78)fd17a8dbf8d08ea5bb656dfef7398215$$aSeibold, Petra$$b26$$udkfz
000181851 7001_ $$aSeoane, Alejandro$$b27
000181851 7001_ $$aSosa-Fajardo, Paloma$$b28
000181851 7001_ $$aSperk, Elena$$b29
000181851 7001_ $$aTaboada-Valladares, Begoña$$b30
000181851 7001_ $$aValdagni, Riccardo$$b31
000181851 7001_ $$aVega, Ana$$b32
000181851 7001_ $$aVeldeman, Liv$$b33
000181851 7001_ $$aWard, Tim$$b34
000181851 7001_ $$aWest, Catharine M$$b35
000181851 7001_ $$aSymonds, R Paul$$b36
000181851 7001_ $$aTalbot, Christopher J$$b37
000181851 7001_ $$aConsortium, REQUITE$$b38$$eCollaboration Author
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