University of Leicester
Browse
Treatment time and circadian genotype.pdf (1.41 MB)

Treatment time and circadian genotype interact to influence radiotherapy side-effects. A prospective European validation study using the REQUITE cohort

Download (1.41 MB)
journal contribution
posted on 2022-11-08, 14:40 authored by AJ Webb, E Harper, T Rattay, ME Aguado-Barrera, D Azria, C Bourgier, M Brengues, E Briers, R Bultijnck, J Chang-Claude, A Choudhury, A Cicchetti, D De Ruysscher, MC De Santis, AM Dunning, RM Elliott, L Fachal, A Gómez-Caamaño, S Gutiérrez-Enríquez, K Johnson, R Lobato-Busto, SL Kerns, G Post, T Rancati, V Reyes, BS Rosenstein, P Seibold, A Seoane, P Sosa-Fajardo, E Sperk, B Taboada-Valladares, R Valdagni, A Vega, L Veldeman, T Ward, CM West, RP Symonds, CJ Talbot
Background: 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. 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 clinical trials could stratify patients treated at optimal times compared to those scheduled normally. Funding: EU-FP7.

History

Author affiliation

Department of Genetics and Genome Biology, University of Leicester

Version

  • VoR (Version of Record)

Published in

eBioMedicine

Volume

84

Pagination

104269

Publisher

Elsevier BV

issn

2352-3964

eissn

2352-3964

Copyright date

2022

Available date

2022-11-08

Spatial coverage

Netherlands

Language

eng

Usage metrics

    University of Leicester Publications

    Categories

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC