TY - JOUR
T1 - Treatment time and circadian genotype interact to influence radiotherapy side-effects. A prospective European validation study using the REQUITE cohort
AU - Webb, Adam J
AU - Harper, Emily
AU - Rattay, Tim
AU - Aguado-Barrera, Miguel E
AU - Azria, David
AU - Bourgier, Celine
AU - Brengues, Muriel
AU - Briers, Erik
AU - Bultijnck, Renée
AU - Chang-Claude, Jenny
AU - Choudhury, Ananya
AU - Cicchetti, Alessandro
AU - De Ruysscher, Dirk
AU - De Santis, Maria Carmen
AU - Dunning, Alison M
AU - Elliott, Rebecca M
AU - Fachal, Laura
AU - Gómez-Caamaño, Antonio
AU - Gutiérrez-Enríquez, Sara
AU - Johnson, Kerstie
AU - Lobato-Busto, Ramón
AU - Kerns, Sarah L
AU - Post, Giselle
AU - Rancati, Tiziana
AU - Reyes, Victoria
AU - Rosenstein, Barry S
AU - Seibold, Petra
AU - Seoane, Alejandro
AU - Sosa-Fajardo, Paloma
AU - Sperk, Elena
AU - Taboada-Valladares, Begoña
AU - Valdagni, Riccardo
AU - Vega, Ana
AU - Veldeman, Liv
AU - Ward, Tim
AU - West, Catharine M
AU - Symonds, R Paul
AU - Talbot, Christopher J
AU - REQUITE consortium
N1 - Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
PY - 2022/10/1
Y1 - 2022/10/1
N2 - 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.
AB - 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.
KW - Circadian rhythm
KW - Radiotherapy
KW - Genetics
KW - Breast cancer
KW - BREAST-CANCER
KW - POLYMORPHISM
KW - SLEEP
U2 - 10.1016/j.ebiom.2022.104269
DO - 10.1016/j.ebiom.2022.104269
M3 - Article
C2 - 36130474
SN - 2352-3964
VL - 84
JO - EBioMedicine
JF - EBioMedicine
M1 - 104269
ER -