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

Adam J Webb; Emily Harper; Tim Rattay; Miguel E Aguado-Barrera; David Azria; Celine Bourgier; Muriel Brengues; Erik Briers; Renée Bultijnck; Jenny Chang-Claude; Ananya Choudhury; Alessandro Cicchetti; Dirk De Ruysscher; Maria Carmen De Santis; Alison M Dunning; Rebecca M Elliott; Laura Fachal; Antonio Gómez-Caamaño; Sara Gutiérrez-Enríquez; Kerstie Johnson; Ramón Lobato-Busto; Sarah L Kerns; Giselle Post; Tiziana Rancati; Victoria Reyes; Barry S Rosenstein; Petra Seibold; Alejandro Seoane; Paloma Sosa-Fajardo; Elena Sperk; Begoña Taboada-Valladares; Riccardo Valdagni; Ana Vega; Liv Veldeman; Tim Ward; Catharine M West; R Paul Symonds; Christopher J Talbot; REQUITE consortium

doi:10.1016/j.ebiom.2022.104269

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

Adam J Webb, Emily Harper, Tim Rattay, Miguel E Aguado-Barrera, David Azria, Celine Bourgier, Muriel Brengues, Erik Briers, Renée Bultijnck, Jenny Chang-Claude, Ananya Choudhury, Alessandro Cicchetti, Dirk De Ruysscher, Maria Carmen De Santis, Alison M Dunning, Rebecca M Elliott, Laura Fachal, Antonio Gómez-Caamaño, Sara Gutiérrez-Enríquez, Kerstie JohnsonRamón Lobato-Busto, Sarah L Kerns, Giselle Post, Tiziana Rancati, Victoria Reyes, Barry S Rosenstein, Petra Seibold, Alejandro Seoane, Paloma Sosa-Fajardo, Elena Sperk, Begoña Taboada-Valladares, Riccardo Valdagni, Ana Vega, Liv Veldeman, Tim Ward, Catharine M West, R Paul Symonds, Christopher J Talbot^*, REQUITE consortium

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	104269
Number of pages	16
Journal	EBioMedicine
Volume	84
Early online date	18 Sept 2022
DOIs	https://doi.org/10.1016/j.ebiom.2022.104269
Publication status	Published - 1 Oct 2022

Keywords

Circadian rhythm
Radiotherapy
Genetics
Breast cancer
BREAST-CANCER
POLYMORPHISM
SLEEP

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10.1016/j.ebiom.2022.104269Licence: CC BY

Cite this

Webb, A. J., Harper, E., Rattay, T., Aguado-Barrera, M. E., Azria, D., Bourgier, C., Brengues, M., Briers, E., Bultijnck, R., Chang-Claude, J., Choudhury, A., Cicchetti, A., De Ruysscher, D., De Santis, M. C., Dunning, A. M., Elliott, R. M., Fachal, L., Gómez-Caamaño, A., Gutiérrez-Enríquez, S., ... REQUITE consortium (2022). Treatment time and circadian genotype interact to influence radiotherapy side-effects. A prospective European validation study using the REQUITE cohort. EBioMedicine, 84, Article 104269. https://doi.org/10.1016/j.ebiom.2022.104269

@article{919e0cacba074365a2f9679150c25d0f,

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

abstract = "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.",

keywords = "Circadian rhythm, Radiotherapy, Genetics, Breast cancer, BREAST-CANCER, POLYMORPHISM, SLEEP",

author = "Webb, {Adam J} and Emily Harper and Tim Rattay and Aguado-Barrera, {Miguel E} and David Azria and Celine Bourgier and Muriel Brengues and Erik Briers and Ren{\'e}e Bultijnck and Jenny Chang-Claude and Ananya Choudhury and Alessandro Cicchetti and {De Ruysscher}, Dirk and {De Santis}, {Maria Carmen} and Dunning, {Alison M} and Elliott, {Rebecca M} and Laura Fachal and Antonio G{\'o}mez-Caama{\~n}o and Sara Guti{\'e}rrez-Enr{\'i}quez and Kerstie Johnson and Ram{\'o}n Lobato-Busto and Kerns, {Sarah L} and Giselle Post and Tiziana Rancati and Victoria Reyes and Rosenstein, {Barry S} and Petra Seibold and Alejandro Seoane and Paloma Sosa-Fajardo and Elena Sperk and Bego{\~n}a Taboada-Valladares and Riccardo Valdagni and Ana Vega and Liv Veldeman and Tim Ward and West, {Catharine M} and Symonds, {R Paul} and Talbot, {Christopher J} and {REQUITE consortium}",

year = "2022",

month = oct,

day = "1",

doi = "10.1016/j.ebiom.2022.104269",

language = "English",

volume = "84",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier",

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Webb, AJ, Harper, E, Rattay, T, Aguado-Barrera, ME, Azria, D, Bourgier, C, Brengues, M, Briers, E, Bultijnck, R, Chang-Claude, J, Choudhury, A, Cicchetti, A, De Ruysscher, D, De Santis, MC, Dunning, AM, Elliott, RM, Fachal, L, Gómez-Caamaño, A, Gutiérrez-Enríquez, S, Johnson, K, Lobato-Busto, R, Kerns, SL, Post, G, Rancati, T, Reyes, V, Rosenstein, BS, Seibold, P, Seoane, A, Sosa-Fajardo, P, Sperk, E, Taboada-Valladares, B, Valdagni, R, Vega, A, Veldeman, L, Ward, T, West, CM, Symonds, RP, Talbot, CJ & REQUITE consortium 2022, 'Treatment time and circadian genotype interact to influence radiotherapy side-effects. A prospective European validation study using the REQUITE cohort', EBioMedicine, vol. 84, 104269. https://doi.org/10.1016/j.ebiom.2022.104269

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

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 -