EBioMedicine (Oct 2022)
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
Affiliations
- Adam J. Webb
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
- Emily Harper
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
- Tim Rattay
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
- Miguel E. Aguado-Barrera
- Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria de Santiago de Compostela, Spain
- David Azria
- Department of Radiation Oncology, Montpellier Cancer Institute, Université Montpellier, Inserm U1194, Montpellier, France
- Celine Bourgier
- Department of Radiation Oncology, Montpellier Cancer Institute, Université Montpellier, Inserm U1194, Montpellier, France
- Muriel Brengues
- Institut de Recherche en Cancérologie de Montpellier, Université Montpellier, Inserm U1194, Montpellier, France
- Erik Briers
- Patient advocate, Hasselt, Belgium
- Renée Bultijnck
- Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Ananya Choudhury
- Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, UK
- Alessandro Cicchetti
- Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Dirk De Ruysscher
- Maastricht University Medical Center, Department of Radiation Oncology (Maastro clinic), GROW School for Oncology and Developmental Biology, Maastricht, the Netherlands
- Maria Carmen De Santis
- Department of Radiation Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Alison M. Dunning
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
- Rebecca M. Elliott
- Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, UK
- Laura Fachal
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
- Antonio Gómez-Caamaño
- Instituto de Investigación Sanitaria de Santiago de Compostela, Spain; Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
- Sara Gutiérrez-Enríquez
- Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Kerstie Johnson
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
- Ramón Lobato-Busto
- Department of Medical Physics, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
- Sarah L. Kerns
- Departments of Radiation Oncology and Surgery, University of Rochester Medical Center, Rochester, New York, NY, United States
- Giselle Post
- Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Tiziana Rancati
- Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Victoria Reyes
- Radiation Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Barry S. Rosenstein
- Department of Radiation Oncology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA.
- Petra Seibold
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Alejandro Seoane
- Medical Physics Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Paloma Sosa-Fajardo
- Instituto de Investigación Sanitaria de Santiago de Compostela, Spain; Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
- Elena Sperk
- Department of Radiation Oncology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- Begoña Taboada-Valladares
- Instituto de Investigación Sanitaria de Santiago de Compostela, Spain; Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
- Riccardo Valdagni
- Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Radiation Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology and Haematology-Oncology, Universita degli Studi di Milano, Italy
- Ana Vega
- Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria de Santiago de Compostela, Spain; Biomedical Network on Rare Diseases (CIBERER), Spain
- Liv Veldeman
- Department of Human Structure and Repair, Ghent University, Ghent, Belgium; Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium
- Tim Ward
- Patient advocate, NCRI CTRad consumer, UK
- Catharine M. West
- Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, UK
- R. Paul Symonds
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
- Christopher J. Talbot
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK; To whom correspondence should be addressed.
- Journal volume & issue
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Vol. 84
p. 104269
Abstract
Summary: 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.
