Treatment time and circadian genotype interact to alter the severity of radiotherapy side-effects
Talbot, C. Webb, A. Harper, E. Azria, D. Choudhury, Ananya de Ruysscher, D. Dunning, A. Elliott, R. Kerns, S. Lambrecht, M.
Talbot, C.
Webb, A.
Harper, E.
Azria, D.
Choudhury, Ananya
de Ruysscher, D.
Dunning, A.
Elliott, R.
Kerns, S.
Lambrecht, M.
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Abstract
Purpose or Objective
Circadian rhythm influences a wide range of biological processes, including efficacy and side effects of cancer treatment.
Earlier evidence disagrees on whether risk of radiotherapy side-effects is affected by treatment time, probably due to
differences in organs irradiated and time analysis methods. We previously showed an interactive effect of time and
genotype of circadian rhythm genes on late toxicity after breast radiotherapy. This study aimed to validate those results in
a larger multi-centre cohort with a more sophisticated time analysis and more SNPs.
Materials and Methods
We collected time of each radiotherapy fraction from patients in REQUITE breast cancer cohorts. Requite was a multi centre, prospective study in Europe and US (www.requite.eu). Enrolment was open for two and a half years through 26
centres in eight countries. Radiotherapy toxicity data was collected at baseline, after radiotherapy and one & two years
later. Genome-wide SNP data was available typed with Illumina OncoArrays. The primary endpoints used were acute
erythema and late breast atrophy assessed by CTCAE v4. 1690 breast cancer patients with complete clinical and SNP data
were included in the analysis. Local date-times for each fraction were converted into solar times as continuous predictors.
Genetic chronotype markers were included in logistic regression analyses to identify predictors of each end-point.
Results
Significant predictors for acute erythema included BMI, breast radiation dose and PER3 genotype. There was weak evidence
for an effect of treatment time on acute toxicity, but with no interaction between time and genotype. In the late toxicity
analysis BMI, breast radiation dose, surgery type, mean treatment time and SNPs in CLOCK (rs1801260), PER3 (rs2087947)
and RASD1 (rs11545787) genes predicted late breast atrophy (p<0×05). There was a significant interaction between time
and the genotypes of the circadian rhythm genes (p=0.005-0.02), with peak time for toxicity determined by genotype.
Conclusion
Late atrophy could be reduce by selecting the optimal treatment time based on the genotypes of circadian genes (Figure
1). For example, PER3 rs2087947C/C genotypes should be treated in the morning; T/T in the afternoon. We predict triple homozygous patients (who are 14% of this cohort) would reduce their chance of atrophy from 70% to 33% by treating in the
morning instead of afternoon. Future clinical trials could stratify patients treated at optimal times compared to those
scheduled conventionally to determine the magnitude of patient benefit.
Description
Date
2022
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Talbot C, Webb A, Harper E, Azria D, Choudhury A, de Ruysscher D, et al. Treatment time and circadian genotype interact to alter the severity of radiotherapy side-effects. Radiotherapy and Oncology. 2022 May;170:S321-S3. PubMed PMID: WOS:000806759200323.