Treatment time and circadian genotype interact to alter the severity of radiotherapy side-effects

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.