Circadian rhythm effects on radiotherapy toxicity

Abstract

Purpose or Objective To test whether there is evidence for a genetically modified time-of-day effect on toxicity after radiotherapy for breast cancer Materials and Methods We collected time of each radiotherapy fraction from patients in the LeND and REQUITE breast cancer cohorts. LeND is a UK retrospective cohort collected 2008-10 with 661 patients. 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. Follow-up was collected for 2.5 years ending in September 2018. The primary endpoints used were acute erythema and late breast atrophy assessed by CTCAE v4. 4438 patients were enrolled in REQUITE, of which 2069 breast cancer patients. Results We earlier showed that genetic variation in the NOCT and PER3 genes predisposed some patients to have worse overall late toxicity if irradiated in the morning compared with afternoon, with less clear results on acute toxicity. In a new study we have carried out a more sophisticated time analysis on a larger cohort. For the acute toxicity end-point of erythema we find an association with the PER3 gene but not time-of-day. For late toxicity, multivariate analysis shows a peak for atrophy in the afternoon with the effect reversed for variants of the PER3 and CLOCK genes. Conclusion In summary we report results that refine our understanding of time-of-day effects on radiotherapy and suggest that target tissues may have different peak times for toxicity dependant on genotypes within known circadian genes.