Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.
Leicester Cancer Research Centre, University of Leicester, Leicester, UK.
EBioMedicine. 2022 Oct;84:104269. doi: 10.1016/j.ebiom.2022.104269. Epub 2022 Sep 18.
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.
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.
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.
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.
EU-FP7.
昼夜节律会影响广泛的生物过程，包括对癌症治疗的反应。关于治疗时间是否会影响放射治疗副作用风险的证据存在冲突，这可能是由于不同的时间分析和靶组织造成的。我们之前已经表明，昼夜节律基因的时间和基因型之间存在交互作用，会影响乳腺癌放射治疗后的晚期毒性，目的是在一个多中心队列中验证这些结果。
使用 1690 例 REQUITE 乳腺癌患者的临床和基因型数据，将红斑（急性；n=340）和乳房萎缩（放射治疗后两年；n=514）作为主要终点。每个部分的本地时间都转换为太阳时间作为预测因子。将遗传生物钟标记物纳入逻辑回归，以确定主要终点的预测因子。
红斑的显著预测因子包括 BMI、辐射剂量和 PER3 基因型（OR 1.27（95%CI 1.03-1.56）；P < 0.03）。治疗时间对急性毒性的影响尚无定论，时间与基因型之间没有相互作用。对于晚期毒性（乳房萎缩），预测因子包括 BMI、辐射剂量、手术类型、治疗时间和 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）和 RASD1（OR 0.56（95%CI 0.35-0.89）；P < 0.02）中的 SNP。昼夜节律基因的时间和基因型之间存在统计学上显著的相互作用（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），毒性的峰值时间由基因型决定。
根据昼夜节律基因型选择最佳治疗时间，可以减轻晚期萎缩（例如，将 PER3 rs2087947C/C 基因型的治疗时间安排在早晨；将 T/T 基因型的治疗时间安排在下午）。我们预测，三重纯合子患者（14%）通过在早晨治疗，将萎缩的几率从 70%降低到 33%。未来的临床试验可以将在最佳时间接受治疗的患者与按计划接受治疗的患者进行分层比较。
欧盟 FP7。
