Circadian Genotypes in PER3 and Time of Prostate Cancer Radiotherapy Interact to Affect Risk of Late Side Effects

Abstract Purpose: We showed previously that patients with breast cancer with certain circadian rhythm genotypes have higher incidences of toxicity when treated with radiotherapy at different times of day. This opens the way to genetically guided chronomodulation as a cost-effective way to reduce side effects while preserving treatment efficacy. We aimed to test whether similar time-of-day effects are observed in prostate cancer. Experimental Design: The analysis used the multinational, prospective observational REQUITE prostate cancer cohort (n = 1,760). All patients received external beam radiotherapy and were followed for 2 years. Regression analyses were performed in patients with complete data, including genotypes and radiotherapy fraction times (n = 877). Least absolute shrinkage and selection operator (LASSO) and logistic regression models incorporated genotypes of single-nucleotide polymorphisms in circadian rhythm genes, time of radiotherapy, and their interaction. Primary endpoints were late rectal bleeding (RB) and urinary incontinence (UI). Results: Multivariable models show significant effects of genotype, treatment timing, and the interaction between PER3 genotypes and treatment timing for both primary endpoints. The 44% of patients with the rs696305 C/C genotype are predicted to reduce their risk of RB from 11% when treated at 9:00 am to 5% when treated at 5:00 pm. Similarly, the analysis predicts a significant reduction in the risk of UI from 15% to 5% by avoiding treatment in the middle of the day for patients heterozygous for rs172933 (36% of patients). Conclusions: These results agree with the earlier findings in patients with breast cancer who have undergone radiotherapy. The interaction between genotype and time of treatment suggests that groups of patients could reduce side effects and improve their quality of life through chronomodulation.