Three genes linked to circadian rhythms could help to predict when breast cancer patients should receive their radiotherapy, British researchers have reported.
Scientists and clinicians from the University of Leicester and University Hospitals of Leicester NHS Trust identified that the genes are associated with an increased risk of side-effects following radiotherapy at particular times in the day.
Writing in *eBioMedicine*, they say their findings add to the evidence for a personalised approach to radiotherapy because patients could be tested for the presence of those gene variants and then treated at the optimal time.
The team analysed clinical and genotype data from 1,690 breast cancer patients across Europe for links with erythema and breast atrophy, following radiotherapy.
Atrophy was seen in 35% of patients and was dependent on body mass index (BMI), radiation dose and the extent of pre-radiotherapy surgery received.
It was thought time of treatment had only a small effect until three circadian genes, PER3, CLOCK and RASD1, were taken into account. This significantly altered the probability of developing atrophy.
They found the greatest effect in patients with two copies of the T variant in PER3, two copies of the A variant of RASD1 and two copies of the G variant of CLOCK – these had the lowest rates of atrophy when treated at 3.30pm.
Patients with the C variants of PER3, the G variants of RASD1 and A variants of CLOCK had the highest probability of atrophy when treated close to 3.30pm.
Dr Adam Webb of the Department of Genetics and Genome Biology at the University of Leicester, said for one combination of the three gene variants, which represents 14% of the population, atrophy could be reduced from 70% to 30% by treating in the morning rather than mid-afternoon.
“Our study has shown that time of day of treatment, adjusted to account for variations in daylight hours in local time zones, can affect the severity of atrophy, and that the highest and lowest risk times are dependent on variations in key circadian genes,” he said.
“This concept of ‘chronoradiotherapy’ could be tested in a randomised trial, with patients randomly allocated their treatment time compared to those treated at an optimal time predicted by genetic testing.
“Radiotherapy is routinely used in the treatment of breast cancer, and atrophy as a side-effect is common. Carefully allocating treatment slots following simple DNA tests could be an effective, simple and low-cost step to improve long-term quality of life for thousands of breast cancer patients every year.”
The study formed art of the EU-funded REQUITE project. Led by the University of Leicester with UK patients recruited in the Hope Cancer Trials Centre at Leicester’s Hospitals, other patients were recruited in France, Belgium, the Netherlands, Italy, Germany and Spain.
Webb AJ, Harper E, Rattay T et al. Treatment time and circadian genotype interact to influence radiotherapy side-effects. A prospective European validation study using the REQUITE cohort. *eBioMedicine* 18 September 2022
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