Time of day matters for breast cancer treatment: new study

Breast shrinkage after breast cancer radiotherapy could be reduced by treating a patient at the optimum time of day, as predicted by their body clock genes.

Scientists and clinicians from the University of Leicester and University Hospitals of Leicester NHS Trust have identified three genes linked to circadian rhythms – our internal body clocks – that are associated with increased risk of side-effects following radiotherapy at particular times in the day.

The results of their study, published online in the journal eBioMedicine, provide more evidence for a personalised approach to radiotherapy, by testing patients for the presence of these three gene variants and then treating at the optimal time.

At least 35,000 women a year in the UK receive radiotherapy as part of treatment for breast cancer. Advances in treatment have doubled survival from this disease in the last 40 years, but a substantial proportion suffer lifelong late effects which can affect quality of life. Breast shrinkage (atrophy) results in changes to the size and appearance of the breast and may cause discomfort.

As part of the EU-funded REQUITE project, the researchers analysed clinical and genotype data from 1690 breast cancer patients across Europe for links with painful inflamed skin (erythema) and breast atrophy, both side-effects of radiotherapy.

Breast shrinkage (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. Time of treatment was seen to have only a small effect until it was considered in combination with variants in three circadian genes (PER3, CLOCK and RASD1) which then radically altered the probability of developing atrophy. 

The greatest effect is seen where 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 have the lowest rates of atrophy when treated at 3.30pm. Conversely patients with the C variants of PER3, the G variants of RASD1 and A variants of CLOCK have 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: “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. 

“Potentially, atrophy could be reduced by selecting the optimum treatment time for individual patients according to their circadian (body clock) genotype. For one combination of the three gene variants, representing 14% of the population, atrophy could be reduced from 70% to 30% simply by treating in the morning as opposed to mid-afternoon.”

Circadian rhythms, or body clocks, are 24-hour cycles which govern the sleep / wake status and numerous cell functions that can affect the response to cancer treatment. These daily rhythms are controlled by the master clock in the brain responding to environmental factors such as light, but also by peripheral clocks in every organ under the control of circadian genes. Normal variation in these circadian genes influence whether an individual is a morning or evening person but crucially affect the time of day when cells are most susceptible to damage from radiation treatment (radiotherapy).

Dr Webb adds: “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.”

• This part of the EU funded REQUITE project was led by the University of Leicester with UK patients recruited in the Hope Cancer Trials Centre at Leicester’s Hospitals. Further patients were recruited in France, Belgium, the Netherlands, Italy, Germany and Spain. Leicestershire and Rutland Cancer Research Charity, Hope Against Cancer are providing funding related to this project for a PhD student.
• Treatment time and circadian genotype interact to influence radiotherapy side-effects. A prospective European validation study using the REQUITE cohort is published in eBioMedicine, DOI: 10.1016/j.ebiom.2022.104269