TOPLINE

In a prospective cohort study of patients receiving radiotherapy for prostate cancer, circadian gene variants were found to interact with the treatment time of day to alter the risk for late side effects.

METHODOLOGY

• Circadian rhythms regulate biological processes relevant to the risk for radiotherapy side effects, such as DNA repair and apoptosis. A recent study of patients with breast cancer found that those with certain circadian rhythm genotypes have a higher risk for toxicity when receiving radiotherapy at particular times of day.
• To see if the same pattern exists in prostate cancer, researchers analyzed data from 877 patients receiving external beam radiotherapy for nonmetastatic prostate cancer in the multinational REQUITE prospective cohort study.
• The researchers focused on variants in specific circadian rhythm genes previously implicated in the risk for radiotherapy side effects (CLOCK, PER3, RASD1, HCRTR2, NOCT, and VAMP3). Regression analyses incorporated patients’ genotypes, the mean solar time of each radiotherapy fraction, and their interaction. Patients with a wide range of treatment times (SD > 3 hours) were excluded.
• Primary endpoints were deterioration of one or more grades from baseline for rectal bleeding or urinary incontinence, assessed by a healthcare provider at 2 years post-radiotherapy.

TAKEAWAY

• Overall, 10% of patients had late rectal bleeding and 15% had late urinary incontinence. Multivariable models demonstrated a significant interaction between several PER3 genotypes and treatment time of day for both endpoints (P < .05).
• Model-based predictions for a typical patient showed that the 44% of patients with the rs696305 C/C PER3 genotype could potentially reduce their risk for rectal bleeding from 11% when treated at 9 AM to 5% when treated at 5 PM.
• Similarly, for urinary incontinence, the 59% of patients with the rs172933 C/C genotype could potentially lower their risk from 13% to 7% by having radiotherapy around noon rather than in the early morning.
• Conversely, patients heterozygous for rs172933 (T/C) may see a lower risk for urinary incontinence with early-morning or evening radiotherapy. Modeling predicted that avoiding midday treatment could potentially reduce the risk from 15% to 5%.

IN PRACTICE

“Our results show the risk of developing late side effects could be mitigated through simple and cost-effective genetically informed scheduling of radiotherapy treatment,” the study authors wrote. They added, however, that more work is needed, including pilot trials that directly test the effects of genetically guided treatment timing.

SOURCE

The study, led by Adam J. Webb, PhD, University of Leicester, Leicester, England, was published online in Clinical Cancer Research.

LIMITATIONS

Power considerations limited examination to a small number of genetic loci, whereas a significantly larger sample would enable a high-density whole-genome approach. The study examined a narrow range of dose and fractionation regimens, and findings may not apply to ultra-hypofractionated regimens.

DISCLOSURES

The study received support from the EU’s Seventh Framework Programme for research. A co-author disclosed funding from AstraZeneca, Bristol Myers Squibb, and other companies outside the submitted work. Full disclosures are available in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.