a discovery the investigators called “striking and unexpected.”
“This has not been shown before [and] we were surprised, indeed,” Nicola Aceto, PhD, professor of molecular oncology, Swiss Federal Institute of Technology Zürich, said in an interview.
The findings carry potential implications for the timing of biopsy and treatment of metastasis-prone cancers, the authors said.
The study was published online in Nature.
Circulating tumor cells (CTCs) are generally believed to shed constantly or following particular events such as surgery or physical activity; however, the processes that regulate tumor cell metastasis and how circadian rhythms may play into tumorigenesis remain unclear.
To better understand these processes, Dr. Aceto and colleagues collected blood samples from 30 women with breast cancer at 4:00 a.m. and 10:00 a.m. – times representing the body’s resting and active phases, respectively.
The researchers observed that more than 78% of all CTCs obtained were from samples taken during the resting phase.
This finding is astounding, Harrison Ball, a PhD candidate, and Sunitha Nagrath, PhD, with the University of Michigan, Ann Arbor, wrote in Nature News & Views .
Dr. Aceto and colleagues also found that CTCs generated at night divide more quickly and therefore have a higher potential to metastasize, compared with those generated during the day, which “are devoid of metastatic ability,” according to the authors, who obtained similar results in a series of mouse models.
The team also observed that key circadian rhythm hormones (such as melatonin, testosterone, and glucocorticoids) regulate CTC generation, and insulin promotes tumor cell proliferation in a time-dependent manner, suggesting a “need for time-controlled approaches for the characterization and treatment of breast cancer,” the authors wrote.
Practice changing?
Dr. Ball and Dr. Nagrath said the time-dependent nature of CTC dynamics could very well transform how cancer patients are assessed and treated.
“The data pointing to CTC proliferation and release during the rest phase suggest that doctors might need to become more conscious of when to administer specific treatments,” they wrote.
Both cautioned, however, that large clinical trials would be needed before any consideration of circadian rhythms is incorporated into standard practice. It’s also unclear whether these results in breast cancer hold true for other tumor types.
Mariana G. Figueiro, PhD, who was not involved in the research, agreed that, if studies confirm more metastatic spread at night, “there is an opportunity to treat patients at strategic times.”
Dr. Figueiro, of the Icahn School of Medicine at Mount Sinai, New York, also saw a potential impact on the timing of blood draws. “I think tightening up on how people do biopsies and bloodwork based on circadian time is important.”
Marleen Meyers, MD, agreed that these findings could have many clinical implications.
“The most obvious is that the time of day [that] treatment is administered may influence efficacy,” said Dr. Meyers, clinical professor of medicine at New York University Langone’s Perlmutter Cancer Center.
But, Dr. Meyers noted, the benefits of treating someone at night would need to be weighed against the downsides of interrupting a person’s normal sleep-wake cycle. “If this finding is clinically important it will be a challenge incorporating this into clinical care,” she said.
The study had no funding reported. Dr. Aceto is a cofounder and member of the board of PAGE Therapeutics, listed as an inventor in patent applications related to circulating tumor cells, a paid consultant for several companies, and a Novartis shareholder. One coauthor is a cofounder of PAGE Therapeutics. All other authors declare no competing interests. Dr. Meyers and Dr. Figueiro reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
