Can sleep problems influence cancer diagnosis and ICI treatments?

From the Phipps Group, Public Health Sciences Division

Between 45-80% of cancer patients have reported trouble sleeping through the night. Examples of sleep disorders include obstructive sleep apnea (OSA), central sleep apnea, upper airway resistance syndrome, insomnia, and narcolepsy. Sleep problems can include poor sleep quality, improper sleep timing, irregularity, non-ideal sleep duration, and others. The stress and anxiety associated with having cancer and receiving cancer therapy can also exacerbate sleep irregularities. Studies have shown that the carcinogenic effects of sleep problems may involve intermittent hypoxia (IH) – which can occur due to the disruption of the 24h circadian rhythm. Mouse models have shown that enhanced tumor growth, invasiveness, and metastasis has been associated with IH. Also, when the 24h circadian rhythms are disrupted, melatonin is reduced, and inflammation and cellular damage is increased.

The current cancer literature suggests that higher tumor-associated T-cell levels improve prognosis of many cancers. In fact, immunotherapies using T-cell response to treat several types of cancers by inhibiting immune-suppressive proteins (cell death, its ligand, and cytotoxic lymphocyte antigen) have shown clinical efficacy., the senior author describes the importance of immune checkpoint inhibitors (ICI): “The use of immune checkpoint inhibitors is increasingly common in cancer treatment. We know these drugs provide a great benefit to many patients, but not for all patients. Several studies have looked at how tumor attributes relate to treatment response for patients receiving checkpoint inhibitors, but virtually no prior studies have looked at how patient attributes relate to treatment response.”  Dr. Phipps explains the objective of the study, “In this analysis we focused on the role sleep problems might play in how patients respond to checkpoint inhibitors. Sleep is so often overlooked as a critical health behavior, but it’s so commonly disrupted in patients with cancer as they navigate the challenges, symptoms, and side effects of cancer treatment – and that can have important implications for immune health.” This study was published in Supportive Care in Cancer.

The researchers utilized data from the Lifestyle Attributes and Sleep in Immunotherapy Response (LASIR) study, conducted at the clinical practice site, Seattle Cancer Care Alliance (SCCA). This study reported on sleep problems, the presence of metastases at diagnosis, and ICI tolerability in cancer patients without previous exposure to ICI therapy.  Electronic health records were also collected 6 months post ICI initiation. The outcome variables were defined as metastatic cancer status (M-stage) and ICI tolerance was defined and examined by SCCA oncologists. Poisson regression was utilized to assess the association between sleep problems and metastatic tumor status at diagnosis. Logistic regression was utilized to assess the associations of OSA and insomnia risk, chronotype, and sleep latency with the number of ICI infusions (>6, <6). 

Over half of the patients in the LASIR study suffered from sleep problems. Two-thirds of participants had intermediate to high sleep apnea risk, reported average sleep or restless nights, clinically significant insomnia, evening chronotype, and a third of participants reported taking longer than 15 mins to fall asleep. The sleep patterns collected at baseline were consistent over time. There was a statistically significant association between intermediate and high risk of OSA and metastatic cancer compared to low risk OSA. However, the patients who took more than 15 minutes to fall asleep were more likely to be diagnosed with metastatic cancer compared to those who reported shorter sleep times. Patients who reported an evening chronotype were more likely to be diagnosed with metastatic cancer compared to patients with a morning chronotype. However, there wasn’t a significant association between OSA risk, insomnia, and the number of infusions after the first 6 months of ICI. Moreover, patients with some sleep problems were more likely to have poor ICI treatment tolerance.

This study strengthens the present literature of sleep problems in cancer cohorts. The Phipps Group is the first to examine the biologically credible impact of sleep problems in cancer patients using ICI therapy. This pilot study has the ability to impact larger studies and result in interventional clinical trials focused on sleep quality in ICI treatment communities. Dr. Phipps concluded by thanking all participating entities: “This work would not have been possible without pilot funding from Public Health Sciences Division and the Premier Chefs fundraiser. This funding support allowed us to do the important work of building new collaborations with clinical care teams at the SCCA and working with care providers to develop a study protocol that fit within their practices and incorporated their insights and interests.” 

This research was supported by the National Institutes of Health and pilot funding provided by the Public Health Sciences Division and Immunotherapy Integrated Research Center at Fred Hutch.

Fred Hutch/UW Cancer Consortium member Dr. Ulrike Peters and Dr. Amanda I. Phipps contributed to this work.

Sillah A, Peters U, Watson NF, Tykodi SS, Hall ET, Silverman A, Malen RC, Thompson JA, Lee SM, Bhatia S, Veatch J. Associating sleep problems with advanced cancer diagnosis, and immune checkpoint treatment outcomes: a pilot study. Supportive Care in Cancer. 2022 Jan 16:1-0.