Decline in Circadian Robustness in Lung Cancer Patients During Immunotherapy is Associated With Increased Risk of Disease Progression and Death

Abstract

Disruptions in sleep and circadian rhythms have been consistently linked to higher mortality rates in the general population. Among cancer patients, these disruptions are not only prevalent but may significantly influence prognosis. Despite this, sleep and circadian trajectories remain unexplored in the context of cancer, particularly related to prognostic outcomes in modern therapies such as immune checkpoint inhibitors (ICIs), which are rapidly transforming oncological care. In this pioneering report, we examined how trajectories of sleep and circadian rhythms relate to prognostic outcomes in patients with non–small cell lung cancer (NSCLC), offering novel insights into their potential role as modifiable biomarkers of clinical outcomes. Forty-nine treatment-naïve NSCLC patients were enrolled in this prospective longitudinal study. Continuous 24-h recordings of circadian function (Circadian Function Index [CFI]) were collected over the first 5 months of treatment, alongside weekly assessments of insomnia severity (Insomnia Severity Index [ISI]) and estimations of total sleep time (TST) derived from sleep diaries every 3 weeks. Follow-up data, time to treatment discontinuation, disease progression, and cancer-related death were obtained from medical records. We estimated hazard ratios (HRs) for these outcomes based on ISI, TST, and CFI, analyzed as continuous variables and median-split. Cox regression analyses indicated that patients with trajectories portraying circadian robustness below the median had a higher risk of earlier progression (HR = 3.75, 95% confidence interval [CI] = [1.475-9.536], p = 0.005) and death (HR = 3.07, 95% CI = [1.128-8.360], p = 0.028). No significant associations were found between insomnia severity, TST, and the prognostic outcomes. Patients with more pronounced declines in circadian robustness demonstrated significantly elevated risks of disease progression and mortality. As the circadian rhythm is modifiable, these findings, if replicated, underscore the need for interventional studies aimed at stabilizing circadian rhythms to further explore potential improvements in patient outcomes and efficacy of cancer therapies.