Sleep, Circadian Hormonal Dysregulation, and Breast Cancer Survival

Recent research provides evidence that disrupted circadian rhythms, including hormonal patterns and sleep, are associated with increased risk of breast cancer incidence and faster progression to mortality. We have observed that a loss of normal diurnal cortisol rhythm associated with more awakenings during the night predicts early mortality with metastatic breast cancer. Other recent studies have shown that nighttime shift work is associated with higher breast cancer incidence, and in a murine model disrupting circadian cortisol cycles produced a doubling of implanted tumor growth. There is also recent evidence that abnormal clock genes are associated with cancer. However, it is not clear whether sleep disruption per se affects breast cancer progression, or whether such an effect is mediated by hormonal and immune dysregulation of this prevalent and hormone-mediated cancer. We propose to study sleep disruption as a prognostic factor in the progression of metastatic breast cancer. We will also examine sleep patterns in association with disrupted circadian rhythms of cortisol, ACTH, and melatonin as well as measures of immune function known to be salient to breast cancer progression. These are natural killer cell cytoxicity and specific cytokine, IL-6. We plan to recruit 105 women 45 years through 75 years with metastatic or recurrent breast cancer and 20 age and SES-matched controls for a two-week at home sleep study with Actiwatch and two nights of in-home EEG monitoring, followed by 28 hours of continuous blood sampling and one night of EEG sleep monitoring in our lab at Stanford. This will provide a full examination of circadian hormones associated with sleep patterns. We will relate these assessments to the subsequent course of breast cancer progression. Results of this study will provide specific evidence regarding how improved sleep management may affect the course of breast cancer. Aim 1: To study 24-hr diurnal rhythms of HPA axis hormones and melatonin in women with metastatic or recurrent breast cancer. Hypothesis 1: Women with metastatic or recurrent breast cancer will have reduced amplitude and disrupted phase of 24-hr diurnal rhythms of cortisol, ACTH, and melatonin. Aim 2: To describe sleep disruption in women with metastatic breast cancer and examine psychosocial, endocrine, and immune factors that may be associated with sleep disruption. Hypothesis 2: Women with metastatic or recurrent breast cancer will have a higher incidence of both at home and laboratory-examined sleep disruption than control women without breast cancer. Hypothesis 3: Poorer sleep quality will be associated with more pain, more emotional suppression in response to stressors, less emotional support, greater depression and anxiety, and greater perceived and traumatic stress. Hypothesis 4: Poorer sleep quality and quantity of sleep and daytime sleepiness and fatigue will be associated with abnormal circadian neuroendocrine (i.e., cortisol, ACTH, and melatonin) and immune patterns (i.e., suppressed day and night time NK activity and loss of NK rhythms; increased day time IL-6 levels and /or loss of IL-6 rhythm). Aim 3: To study the relationship between sleep disruption and survival time among metastatic and recurrent breast cancer patients. Hypothesis 5: Poorer sleep quality and quantity of sleep will predict shorter survival. Hypothesis 6: Reduced diurnal amplitude and an abnormal phase of cortisol will predict shorter survival. Explanatory Aim 4: To investigate whether sleep disruption mediates the relation of psychosocial factors to health outcomes.