This study confirms high levels of fatigue, depressive symptoms, and sleep disturbance in patients with breast cancer who have recently completed primary treatment, particularly among those treated with chemotherapy. Scores for all three symptoms were much greater than levels seen in comparison samples of healthy women,36,42,43
which highlights the importance of these behavioral disturbances in the immediate post-treatment period. However, despite strong correlations among symptoms, we found no evidence for a common inflammatory mechanism driving symptom expression. Instead, the only symptom associated with the inflammatory markers assessed was fatigue, which was correlated specifically with elevations in sTNF-RII. These findings are consistent with previous research linking sTNF-RII and fatigue in longer-term survivors of breast cancer,22
and they extend those results to demonstrate an association between TNF and fatigue in the immediate post-treatment period. Exposure to chemotherapy was also associated with elevations in sTNF-RII, and the strongest association between sTNF-RII and fatigue was seen in chemotherapy-treated patients.
In contrast with fatigue, neither depressive symptoms nor sleep disturbance was associated with sTNF-RII or other circulating markers of inflammation. A recent meta-analysis showed a reliable association between inflammatory markers (including CRP and IL-1ra) and self-reported depressive symptoms, although this effect was small, and studies in patients with cancer are extremely limited.16
In addition, few studies have differentiated between affective and vegetative symptoms of depression, which may have distinct biologic correlates. For example, among patients with ovarian cancer, plasma and ascites levels of IL-6 were correlated with vegetative symptoms of depression, including fatigue, but not with affective symptoms (eg, sadness).44
Among patients undergoing interferon alfa therapy for malignant melanoma, fatigue and other vegetative symptoms emerged earlier than depressed mood and were less responsive to paroxetine treatment,45
which was similar to findings in other cancer populations.46
In our previous research in patients with breast cancer, general depressive symptoms were not associated with markers of inflammation, including sTNF-RII, IL-1ra, and CRP.20,22
These findings suggest that fatigue and depression, though closely related, may have distinct biologic underpinnings, and that fatigue may be more closely tied to inflammatory processes in the context of breast cancer.
Inflammation is common among individuals with sleep disorders47
and in those with objectively-assessed sleep disturbance.48–51
However, evidence that self-reported sleep problems are associated with circulating markers of inflammation is mixed.52–55
The current findings suggest that elevations in circulating inflammatory markers, specifically sTNF-RII, IL-1ra, and CRP, may not contribute to subjective sleep disturbance at the completion of breast cancer treatment, despite high levels of sleep problems at this time. Instead, other research suggests that affective and cognitive/behavioral factors may contribute to cancer-related insomnia.56
Future studies should probe biologic, affective, and cognitive/behavioral factors that may contribute to fatigue, depression, and sleep problems to identify unique and common mechanisms for these symptoms.
These findings suggest a role for TNF-α in chemotherapy-induced fatigue. Results showed that sTNF-RII, rather than IL-1ra or CRP, was specifically associated with fatigue. The soluble TNF receptor is shed from a cell surface after stimulation of the cell by the proinflammatory cytokine TNF-α and, therefore, serves as a marker for TNF-α activity.57
In animal models, treatment with the chemotherapy agent adriamycin induces elevations in peripheral TNF-α, which then migrates across the blood brain barrier and causes inflammation and oxidative stress in the brain.58
Conversely, pharmacologic blockade of TNF with etanercept led to reduced fatigue in patients with cancer who were undergoing chemotherapy.59
In the current sample, circulating concentrations of sTNF-RII in chemotherapy-treated patients were quite high, comparable to those seen in our previous research with persistently fatigued survivors of breast cancer.22
In contrast, plasma levels of IL-1ra in this sample were much less than levels linked to cancer-related fatigue in our previous research20,22,23
and may have been insufficient to induce behavioral changes. Levels of CRP in this sample were high, comparable to levels associated with fatigue in previous studies.20
It is possible that inflammatory cytokines, although correlated, may have distinct associations with the CNS and physical health. For example, sTNF-RII, but not IL-6, was correlated with stress-induced changes in the CNS,60
and sTNF-RII predicted coronary heart disease independent of CRP.61
Despite growing interest in behavioral adverse effects of cancer treatment and their interrelationships, no previous studies have comprehensively examined fatigue, depressive symptoms, and sleep disturbance and their biologic underpinnings. The current findings suggest that, although these symptoms frequently co-occur in the aftermath of breast cancer treatment, they do not necessarily share a common underlying inflammatory biology at this point in the cancer trajectory. Conclusions are limited by the cross-sectional nature of the data, which particularly limits conclusions about causality; for example, women may have had elevated fatigue and sTNF-RII before treatment. Longitudinal studies are required to additionally probe the associations among these symptoms and the mechanisms that contribute to their onset and persistence over time. In addition, we focused on three biomarkers that serve as proxies for the activity of three key proinflammatory cytokines—IL-1β (IL-1ra), TNF-α (sTNF-RII), and IL-6 (CRP) —and have been correlated with cancer-related fatigue20,22–25
and with depression and sleep disturbance in noncancer populations.18,53,54
However, it is possible that other markers of inflammation not assessed here may contribute to these symptoms. It is also possible that elevated inflammatory markers may be more apparent in women with clinical depression and/or sleep disorders. Moreover, although women were screened for neurologic and immune-related medical conditions, other potential causes of behavioral symptoms, including anemia and thyroid dysfunction, were not assessed.
The present results implicate TNF-α signaling as one mechanism underlying the development of treatment-related fatigue and highlight the need for future studies to define other biologic mechanisms driving the emergence of sleep disturbance and depressive symptoms. Identification of unique and common mechanisms for these common adverse effects of cancer treatment is essential for the development of targeted interventions.