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Fatigue and Proinflammatory Cytokine Activity in Breast Cancer Survivors

From the Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center (J.E.B., P.A.G.), the Schools of Medicine and Public Health (P.A.G.), the Center for Interdisciplinary Research in Immunology and Disease (N.A.), and the Department of Microbiology and Immunology (J.L.F.), the University of California, Los Angeles, California.

Address reprint requests to: Julienne E. Bower, PhD, Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center at UCLA, 650 Charles Young Drive South, Room A2-125 CHS, Box 956900, Los Angeles, CA 90095-6900. Email: jbower{at}ucla.edu

OBJECTIVE: Fatigue is a common problem among cancer patients and survivors, yet the mechanisms underlying the occurrence and persistence of this symptom are not known. Activation of the immune system may evoke feelings of fatigue, which are mediated by proinflammatory cytokines. We examined whether fatigued breast cancer survivors would show elevations in proinflammatory cytokines and markers of cytokine activity compared with nonfatigued survivors. Differences in lymphocyte subsets, cortisol, and behavioral symptoms associated with proinflammatory cytokines were also assessed.

METHODS: Forty breast cancer survivors (20 fatigued, 20 nonfatigued) provided blood samples at visits scheduled to control for diurnal variability. Cytokines, soluble markers of cytokine activity, and cortisol were measured by immunoassay and lymphocyte subsets by flow cytometry. Participants also completed questionnaires measuring demographic, medical, and behavioral variables.

RESULTS: Fatigued breast cancer survivors had significantly higher serum levels of several markers associated with proinflammatory cytokine activity than nonfatigued survivors, including interleukin-1 receptor antagonist (IL-1ra), soluble tumor necrosis factor receptor type II (sTNF-RII), and neopterin. They were also more likely to report behavioral problems that co-occur with fatigue in the context of immune activation. Fatigued survivors had significantly lower serum levels of cortisol than the nonfatigued group as well as differences in two lymphocyte populations.

CONCLUSIONS: Fatigued breast cancer survivors showed elevations in serum markers associated with proinflammatory cytokine activity an average of 5 years after diagnosis. Results suggest mechanisms through which enduring immune activation may occur, including alterations in cortisol and in lymphocyte subsets.

Key Words: fatigue • breast cancer • proinflammatory cytokines • sickness behavior • cortisol

Abbreviations: ANCOVA = analysis of covariance; HPA = hypothalamic-pituitary-adrenal;; IL-1ß = interleukin-1 beta;; IL-1ra = interleukin-1 receptor antagonist; IL–6 = interleukin–6;; sTNF-RII = soluble tumor necrosis factor receptor II;; TNF- = tumor necrosis factor alpha.

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