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Inflammatory Biomarkers for Persistent Fatigue in Breast Cancer Survivors

Authors' Affiliations: ¹ Cousins Center for Psychoneuroimmunology, University of California at Los Angeles Semel Institute for Neuroscience and Human Behavior, ² Division of Cancer Prevention and Control, Jonsson Comprehensive Cancer Center, University of California at Los Angeles School of Medicine and Public Health, and ³ Department of Medicine, David E. Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California

Requests for reprints: Michael R. Irwin, Cousins Center for Psychoneuroimmunology, University of California at Los Angeles Semel Institute for Neuroscience and Human Behavior, 300 Medical Plaza, Room 3109, Los Angeles, CA 90095-7076; E-mail: mirwin1{at}ucla.edu.

Purpose: This study seeks to define immunologic and inflammatory variables associated with persistent post-treatment fatigue in breast cancer survivors.

Experimental Design: Leukocyte subsets, plasma inflammatory markers, and ex vivo proinflammatory cytokine production were assessed in 50 fatigued and nonfatigued breast cancer survivors recruited 2 years after successful primary therapy. Multivariate statistical analyses were used to define a composite immunologic biomarker of fatigue risk.

Results: Fatigued breast cancer survivors were distinguished from nonfatigued survivors by increased ex vivo monocyte production of interleukin (IL)-6 and tumor necrosis factor- following lipopolysaccharide stimulation, elevated plasma IL-1ra and soluble IL-6 receptor (sIL-6R/CD126), decreased monocyte cell-surface IL-6R, and decreased frequencies of activated T lymphocytes and myeloid dendritic cells in peripheral blood (all P < 0.05). An inverse correlation between sIL-6R and cell-surface IL-6R was consistent with inflammation-mediated shedding of IL-6R, and in vitro studies confirmed that proinflammatory cytokines induced such shedding. Multivariate linear discriminant function analysis identified two immunologic markers, the ratio of sIL-6R to monocyte-associated IL-6R and decreased circulating CD69⁺ T lymphocytes, as highly diagnostic of fatigue (P = 0.0005), with cross-validation estimates indicating 87% classification accuracy (sensitivity = 0.83; specificity = 0.83).

Conclusion: These results extend links between fatigue and inflammatory markers to show a functional alteration in proinflammatory cytokine response to lipopolysaccharide and define a prognostic biomarker of behavioral fatigue.

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