Inflammatory biomarkers for persistent fatigue in breast cancer survivors.

TitleInflammatory biomarkers for persistent fatigue in breast cancer survivors.
Publication TypeJournal Article
Year of Publication2006
AuthorsCollado-Hidalgo A, Bower JE, Ganz PA, Cole SW, Irwin MR
JournalClin Cancer Res
Date Published2006 May 1
KeywordsBiomarkers, Breast Neoplasms, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cytokines, Fatigue, Female, Humans, Inflammation, Lymphocyte Count, Middle Aged, Survivors

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 > or = 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-alpha 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.

Alternate JournalClin. Cancer Res.
PubMed ID16675568
Grant ListK07 CA90407 / CA / NCI NIH HHS / United States
M01RR00865 / RR / NCRR NIH HHS / United States
T32-MH-19925 / MH / NIMH NIH HHS / United States