Inflammatory Biomarkers for Persistent Fatigue in Breast Cancer Survivors

Abstract

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 z2 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-a 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.

Associations between quality of life, fatigue, and cytokine levels in patients aged 50+ with acute myeloid leukemia

“…Similar to Meyers et al [30], we found weak correlations between IL-6 and fatigue. However, several studies in other cancers found no such relationship [2,13,16,18,29]. However, in contrast to Meyers et al, we did not find a relationship between TNF-α and fatigue.…”

“…However, in contrast to Meyers et al, we did not find a relationship between TNF-α and fatigue. This result was consistent with other studies that examined the relationship between fatigue and TNF-α relationship in cancer populations [2,13,18,29].…”

“…These warrant further investigation in a larger, more controlled study. Although we studied a fairly broad panel of cytokines, future studies may also wish to include cytokine receptors, such as IL-1ra, sIL-6R, and sTNF-rII, which have been found in higher concentrations in fatigued patients with various malignancies [6,13,30].…”

Fatigue Is Associated with Increased Risk of Mortality in Patients on Chronic Hemodialysis

“…At the moment of inclusion in the study, fatigue levels were assessed in patients using the Vitality Scale of SF-36 (SF-36 VS) [19,20]. Vitality Scale scores range from 0 to 100, with higher scores indicating better functioning.…”

Assessment of fatigue using the identity-consequence fatigue scale in patients with lung cancer

“…In attempts to explain fatigue, models have been developed based on both physiological and psychological aspects. The mechanisms involve effects of cancer or of its treatment on the central nervous system, muscle energy metabolism, sleep/circadian rhythms, (8,9) mediators of inflammation, (10) stress, (10) immune activation, (11) and hormonal changes related to effects on the hypothalamic-pituitary axis. (12)(13)(14) Immune activation has been associated with fatigue and depression in patients with cancer or other chronic diseases.…”