Inflammatory Biomarkers for Persistent Fatigue in Breast Cancer 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 a...

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Veröffentlicht in:Clinical cancer research 2006-05, Vol.12 (9), p.2759-2766
Hauptverfasser: COLLADO-HIDALGO, Alicia, BOWER, Julienne E, GANZ, Patricia A, COLE, Steve W, IRWIN, Michael R
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container_end_page 2766
container_issue 9
container_start_page 2759
container_title Clinical cancer research
container_volume 12
creator COLLADO-HIDALGO, Alicia
BOWER, Julienne E
GANZ, Patricia A
COLE, Steve W
IRWIN, Michael R
description 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-α 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.
doi_str_mv 10.1158/1078-0432.CCR-05-2398
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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-α 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 &lt; 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). 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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-α 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 &lt; 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.</description><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Biomarkers - blood</subject><subject>breast cancer survivor</subject><subject>Breast Neoplasms - physiopathology</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>Cytokines - blood</subject><subject>fatigue</subject><subject>Fatigue - physiopathology</subject><subject>Female</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>IL-6</subject><subject>Inflammation</subject><subject>Lymphocyte Count</subject><subject>Mammary gland diseases</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Pharmacology. 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Andrology. Obstetrics</topic><topic>Humans</topic><topic>IL-6</topic><topic>Inflammation</topic><topic>Lymphocyte Count</topic><topic>Mammary gland diseases</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Pharmacology. Drug treatments</topic><topic>Survivors</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>COLLADO-HIDALGO, Alicia</creatorcontrib><creatorcontrib>BOWER, Julienne E</creatorcontrib><creatorcontrib>GANZ, Patricia A</creatorcontrib><creatorcontrib>COLE, Steve W</creatorcontrib><creatorcontrib>IRWIN, Michael R</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>COLLADO-HIDALGO, Alicia</au><au>BOWER, Julienne E</au><au>GANZ, Patricia A</au><au>COLE, Steve W</au><au>IRWIN, Michael R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inflammatory Biomarkers for Persistent Fatigue in Breast Cancer Survivors</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2006-05-01</date><risdate>2006</risdate><volume>12</volume><issue>9</issue><spage>2759</spage><epage>2766</epage><pages>2759-2766</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Purpose: This study seeks to define immunologic and inflammatory variables associated with persistent post-treatment fatigue in breast cancer survivors. 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subjects Antineoplastic agents
Biological and medical sciences
Biomarkers - blood
breast cancer survivor
Breast Neoplasms - physiopathology
CD4-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - immunology
Cytokines - blood
fatigue
Fatigue - physiopathology
Female
Gynecology. Andrology. Obstetrics
Humans
IL-6
Inflammation
Lymphocyte Count
Mammary gland diseases
Medical sciences
Middle Aged
Pharmacology. Drug treatments
Survivors
Tumors
title Inflammatory Biomarkers for Persistent Fatigue in Breast Cancer Survivors
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