A systematic review of the association between immunogenomic markers and cancer-related fatigue

doi:10.1016/j.bbi.2012.05.004

Brain, Behavior, and Immunity

Volume 26, Issue 6, August 2012, Pages 830-848

https://doi.org/10.1016/j.bbi.2012.05.004 Get rights and content

Abstract

Fatigue, which is one of the most commonly reported symptoms in cancer, can negatively impact the functional status and the health-related quality of life of individuals. This paper systematically reviews 34 studies to determine patterns of associations between immunogenomic markers and levels of cancer-related fatigue (CRF). Findings from the longitudinal studies revealed that elevated fatigue symptoms especially of women with early stages of breast cancer were associated with high levels of neutrophil/monocyte, IL-1ra, and IL-6 during radiation therapy; high levels of CD4+, IL-1β, and IL-6 with stressing stimuli; high levels of IL-1β during chemotherapy; low NK cell levels after chemotherapy; and presence of homozygous IL-6 and TNF alleles. In the cross-sectional studies, associations between levels of fatigue and immune/inflammatory markers were not consistently found, especially when covariates such as BMI, ethnicity, menopausal status, and educational level were controlled in the statistical analyses. However, a number of genomic markers were observed to be elevated mostly in fatigued breast cancer survivors in the cross-sectional studies. Gaps in knowledge and recommendations for future research are discussed.

Highlight

► This review identified patterns of associations between immunogenomic markers and CRF, and gaps in knowledge needed to advance the science of CRF research.

Introduction

Advances in cancer treatment have led to high survival rates and prolonged the natural history of the disease. However, improved survival rates are mitigated by symptoms associated with treatments that lower the health-related quality of life (HRQOL) for survivors. Fatigue is one of the most commonly reported symptoms in cancer with a prevalence rate of 59% to 100% depending on the clinical status of the disease (Weis, 2011).

Cancer-related fatigue (CRF) is defined as a “distressing, persistent subjective sense of tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and that interferes with usual functioning” (Berger et al., 2010, p. 906). CRF considerably impacts the functional status and HRQOL of individuals by imposing physical limitations and psychological impairments (Curt et al., 2000). Although studies have been conducted to identify associations between immune and inflammatory markers with the severity and intensity of CRF, no causation between a specific biomarker and CRF has been established, contributing to its inadequate clinical management.

The diversity of factors that predispose to CRF suggests that it is a multidimensional symptom that has common related molecular pathways with multiple contributory mechanisms (Miakowski, 2002). The current understanding about the etiology of CRF is based on limited evidence that environmental, genetic, psychological, and physiological factors play important roles in the impairment of oxygen supply, neuromuscular signaling, and the hypothalamus–pituitary–adrenal axis functioning. The goal of this literature review was to systematically review studies that evaluated immunogenomic markers and CRF in order to identify patterns of associations between these variables.

Section snippets

Methods

An initial generic search in PubMed (any date) using the following key words, “Fatigue AND cancer”[title] yielded 867 articles. A basic search query based on the terms from the 867 articles was developed. These key words/phrases include: (“Neoplasms” [Medical Subject Heading (Mesh)]) AND (“Fatigue/blood”[Mesh] OR “Fatigue/cerebrospinal fluid”[Mesh] OR “Fatigue/enzymology”[Mesh] OR “Fatigue/etiology”[Mesh] OR “Fatigue/genetics”[Mesh] OR “Fatigue/immunology”[Mesh] OR “Fatigue/pathology”[Mesh] OR

Results

The 34 articles that met the eligibility criteria were reviewed. The earliest article appeared in 2001 and 73.5% (n = 25) of the articles were published from 2006 to the present. Ten (29%) of the studies used longitudinal designs, while 24 (71%) were cross-sectional. Eighteen (53%) studies enrolled only women subjects, most with breast cancer (94%). Of these, 24% studied women in early stages of breast cancer and 65% studied breast cancer survivors (BCS). About 39% of studies (N = 7/18)

Summary

Findings from the longitudinal studies reveal that elevated fatigue symptoms especially of women with early stages of breast cancer were associated with high levels of neutrophil/monocyte, IL-1ra, and IL-6 during RT; as well as high levels of CD4⁺, IL-1β, and IL-6 with stressing stimuli. There were too few longitudinal studies that focused on terminal (Olson et al., 2002) and pediatric cases (Vallance et al., 2010) to identify a trend in association between CRF and immunogenomic markers. In

Discussion

The goal of this review was to determine patterns of associations between immunogenomic markers and CRF. In the longitudinal studies, there were trends of associations between levels of CRF and markers of inflammation and immune response, especially in women with early stage of breast cancer. It is premature to specify potential biomarkers for CRF based on the findings because all results were based on associations and therefore do not prove causation. However, this review provides empirical

Conclusion

This review identified some patterns of associations between specific immunogenomic markers and fatigue in survivors with early stages of cancer. Inconsistent associations between fatigue and immunogenomic markers were found in subjects with terminal cases of cancer and when other covariates where considered in the analysis. The most important findings of this review are the identification of the gaps of knowledge that must be addressed in order to advance the science of CRF research. Future

Conflict of interest

The authors have declared that there is no conflict of interest.

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Fatigue is a common side effect of cancer and its treatment and is thought to be driven in part by activation of the proinflammatory cytokine network. However, the cellular and molecular underpinnings of cancer-related fatigue (CRF) have not been determined, nor have immune pathways beyond inflammation been carefully investigated. The goal of this study was to examine the association between CRF and activation of canonical proinflammatory gene regulation pathways and Type I interferon (IFN) signaling pathways in breast cancer patients during and after treatment.
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Results revealed unexpected complexity in the immune underpinnings of CRF and identify a novel role for IFN signaling as a robust contributor to this symptom before, during, and after treatment. Pro-inflammatory gene expression emerged as a predictor of fatigue later in the cancer trajectory, and that effect was primarily accounted for by a concurrent increase in monocyte prevalence.
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Cancer-related fatigue (CRF) is a distressing side effect of cancer and treatment, affecting both patients during active treatment and survivors, negatively impacting quality of life. While its exact cause remains uncertain, various mechanisms such as immune dysfunction, HPA-axis dysfunction, and treatment toxicity are proposed. Inflammatory biomarkers of CRF have been explored in previous research, but non-inflammatory markers have not been comprehensively studied. This systematic review analysed 33 studies to identify non-inflammatory peripheral blood biomarkers associated with CRF. Promising markers included Hb, blood coagulation factors, BDNF, tryptophan, GAA, mtDNA, platinum, CA125, and cystatin-C. Inconsistent findings were observed for other markers like VEGF, leptin, and stress hormones. Most studies focused on adults. Research in pediatrics is limited. This review showed partial evidence for the inflammaging hypothesis (neurotoxicity due to neuro-inflammation) laying at the basis of CRF. Further research, especially in pediatrics, is needed to confirm this hypothesis and guide future biomarker studies.
Relationship of cancer-related fatigue with psychoneurophysiological (PNP) symptoms in breast cancer survivors
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Cancer-related fatigue (CRF) is a highly prevalent and debilitating symptom reported by breast cancer survivors (BCS). CRF has been associated with the co-occurrence of anxiety, depression, poor sleep quality, cognitive impairment, which are collectively termed as psychoneurophysiological (PNP) symptoms. CRF and these PNP symptoms are often reported during and after treatment with long-lasting distress. It is unclear how CRF and these PNP symptoms influence each other. This study aimed to explore predictive factors (i.e., PNP symptoms and social-demographic factors) of CRF, and test exploratory path models of the relationships of CRF with PNP symptoms (depression, anxiety, sleep disturbance, pain, and cognitive function) in BCS.
This paper is part of a larger descriptive, correlational, and cross-sectional study. Validated and reliable instruments assessed CRF, depression, anxiety, sleep disturbance, pain, and cognitive function. Descriptive statistics, Pearson correlation, multiple linear regression models, and path analysis were employed.
Patients (N = 373) who reported less bodily pain had worst CRF (r = −0.45, p < .01). Significant predictors of CRF included depression, sleep disorder, bodily pain, perceived cognitive ability, and dispositional (state) optimism. Depression alone accounted for 31% of the variance in CRF. An integrative path model with bodily pain, neuropathic pain, CRF, and depression showed a good fit across different indices (CFI = 0.993, RMSEA = 0.047, 90% CI 0–0.12, SRMR = 0.027).
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African-American breast cancer patients in a moderate-intensity 75 min/wk aerobic exercise intervention had marginally lower fatigue at 8-wk follow-up compared to baseline. The control group participants had marginally higher fatigue at 8-wk follow-up compared to baseline. Participants in the intervention group reported slightly better quality of life at 8-wk follow-up compared to baseline (P = 0.06).
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Citation Excerpt :
Several pro-inflammatory cytokines are linked to impaired central nervous system activity leading to “sickness behavior” (Cleeland et al., 2003). For instance, inflammatory cytokines produced by monocytes are directly linked to fatigue, with high levels of intracellular IL-ß, IL-6, and TNF were reported in fatigued breast cancer patients (Collado-Hidalgo et al., 2006; Saligan and Kim, 2012). Our findings in breast cancer survivors are consistent with previous work showing monocytes pro-inflammatory cytokines production was lower in trained compared to untrained apparently healthy individuals (Selkirk et al., 2009).
Exercise training reduces inflammation in breast cancer survivors; however, the mechanism is not fully understood.
The effects of acute and chronic exercise on monocyte toll-like receptor (TLR2 and 4) expression and intracellular cytokine production were examined in sedentary breast cancer survivors.
Eleven women with stage I, II, or III breast cancer within one year of treatment completion performed an acute, intermittent aerobic exercise trial. Blood samples were obtained before, immediately, and 1 h after a 45-min acute exercise trial that was performed before and after 16 weeks of combined aerobic and resistance. LPS-stimulated intracellular IL-1ß, TNF, and IL-6 production, and TLR2 and TLR4 expression were evaluated in CD14⁺CD16^- and CD14⁺CD16⁺ monocytes using flow cytometry.
Exercise training decreased IL-1ß⁺CD14⁺CD16^- proportion (24.6%, p=0.016), IL-1ß⁺CD14⁺CD16^- mean fluorescence intensity (MFI) (−9989, p=0.014), IL-1ß⁺CD14⁺CD16⁺ MFI (−11101, p=0.02), and IL-6⁺CD14⁺CD16^- proportion (16.9%, P=0.04). TLR2 and TLR4 expression did not change following exercise training but decreased 1 h after acute exercise in CD14⁺CD16^- (−63, p=0.002) and CD14⁺CD16⁺ (−18, p=0.006) monocytes, respectively. Immediately after the acute exercise, both monocyte subgroup cell concentration increased, with CD14⁺CD16⁺ concentrations being decreased at 1 h post without changes in intracellular cytokine production.
Exercise training reduced monocyte intracellular pro-inflammatory cytokine production, especially IL-1ß, although these markers did not change acutely. While acute exercise downregulated the expression of TLR2 and TLR4 on monocytes, this was not sustained over the course of training. These results suggest that the anti-inflammatory effect of combined aerobic and resistance exercise training in breast cancer survivors may be, in part, due to reducing resting monocyte pro-inflammatory cytokine production.

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Full Length ReviewA systematic review of the association between immunogenomic markers and cancer-related fatigue

Abstract

Highlight

Introduction

Section snippets

Methods

Results

Summary

Discussion

Conclusion

Conflict of interest

Eur. J. Cancer

Brain Behav. Immun.

Brain Behav. Immune.

Brain Behav. Immun.

Immunol. Today

Brain Res.

Int. J. Radiat. Oncol. Biol. Phys.

J. Pain Symptom Manage.

Int. Rev. Neurobiol.

Eur. J. Cancer

Semin. Immunol.

J. Pain Symptom Manage.

Biol. Psychol.

Ann. Oncol.

J. Pain Symptom Manage.

J. Psychosom. Res.

J. Pain Symptom Manage.

J. Psychosom. Res.

Brain Behav. Immun.

Brain Behav. Immun.

Cytokine Growth Factor Rev.

Clin. Nutr.

FEBS Lett.

Eur. J. Cancer

J. Pain Symptom Manage.

J. Allergy Clin. Immunol.

Int. J. Radiat. Oncol. Biol. Phys.

Levels of fatigue compared to levels of cytokines and hemoglobin during pelvic radiotherapy: a pilot study

Biol. Res. Nurs.

Preliminary evidence of a genetic association between tumor necrosis factor alpha and the severity of sleep disturbance and morning fatigue

Biol. Res. Nurs.

The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor–host interactions

Cancer Metastasis Rev.

Permeability of the blood–brain barrier to soluble cytokine receptors

Neuroimmunomodulation

Full Length Review
A systematic review of the association between immunogenomic markers and cancer-related fatigue