Inflammation Mediates Exercise Effects on Fatigue in Patients with Breast Cancer

Abstract

Purpose: The randomized controlled OptiTrain trial showed beneficial effects on fatigue after a 16-wk exercise intervention in patients with breast cancer undergoing adjuvant chemotherapy. We hypothesize that exercise alters systemic inflammation and that this partially mediates the beneficial effects of exercise on fatigue.

Methods: Two hundred and forty women scheduled for chemotherapy were randomized to 16 wk of resistance and high-intensity interval training (RT-HIIT), moderate-intensity aerobic and high-intensity interval training (AT-HIIT), or usual care (UC). In the current mechanistic analyses, we included all participants with >60% attendance and a random selection of controls (RT-HIIT = 30, AT-HIIT = 27, UC = 29). Fatigue (Piper Fatigue Scale) and 92 markers (e.g., interleukin-6 [IL-6] and tumor necrosis factor α [TNF-α]) were assessed at baseline and postintervention. Mediation analyses were conducted to explore whether changes in inflammation markers mediated the effect of exercise on fatigue.

Results: Overall, chemotherapy led to an increase in inflammation. The increases in IL-6 (pleiotropic cytokine) and CD8a (T-cell surface glycoprotein) were however significantly less pronounced after RT-HIIT compared with UC (-0.47, 95% confidence interval = -0.87 to -0.07, and -0.28, 95% confidence interval = -0.57 to 0.004, respectively). Changes in IL-6 and CD8a significantly mediated the exercise effects on both general and physical fatigue by 32.0% and 27.7%, and 31.2% and 26.4%, respectively. No significant between-group differences in inflammatory markers at 16 wk were found between AT-HIIT and UC.

Conclusions: This study is the first showing that supervised RT-HIIT partially counteracted the increase in inflammation during chemotherapy, i.e., IL-6 and soluble CD8a, which resulted in lower fatigue levels postintervention. Exercise, including both resistance and high-intensity aerobic training, might be put forward as an effective treatment to reduce chemotherapy-induced inflammation and subsequent fatigue.

Trial registration: ClinicalTrials.gov NCT02522260.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.

Figures

FIGURE 1

Flowchart of patients participating in the OptiTrain study and included in the current analyses.

FIGURE 2

A, Heat map of changes in inflammatory marker expression after chemotherapy in exercising (RT-HIIT and AT-HIIT) and UC groups. Colors indicate log2 fold changes in post- vs prechemotherapy expression values (red—increased, blue—decreased, white—unchanged). B, Heat map of significantly altered inflammatory marker expression after chemotherapy in exercising (RT-HIIT and AT-HIIT) and UC groups. Colors indicate log2 fold changes in post- vs prechemotherapy expression values (red—increased, blue—decreased, white—unchanged). Comparisons were made using ANCOVA, and P values <0.2 were deemed significant. C, Hierarchical cluster analysis heat maps showing nearest-neighbor correlations of inflammatory markers in the RT-HIIT, AT-HIIT, and UC groups. Positive correlations are represented in graded shades of blue, whereas negative correlations are represented in graded shades of red. Clusters A and B positively correlated within the RT-HIIT and UC groups. All correlations were weaker in the AT-HIIT group.