Novel Biomarkers Of Treatment-Induced Muscle Damage, Exercise And Fatigue: An RCT In Breast Cancer Patients

Abstract

Radiation and hormone therapy may damage skeletal muscle and lead to cancer-related fatigue (CRF). Developmental myosin light chain 5 (MYL5) and myosin heavy chain 8 (MYH8) are required for normal muscle regeneration. Up-regulated serum levels of MYL5 and MYH8 resulting from radiation and hormone therapy may increase muscle degradation and lead to CRF, especially physical CRF—one of the multidimensional subcomponents of overall CRF. PURPOSE: To investigate the effect of a 6-week aerobic and anaerobic exercise intervention, called Exercise for Cancer Patients (EXCAP), on (1) CRF (overall and physical), (2) serum protein levels of MYL5 and MYH8, and (3) the association of CRF (overall and physical) with these novel biomarkers. METHODS: Ninety sedentary breast cancer patients (55.5±9.6 years, 79% white, 52% receiving radiation therapy, 48% receiving hormone therapy) were consented and participated in this phase II RCT. Patients were randomized into two arms: (1) standard cancer treatment (Control) or (2) standard cancer treatment plus EXCAP. Serum levels of MYL5 and MYH8 by ELISA assays and CRF (total and physical) by patient-report via the Multidimensional Fatigue Symptom Inventory were assessed pre- and post-intervention. RESULTS: T-tests showed significant reductions in overall CRF and physical CRF among exercisers (overall CRF: -4.9±2.6, p=0.07, physical CRF: -1.0±0.5, p=0.05) but not in controls, with significant group differences (overall CRF: -7.9±3.4, p=0.02; physical CRF: -1.9±0.7, p<0.01). T-tests also revealed statistical trends for down-regulation of MYL5 (-0.5±0.3, p=0.17) and MYH8 (-0.4±0.3, p=0.17) serum protein levels from pre- to post-intervention in exercisers, but not in controls. Spearman correlations also reveal statistical trends, in exercisers, where decreases in MYL5 and MYH8 serum protein levels are directly associated with decreases in total CRF (MYL5 r=0.23, p=0.17; MYH8 r=0.30, p=0.07) and physical CRF (MYL5 r=0.29, p=0.08; MYH8 r=0.39, p=0.02). CONCLUSIONS: EXCAP improves overall and physical CRF. EXCAP may also protect against cancer treatment-induced skeletal muscle damage via its effects on MYL5 and MYH8. Changes in these novel biomarkers may mediate changes in overall and physical CRF. Further phase III RCTs are needed to confirm these findings.