Exercise Intolerance in Anthracycline‐Treated Breast Cancer Survivors: The Role of Skeletal Muscle Bioenergetics, Oxygenation, and Composition

• Published in: The oncologist (Dayton, Ohio) Ohio), 2020-05, Vol.25 (5), p.e852-e860
• Main Authors: Beaudry, Rhys I., Kirkham, Amy A., Thompson, Richard B., Grenier, Justin G., Mackey, John R., Haykowsky, Mark J.
• Format: Article
• Language: English
• Subjects: Anthracyclines; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cancer Survivors; Energy Metabolism; Female; Humans; Intermuscular fat; Magnetic resonance imaging; Middle Aged; Muscle bioenergetics; Muscle, Skeletal - metabolism; Oxygen Consumption; Oxygen uptake; Skeletal muscle; Symptom Management and Supportive Care
• ISSN: 1083-7159; 1549-490X; 1549-490X
• DOI: 10.1634/theoncologist.2019-0777

Background Peak oxygen consumption (VO2) is reduced in women with a history of breast cancer (BC). We measured leg blood flow, oxygenation, bioenergetics, and muscle composition in women with BC treated with anthracycline chemotherapy (n = 16, mean age: 56 years) and age‐ and body mass index–matched controls (n = 16). Materials and Methods Whole‐body peak VO2 was measured during cycle exercise. 31Phosphorus magnetic resonance (MR) spectroscopy was used to measure muscle bioenergetics during and after incremental to maximal plantar flexion exercise (PFE). MR imaging was used to measure lower leg blood flow, venous oxygen saturation (SvO2), and VO2 during submaximal PFE, and abdominal, thigh, and lower leg intermuscular fat (IMF) and skeletal muscle (SM). Results Whole‐body peak VO2 was significantly lower in BC survivors versus controls (23.1 ± 7.5 vs. 29.5 ± 7.7 mL/kg/minute). Muscle bioenergetics and mitochondrial oxidative capacity were not different between groups. No group differences were found during submaximal PFE for lower leg blood flow, SvO2, or VO2. The IMF‐to‐SM ratio was higher in the thigh and lower leg in BC survivors (0.36 ± 0.19 vs. 0.22 ± 0.07, p = .01; 0.10 ± 0.06 vs. 0.06 ± 0.02, p = .03, respectively) and were inversely related to whole‐body peak VO2 (r = −0.71, p = .002; r = −0.68, p = .003, respectively). In the lower leg, IMF‐to‐SM ratio was inversely related to VO2 and O2 extraction during PFE. Conclusion SM bioenergetics and oxidative capacity in response to PFE are not impaired following anthracycline treatment. Abnormal SM composition (increased thigh and lower leg IMF‐to‐SM ratio) may be an important contributor to reduced peak VO2 during whole‐body exercise among anthracycline‐treated BC survivors. Implications for Practice Peak oxygen consumption (peak VO2) is reduced in breast cancer (BC) survivors and is prognostic of increased risk of cardiovascular disease‐related and all‐cause mortality. Results of this study demonstrated that in the presence of deficits in peak VO2 1 year after anthracycline therapy, skeletal muscle bioenergetics and oxygenation are not impaired. Rather, body composition deterioration (e.g., increased ratio of intermuscular fat to skeletal muscle) may contribute to reduced exercise tolerance in anthracycline BC survivors. This finding points to the importance of lifestyle interventions including caloric restriction and exercise training to restore body composition and cardiovascular health in the BC sur