We commend Dr Johansen et al1 on the landmark CAUSE (Cardiovascular Survivors Exercise) trial, which provides robust, long awaited evidence on the effects of aerobic exercise in long-term, anthracycline-treated breast cancer survivors. Their direct comparison with a cancer-naive cohort is a key methodological strength, yielding an observation of high importance: a persistent and significant blunting of the cardiorespiratory fitness (CRF) response in survivors, even more than a decade after treatment completion.
Although the investigators discussed both central (cardiac) and peripheral (muscle) factors contributing to exercise intolerance, we hypothesize that the explanation for this attenuated CRF gain may lie predominantly within the skeletal muscle itself (ie, a long-lasting “myotoxicity” that complements the well-documented cardiotoxicity of anthracyclines). We hypothesize that persistent mitochondrial dysfunction and impaired capillary function and density in skeletal muscle, induced by chemotherapy, act as the rate-limiting factor for improved oxygen extraction (the arteriovenous oxygen difference) during exercise.
We believe this hypothesis is biologically plausible for a number of reasons. Previous studies have established that anthracyclines induce significant oxidative stress and damage to skeletal muscle mitochondria, impairing their respiratory capacity.2,3 This results in a reduced ability to use delivered oxygen at the tissue level. Therefore, even if central cardiac output improves with training, a compromised peripheral “engine” will inherently limit the overall improvement in peak oxygen uptake. This aligns with findings from Beaudry et al,4 which implicated impaired skeletal muscle bioenergetics as a key determinant of exercise intolerance in anthracycline-treated breast cancer survivors.4
As the efficacy of exercise therapy for improving CRF in cancer survivors is well established,5 we propose that the blunted response observed by Johansen et al1 should prompt a research shift toward the “myo-oncology” of survivorship.5 Although the psychological benefits of exercise for survivors are clear and invaluable, optimizing their physiological adaptations may require novel approaches. Future trials should incorporate direct assessments of peripheral function, such as muscle biopsy for mitochondrial analysis or near infrared spectroscopy for muscle oxygenation dynamics. Consequently, future therapeutic strategies should aim to improve muscular and mitochondrial health. Interventions such as combined aerobic and resistance training, or the addition of targeted pharmacologic agents, may be promising strategies to maximize the benefits of exercise therapy in the growing survivor population
Footnotes
This work was supported in part by the Natural Science Basic Research Program of Shaanxi (2025JC-YBQN-1093) and the Institutional Foundation of the First Affiliated Hospital of Xi’an Jiaotong University (2024-QN-26). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
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