Background Chemotherapy is extensively used to treat breast cancer and is associated with skeletal muscle deconditioning, which is known to reduce patients' quality of life, treatment efficiency, and overall survival. To date, skeletal muscle mitochondrial alterations represent a major aspect explored in breast cancer patients; nevertheless, the cellular mechanisms remain relatively unknown. This study was dedicated to investigating overall skeletal muscle mitochondrial homeostasis in early breast cancer patients undergoing chemotherapy, including mitochondrial quantity, function, and dynamics. Methods Women undergoing (neo)adjuvant anthracycline-cyclophosphamide and taxane-based chemotherapy participated in this study (56 ± 12 years). Two muscle biopsies were collected from the vastus lateralis muscle before the first and after the last chemotherapy administration. Mitochondrial respiratory capacity, reactive oxygen species production, and western blotting analyses were performed. Results Among the 11 patients, we found a decrease in key markers of mitochondrial quantity, reaching À52.0% for citrate synthase protein levels (P = 0.02) and À38.2% for VDAC protein levels (P = 0.04). This mitochondrial content loss is likely explained by reduced mitochondrial biogenesis, as evidenced by a decrease in PGC-1α1 protein levels (À29.5%; P = 0.04). Mitochondrial dynamics were altered, as documented by a decrease in MFN2 protein expression (À33.4%; P = 0.01), a key marker of mitochondrial outer membrane fusion. Mitochondrial fission is a prerequisite for mitophagy activation, and no variation was found in either key markers of mitochondrial fission (Fis1 and DRP1) or mitophagy (Parkin, PINK1, and Mul1). Two contradictory hypotheses arise from these results: defective mitophagy, which probably increases the number of damaged and fragmented mitochondria, or a relative increase in mitophagy through elevated mitophagic potential (Parkin/VDAC ratio; +176.4%; P < 0.02). Despite no change in mitochondrial respiratory capacity and COX IV protein levels, we found an elevation in H 2 O 2 production (P < 0.05 for all substrate additions) without change in antioxidant enzymes. We investigated the apoptosis pathway and found an increase in the protein expression of the apoptosis initiation marker Bax (+72.0%; P = 0.04), without variation in the anti-apoptotic protein Bcl-2. Conclusions This study demonstrated major mitochondrial alterations subsequent to chemotherapy in early breast cancer patients: (i) a striking reduction in mitochondrial biogenesis, (ii) altered mitochondrial dynamics and potential mitophagy defects, (iii) exacerbated H 2 O 2 production, and (iv) increased initiation of apoptosis. All of these alterations likely explain, at least in part, the high prevalence of skeletal muscle and cardiorespiratory deconditioning classically observed in breast cancer patients.
Breast cancer is the most common cancer among women. Localized breast cancer treatments involve taxanes which are often responsible for acute peripheral neuropathy. The persistence of taxane‐induced peripheral neuropathy (TIPN) is scarcely described among elderly women. A monocenter historical cohort study including all women over 65 years of age treated between 2001 and 2016 with a taxane‐based chemotherapy for localized breast cancer was carried out at the Paul Strauss Regional Comprehensive Cancer Center. All cases included were followed up for at least 2 years, deaths from causes unrelated to TIPN were excluded. We report on the frequency and risk factors and establish a prognostic score of persistent Common Terminology Criteria for Adverse Events (CTCAE) grade 2 and 3 TIPN. Among the 302 included patients, 21% and 9% developed persistent TIPN of grade 2 and 3, respectively. Two patients died from complications of grade 3 TIPN. Risk factors of persistent grade 2 and higher neuropathy included age (P < .0001), body mass index (P < .0001), and diabetes (P = .0093). Persistent TIPN was more frequent with paclitaxel than docetaxel (OR = 5.43; P < .0001). Patients presenting all four major risk factors had a 97.2% probability of developing long‐term symptoms against 1.2% for patients showing no risk factor. We therefore identified 3 prognostic groups. TIPN is a frequent and sometimes severe persistent side effect of breast cancer treatment among elderly women with a major impact on health‐related quality of life. Chemotherapy regimens without taxane could therefore be a valid option in elderly patients with neurotoxicity risk factors.
Background Fatigue is a hallmark of breast cancer and is associated with skeletal muscle deconditioning. If cancer‐related fatigue occurs early during chemotherapy (CT), the development of skeletal muscle deconditioning and its effect on exercise capacity remain unclear. The aim of this study was to investigate the evolution of skeletal muscle deconditioning and exercise capacity in patients with early‐stage breast cancer during CT. Methods Patients with breast cancer had a visit before undergoing CT, at 8 weeks, and at the end of chemotherapy (post‐CT). Body composition was determined through bioelectrical impedance analysis. Knee extensor, handgrip muscle force and fatigue was quantified by performing maximal voluntary isometric contractions and exercise capacity using the 6‐min walking test. Questionnaires were also administered to evaluate quality of life, cancer‐related fatigue, and physical activity level. Results Among the 100 patients, reductions were found in muscle mass (−2.3%, p = .002), exercise capacity (−6.7%, p < .001), and knee extensor force (−4.9%, p < .001) post‐CT, which occurred within the first 8 weeks of treatment with no further decrease thereafter. If muscle fatigue did not change, handgrip muscle force decreased post‐CT only (−2.5%, p = .001), and exercise capacity continued to decrease between 8 weeks and post‐CT (−4.6%, p < .001). Quality of life and cancer‐related fatigue were impaired after 8 weeks (p < .001) and remained stable thereafter, whereas the physical activity level remained stable during chemotherapy. Conclusions Similar to cancer‐related fatigue, skeletal muscle deconditioning and reduced exercise capacity occurred early during breast cancer CT. Thus, it appears essential to prevent these alterations through exercise training implemented during CT.
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