Jung-Woo Chae1,2,3, Peh Siang Chua1, Terence Ng1,2,4, Angie Hui Ling Yeo1, Maung Shwe1,2, Yan Xiang Gan1,2, Sreemanee Dorajoo1, Koon Mian Foo5, Kiley Wei-Jen Loh4, Si-Lin Koo4, Wen Yee Chay4, Tira Jing Ying Tan4, Sok Yuen Beh4, Elaine Hsuen Lim4, Guek Eng Lee4, Rebecca Dent4,6, Yoon Sim Yap4, Raymond Ng4,6, Han Kiat Ho1, Alexandre Chan7,8,9. 1. Department of Pharmacy, National University of Singapore, Blk S4A Level 3, 18 Science Drive 4, Singapore, 117543, Singapore. 2. Department of Pharmacy, National Cancer Centre Singapore, Singapore, Singapore. 3. College of Pharmacy, Chungnam National University, Daejeon, South Korea. 4. Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore. 5. Department of Pharmacy, K.K. Women's and Children's Hospital, Singapore, Singapore. 6. Duke-NUS Graduate Medical School Singapore, Singapore, Singapore. 7. Department of Pharmacy, National University of Singapore, Blk S4A Level 3, 18 Science Drive 4, Singapore, 117543, Singapore. phaac@nus.edu.sg. 8. Department of Pharmacy, National Cancer Centre Singapore, Singapore, Singapore. phaac@nus.edu.sg. 9. Duke-NUS Graduate Medical School Singapore, Singapore, Singapore. phaac@nus.edu.sg.
Abstract
PURPOSE: Cancer-related fatigue (CRF) and chemotherapy-related cognitive impairment (CRCI) are reported to be associated with mitochondrial dysfunction. Hence, mitochondrial DNA (mtDNA) content, a biomarker of mitochondrial dysfunction, is hypothesized to correlate with the onset of CRF and CRCI. This study aims to evaluate the association between peripheral blood mtDNA content reduction and severity of CRF and CRCI in patients receiving chemotherapy. METHODS: This was a prospective cohort study. Early-stage breast cancer patients receiving anthracycline- or taxane-based chemotherapy were recruited. CRF was assessed using MFSI-SF, and CRCI was assessed using FACT-Cog and CANTAB at two timepoints: baseline (T1; prior to treatment) and 6 weeks after initiation of treatment (T2). mtDNA content was measured at both timepoints using real-time quantitative polymerase chain reaction. Multiple logistic regression was utilized to evaluate the association between mtDNA reduction and worsening of CRF and CRCI, adjusting for age, anxiety, insomnia, plasma cytokines concentrations, and other clinically important covariates. RESULTS: A total of 108 patients (age 52.0 ± 9.2 years; 82.4% Chinese; 64.8% receiving anthracycline-based chemotherapy) were recruited. Proportions of patients with worsening of CRF increased from the lower to the upper quartiles of mtDNA reduction (22.2, 33.3, 55.6, and 63.0% in quartiles 1, 2, 3, and 4, respectively, p = 0.001 for trend). Reduction of mtDNA content was significantly greater among those with worsening of CRF and CRCI compared to those without CRF [mean reduction (± SD): 36.5 (46.1) vs. 9.4 (34.5), p < 0.001]. After adjusting for covariates, every 1-unit reduction of the mtDNA content was associated with a 4% increased risk for worsening of CRF (95% CI, 1-6%; p = 0.009). CONCLUSIONS: This is the first study to show that the reduction of mtDNA content in peripheral blood is associated with the onset of CRF in patients receiving chemotherapy. Further validation studies are required to confirm the findings.
PURPOSE:Cancer-related fatigue (CRF) and chemotherapy-related cognitive impairment (CRCI) are reported to be associated with mitochondrial dysfunction. Hence, mitochondrial DNA (mtDNA) content, a biomarker of mitochondrial dysfunction, is hypothesized to correlate with the onset of CRF and CRCI. This study aims to evaluate the association between peripheral blood mtDNA content reduction and severity of CRF and CRCI in patients receiving chemotherapy. METHODS: This was a prospective cohort study. Early-stage breast cancerpatients receiving anthracycline- or taxane-based chemotherapy were recruited. CRF was assessed using MFSI-SF, and CRCI was assessed using FACT-Cog and CANTAB at two timepoints: baseline (T1; prior to treatment) and 6 weeks after initiation of treatment (T2). mtDNA content was measured at both timepoints using real-time quantitative polymerase chain reaction. Multiple logistic regression was utilized to evaluate the association between mtDNA reduction and worsening of CRF and CRCI, adjusting for age, anxiety, insomnia, plasma cytokines concentrations, and other clinically important covariates. RESULTS: A total of 108 patients (age 52.0 ± 9.2 years; 82.4% Chinese; 64.8% receiving anthracycline-based chemotherapy) were recruited. Proportions of patients with worsening of CRF increased from the lower to the upper quartiles of mtDNA reduction (22.2, 33.3, 55.6, and 63.0% in quartiles 1, 2, 3, and 4, respectively, p = 0.001 for trend). Reduction of mtDNA content was significantly greater among those with worsening of CRF and CRCI compared to those without CRF [mean reduction (± SD): 36.5 (46.1) vs. 9.4 (34.5), p < 0.001]. After adjusting for covariates, every 1-unit reduction of the mtDNA content was associated with a 4% increased risk for worsening of CRF (95% CI, 1-6%; p = 0.009). CONCLUSIONS: This is the first study to show that the reduction of mtDNA content in peripheral blood is associated with the onset of CRF in patients receiving chemotherapy. Further validation studies are required to confirm the findings.
Entities:
Keywords:
Breast cancer; Cancer-related fatigue; Chemotherapy-related cognitive impairment; MFSI-SF; Mitochondrial DNA content; Mitochondrial dysfunction
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