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Association of mitochondrial DNA content in peripheral blood with cancer-related fatigue and chemotherapy-related cognitive impairment in early-stage breast cancer patients: a prospective cohort study

  • Epidemiology
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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.

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Funding

This study was financed by research grant awarded by the National Medical Research Council Singapore (NMRC/CIRG/1386/2014).

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Authors and Affiliations

  1. Department of Pharmacy, National University of Singapore, Blk S4A Level 3, 18 Science Drive 4, Singapore, 117543, Singapore

    Jung-Woo Chae, Peh Siang Chua, Terence Ng, Angie Hui Ling Yeo, Maung Shwe, Yan Xiang Gan, Sreemanee Dorajoo, Han Kiat Ho & Alexandre Chan

  2. Department of Pharmacy, National Cancer Centre Singapore, Singapore, Singapore

    Jung-Woo Chae, Terence Ng, Maung Shwe, Yan Xiang Gan & Alexandre Chan

  3. Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore

    Terence Ng, Kiley Wei-Jen Loh, Si-Lin Koo, Wen Yee Chay, Tira Jing Ying Tan, Sok Yuen Beh, Elaine Hsuen Lim, Guek Eng Lee, Rebecca Dent, Yoon Sim Yap & Raymond Ng

  4. Department of Pharmacy, K.K. Women’s and Children’s Hospital, Singapore, Singapore

    Koon Mian Foo

  5. Duke-NUS Graduate Medical School Singapore, Singapore, Singapore

    Rebecca Dent, Raymond Ng & Alexandre Chan

  6. College of Pharmacy, Chungnam National University, Daejeon, South Korea

    Jung-Woo Chae

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  1. Jung-Woo Chae
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Correspondence to Alexandre Chan.

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The authors have declared no conflicts of interest.

Ethical approval

SingHealth Institutional Ethics Review Board (CIRB 2014/754/B) approved the study in both the centers before commencement. This study was carried out in accordance with the ethical principles as set out in the Declaration of Helsinki. Written consent was obtained from all the participants in the study.

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Chae, JW., Chua, P.S., Ng, T. et al. Association of mitochondrial DNA content in peripheral blood with cancer-related fatigue and chemotherapy-related cognitive impairment in early-stage breast cancer patients: a prospective cohort study. Breast Cancer Res Treat 168, 713–721 (2018). https://doi.org/10.1007/s10549-017-4640-7

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