Inflammatory Biomarkers, Hematopoietic Stem Cells, and Symptoms in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy

Wei Shi; Shagun Misra; Madeline Li; Jie Su; Lisa P Chong; Megan McCuske; Justin Williams; Wei Xu; Laleh S Ghoraie; D Robert Sutherland; Kathy Han; Mark D Minden; Scott V Bratman; Kenneth W Yip; Fei-Fei Liu

doi:10.1093/jncics/pkaa037

Inflammatory Biomarkers, Hematopoietic Stem Cells, and Symptoms in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy

JNCI Cancer Spectr. 2020 May 8;4(5):pkaa037. doi: 10.1093/jncics/pkaa037. eCollection 2020 Oct.

Authors

Wei Shi¹, Shagun Misra^{2

3}, Madeline Li^{4

5}, Jie Su⁶, Lisa P Chong^{1

2}, Megan McCuske⁴, Justin Williams¹, Wei Xu^{6

7}, Laleh S Ghoraie¹, D Robert Sutherland⁸, Kathy Han^{2

3}, Mark D Minden^{8

9}, Scott V Bratman^{1

2

3

9}, Kenneth W Yip¹, Fei-Fei Liu^{1

2

3

9}

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
² Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
³ Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
⁴ Department of Supportive Care, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
⁵ Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
⁶ Division of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
⁷ Department of Biostatistics, University of Toronto, Toronto, Ontario, Canada.
⁸ Department of Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
⁹ Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Abstract

Background: Fatigue and insomnia are common symptoms experienced by breast cancer patients undergoing adjuvant radiation therapy (RT), yet the underlying mechanisms of these symptoms are unclear. In particular, the roles of hematopoietic stem cells (HSCs) and inflammatory cytokines remain to be elucidated.

Methods: Breast cancer patients (n = 147) completed questionnaires to longitudinally assess symptoms before, during, and after adjuvant RT. Phlebotomies were performed prior to RT, at the second and fifth treatment fractions, end of treatment (EOT), and 1 month after completing RT, assessing for CD34⁺, CD45⁺, full hematology, and 17 inflammatory cytokines. The associations between symptoms and all biomarkers were evaluated. All statistical tests were 2-sided.

Results: General fatigue and insomnia worsened with RT, with peak levels observed at EOT, which remained statistically significant even after controlling for anxiety and depression (P < .05 for all). CD34⁺, CD45⁺, white blood cell, and lymphocyte counts decreased, with the lowest levels also observed at EOT (P < .001). Fatigue and insomnia were associated with changes in both interferon γ-induced protein 10 (IP-10) - (P = .03 and P = .01, respectively) and tumor necrosis factor receptor II (TNF-RII) (P = .02 and P = .006, respectively), while mental fatigue was associated with increased matrix metalloproteinases-2 (MMP-2) levels (P = .03). Patients who received prior chemotherapy demonstrated statistically significantly greater severity in all symptoms, with lower baseline HSC levels.

Conclusions: This is the first longitudinal study to examine linkages between symptoms, HSCs, and cytokines, demonstrating that fatigue and insomnia shared associations with increasing serum levels of IP-10 and TNF-RII, and mental fatigue was associated with increasing serum levels of MMP-2. Our findings highlight opportunities for further research into mechanisms and potential interventions for these symptoms.