BACKGROUND: Inflammation is an important candidate mechanism underlying cancer and cancer treatment-related cognitive impairment. We investigated levels of blood cell-based inflammatory markers in breast cancer survivors on average 20 years after chemotherapy and explored the relation between these markers and global cognitive performance. METHODS: One hundred sixty-six breast cancer survivors who received post-surgical radiotherapy and six cycles of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy on average 20 years before enrollment were compared with 1344 cancer-free women from a population-based sample (50-80 years old). Breast cancer survivors were excluded if they used adjuvant hormonal therapy or if they developed relapse, metastasis, or second primary malignancies. Systemic inflammation status was assessed by the granulocyte-to-lymphocyte ratio (GLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). Cognitive performance was assessed using an extensive neuropsychological test battery from which the general cognitive factor was derived to evaluate global cognitive performance. We examined the association between cancer, the general cognitive factor, and inflammatory markers using linear regression models. RESULTS: Breast cancer survivors had a lower general cognitive factor than non-exposed participants from the comparator group (mean difference = -0.21; 95% confidence interval (CI) -0.35 to -0.06). Inflammatory markers were higher in cancer survivors compared with non-exposed participants (mean difference for log(GLR) = 0.31; 95% CI 0.24 to 0.37, log(PLR) = 0.14; 95% CI 0.09 to 0.19, log(SII) = 0.31; 95% CI 0.24 to 0.39). The association between higher levels of inflammatory markers and lower general cognitive factor was statistically significant in cancer survivors but not among non-exposed participants. We found a group-by-inflammatory marker interaction; cancer survivors showed additional lower general cognitive factor per standard deviation increase in inflammatory markers (P for interaction for GLR = 0.038, PLR = 0.003, and SII = 0.033). CONCLUSIONS: This is the first study to show that (1) cancer survivors have increased levels of inflammation on average 20 years after treatment and (2) these inflammatory levels are associated with lower cognitive performance. Although this association needs verification by a prospective study to determine causality, our findings can stimulate research on the role of inflammation in long-term cognitive problems and possibilities to diminish such problems.

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Keywords Breast cancer, Cancer/cancer treatment-related side effects, Cognitive performance, Inflammation
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Journal Breast Cancer Research (Print)
van der Willik, K.D, Koppelmans, V, Hauptmann, M, Compter, A, Ikram, M.A, & Schagen, S.B. (2018). Inflammation markers and cognitive performance in breast cancer survivors 20 years after completion of chemotherapy: a cohort study. Breast Cancer Research (Print), 20(1). doi:10.1186/s13058-018-1062-3