Pro-inflammatory cytokines increase temporarily after adjuvant treatment for breast cancer in postmenopausal women: a longitudinal study

Abstract

Background: Breast cancer patients have an increased risk of cardiometabolic disease and for many patients, adjuvant therapy causes an altered lipid profile, insulin resistance and inflammation. Previous follow-up studies are inconclusive regarding the duration of therapy-induced inflammation. We examined the acute and persistent changes of adjuvant chemotherapy on inflammatory and metabolic health markers in breast cancer patients.

Methods: Plasma levels of IL-6, IL-8, IL-10, IFN-γ, TNF-α, high-sensitivity C-reactive protein (hsCRP) and metabolic health parameters were analyzed before, shortly after and every six months up to two years after adjuvant chemotherapy treatment in 51 postmenopausal early breast cancer (EBC) patients, as well as in 41 healthy age- and BMI-matched controls. A target-specific multiplex assay was applied for cytokine measurements.

Results: Before initiation of adjuvant therapy, plasma IL-8 levels were higher in EBC patients (31%, p = 0.0001). Also, a larger proportion of the patients had a hsCRP level above 2 mg/L (41%) compared to the controls (17%, Χ² = 5.15, p = 0.023). Plasma levels of all five cytokines, but not hsCRP, were significantly increased after compared to before adjuvant chemotherapy (15-48% increase; all p ≤ 0.05). Already six months after ending chemotherapy treatment, all plasma cytokine levels were significantly reduced and close to pre-chemotherapy levels. Adjuvant chemotherapy caused a worsened lipid profile (increased triglycerides, lower HDL levels), insulin resistance and increased plasma insulin levels that remained high during the first year after chemotherapy.

Conclusion: Postmenopausal women with EBC have temporarily increased plasma levels of pro-inflammatory cytokines after adjuvant chemotherapy. Although transient, the therapy-induced increase in plasma cytokine levels, together with dyslipidemia and insulin resistance, may contribute to cardiometabolic risk in breast cancer patients treated with adjuvant chemotherapy.

Trial registration: The clinical trial (registration number NCT03784651) was registered on www.

Clinicaltrials: gov on 24 December 2018.

Keywords: Breast cancer; Cardiometabolic; Chemotherapy; Cytokines; Inflammation; Metabolism; Side effects.

Fig. 1

Study design. Early breast cancer patients were included in the clinical trial before initiation of chemotherapy treatment (Pre) and examined again shortly after (Post) and 6, 12, 18 and 24 months after completing chemotherapy. The number of patients included at each visit is indicated. 41 healthy controls matched for age and BMI were also included in the study, not visualized in this figure

Fig. 2

Cytokine and hsCRP levels in 51 EBC patients before chemotherapy vs 41 healthy controls. Data are presented by boxplots indicating medians, interquartile range (25th to 75th percentile) and minimum to maximum (whiskers). Differences between groups were analyzed with Mann–Whitney tests. EBC, early breast cancer. hsCRP, high-sensitivity C-reactive protein. HC, healthy controls. Pre, before chemotherapy

Fig. 3

Cytokine and hsCRP levels in EBC patients before versus after chemotherapy. 51 EBC patients were investigated before (Pre, grey bars) and 47 of them after (Post, pink bars) chemotherapy. Differences between groups were examined by Wilcoxon tests. EBC, early breast cancer. hsCRP, high-sensitivity C-reactive protein. Pre, before chemotherapy. Post, after chemotherapy

Fig. 4

Cytokine and hsCRP fluctuations before and during two years after adjuvant chemotherapy for EBC. Cytokines levels were measured for all plasma samples that were available from EBC patients in the clinical trial by April 2022 (Pre: n = 51, Post: n = 47; 6 months: n = 36, 12 months: n = 30, 18 months: n = 18 and 24 months: n = 13) and from 41 healthy controls. Boxplots display data indicating median values, interquartile range (25th to 75th percentile) and minimum to maximum (whiskers). P-values are based on Wilcoxon tests (Pre vs Post) and linear mixed models (Post vs. 6, 12, 18 and 24 months) of ln-transformed data. Of note, all available data are presented in the figures, whereas statistical tests are based on paired data only. EBC, early breast cancer. HC, healthy controls. hsCRP, high-sensitivity C-reactive protein. Pre, before chemotherapy. Post, after chemotherapy