Moderate physical activity during neoadjuvant chemotherapy in breast cancer patients: effect on cancer-related inflammation and pathological complete response-the Neo-Runner study

Abstract

Background: Physical activity (PA) reduces the risk of developing breast cancer (BC) and mortality rate in BC patients starting PA after diagnosis. Immunomodulation is considered responsible for these effects. However, limited data exist on the immunomodulation induced by moderate PA (mPA) during neoadjuvant chemotherapy (NACT). We have investigated the longitudinal change of cytokines during NACT alone or combined with mPA.

Materials and methods: Twenty-three cytokines were analyzed in BC patients at consecutive timepoints: at baseline (T0), before starting mPA (T1), before surgery (T2), and after surgery (T3). mPA consisted of 3-weekly brisk-walking sessions for 9-10 consecutive weeks.

Results: Ninety-two patients were assessed: 21 patients refused mPA (untrained) and 71 agreed (trained). At T1, NACT induced significant up-regulation of interleukin (IL)-5, IL-6, IL-15, chemokine ligand (CCL)-2, interferon-γ, and C-X-C motif ligand (CXCL)-10 and reduction of expression of IL-13 and CCL-22. At T2, NACT and mPA induced up-regulation of IL-21, CCL-2, and tumor necrosis factor-α and reduction of expression of IL-8, IL-15, vascular endothelial growth factor, and soluble interleukin 6 receptor. Only CXCL-10 increased in untrained patients. A cytokine score (CS) was created to analyze, all together, the changes between T1 and T2. At T2 the CS decreased in trained and increased in untrained patients. We clustered the patients using cytokines and predictive factors and identified two clusters. The cluster A, encompassing 90% of trained patients, showed more pathological complete response (pCR) compared to the cluster B: 78% versus 22%, respectively.

Conclusions: mPA interacts with NACT inducing CS reduction in trained patients not observed in untrained patients, suggesting a reduction of inflammation, notwithstanding chemotherapy. This effect may contribute to the higher rate of pCR observed in the cluster A, including most trained patients.

Keywords: breast cancer; cytokines; immune system; moderate physical activity; neoadjuvant chemotherapy; pathological complete response.

Figure 1

Study design and timeline of blood samples collection.

Figure 2

Distribution of cytokines in the trained (TR) and untrained (UN) group at T1 and T2. ∗P < 0.05, ∗∗ P < 0.01, ∗∗∗P < 0.001. The difference among the means of these eight variables was tested using analysis of covariance multivariate analysis while controlling for several covariates (age, BMI, and tumor subtype). Levene’s test and normality check were carried out and the assumptions were met. BMI, body mass index; CCL, chemokine ligand; CXCL, C-X-C motif ligand; IL, interleukin; sIL-6R, soluble interleukin 6 receptor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

Figure 3

Cytokine score (T2-T1) for the 16 cytokines selected both in the trained (TR) and untrained (UN) group. ∗P < 0.05 (descriptive).