Biomarkers of fatigue related to adjuvant chemotherapy for breast cancer: evaluation of plasma and lymphocyte expression

Felipe M Cruz, Bruna A Munhoz, Beatriz Ca Alves, Flavia S Gehrke, Fernando LA Fonseca, Renata K Kuniyoshi, Daniel Cubero, Luke J Peppone, Auro Del Giglio, Felipe M Cruz, Bruna A Munhoz, Beatriz Ca Alves, Flavia S Gehrke, Fernando LA Fonseca, Renata K Kuniyoshi, Daniel Cubero, Luke J Peppone, Auro Del Giglio

Abstract

Background: Fatigue is common in cancer patients receiving adjuvant chemotherapy. To further understand the mechanism of fatigue and search for potential biomarkers, we conducted this prospective study. Methods We enrolled breast cancer (BC) patients before their first adjuvant Adriamycin-based chemotherapy cycle. Patients responded to the brief fatigue inventory (BFI) and Chalder fatigue questionnaires and had their blood drawn for both plasma evaluation and evaluation of the peripheral mononuclear cell fraction (PMNCF) mRNA expression of various biomarkers. We evaluated FSH, LH, estradiol, DHEA, DHEAS, IL6, IL2, ILIRA, IL1β, CRP, Cortisol in the plasma and IL2, IL10, IL6, TGF-β, KLRC1, TNF, BTP, SNCA, SOD1, BLNK, PTGS2 and INF γ expression in the PMNCF.

Results: 11 patients did not exhibit an increase in their BFI scores and served as controls, whereas 32 patients exhibited an increase in their BFI scores compared with the baseline scores. From the biomarkers we evaluated in the PMNCF, the only one significantly associated with fatigue was TGF-β (p = 0.0343), while there was a trend towards significance with KLRC1 (p = 0.0627). We observed no evidence of significant associations of any plasma biomarkers with the development of fatigue. However when we analyzed patients with more severe fatigue, plasma IL1-RA levels correlated directly with higher fatigue scores (p = 0.0136).

Conclusions: We conclude that fatigue induced by chemotherapy in BC patients is associated with changes in IL1-ra plasma levels and in TGF-β lymphocyte expression. Its mechanism may be different than that observed in long-term BC survivors or that induced by radiation therapy.

Trial registration: NCT02041364 [ClinicalTrials.gov].

Keywords: Biomarkers; Breast Cancer; Chemotherapy; Fatigue; IL1-ra; TGF-β.

Figures

Figure 1
Figure 1
The significant variations in fatigue in the 3 groups evaluated in Figures2and3, namely patients at the screening stage (inclusion, all patients), including all 43 patients (32 patients whose fatigue worsened after chemotherapy and 11 patients whose fatigue did not worsen after chemotherapy and who served as controls for this stage of data analysis). The black dots represent the outliers.
Figure 2
Figure 2
Evaluation of plasma analytes in patients in the inclusion phase whose fatigue worsened and in patients whose fatigue did not worsen after the first cycle of chemotherapy (controls). The black dots represent the outliers.
Figure 3
Figure 3
Evaluation of lymphocyte expression of selected genes in the first phase of the study in patients in the inclusion phase whose fatigue deteriorated and in patients whose fatigue did not worsen after the first cycle of chemotherapy (controls). The black dots represent the outliers.
Figure 4
Figure 4
Patients who developed fatigue where separated in two groups: those who had higher BFI fatigue scores (HF), ie who had an increase equal or above 1 standard deviation (20 points) in their BFI scores as compared to the triage (T) level and 2) those who had lower increases in their BFI scores (FL). Also shown are those patients who had a decrease in their BFI scores after the first cycle of chemotherapy who were considered as controls (C).

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