Role of neutrophils in the early presymptomatic stages of doxorubicin cardiotoxicity in breast cancer.

Abstract

98 Background: Doxorubicin (DOX) cardiotoxicity is cumulative-dose-dependent and begins with the first dose of chemotherapy. No biomarker for early presymptomatic detection of DOX cardiotoxicity has been validated. Our preliminary microarray-based study on DOX cardiotoxicity of breast cancer patients showed that neutrophil-associated inflammation was partly responsible for this side effect of DOX Based on our preliminary finding, the aim of this study was to examine the expression of the top dysregulated neutrophil-specific genes, including alpha-defensins, arginase, cathepsin G, elastase, haptoglobin, metalloprotease 9, cathelicidin 8 in the peripheral blood mononuclear cells (PBMCs) of breast cancer patients treated with DOX-based chemotherapy. Methods: Blood samples of 15 women treated for breast cancer with DOX-based chemotherapy were collected before the start and after the 1st cycle of chemotherapy. Cardiac function was assessed before the start and after the completion of chemotherapy. A decrease of left ventricle ejection fraction (LVEF) > 10% or < 55% was considered abnormal. PBMC gene expressions of the target genes were assessed by quantitative RT-PCR and normalized to 18S. Data were analyzed using 2-deltadelta CT method and compared between patients with abnormal versus those with normal LVEF. Results: A single dose of DOX-based chemotherapy induced significantly greater mRNA levels of the examined genes in PBMC of patients with subsequent abnormal decline of LVEF (n = 5) versus those patients who maintained a normal LVEF. The elevated neutrophil-associated transcripts in the early stages of DOX-based chemotherapy were independent of the neutrophil count. Conclusions: We have identified a set of transcripts in the early stages of DOX-based chemotherapy that can serve as biomarkers for prediction of later impairment of cardiac function in breast cancer patients. Biomarkers for early prediction of DOX-induced cardiotoxicity could allow individualization of chemotherapy and/or testing the effectiveness of cardio-preventive medication, and ultimately will help to reduce the incidence of the cardiotoxicity-associated morbidity and mortality in cancer survivors.