Systemic Immune Activation and Peripheral Blood Lymphocytes during Primary Chemotherapy with the Combination of Doxorubicin and Paclitaxel in Patients with Breast Carcinoma

Abstract

Abstract In recent years, there has been interest in the study of alterations of the immune system of breast carcinoma patients undergoing primary chemotherapy. Changes in the phenotype, function of peripheral blood lymphocytes as well as alterations in the release of pro-inflammatory cytokines accompanying the administration of primary chemotherapy have been described. We have investigated urinary neopterin and peripheral blood leukocyte phenotype in 44 breast carcinoma patients treated with the combination of doxorubicin and paclitaxel. Compared to controls, patients with breast carcinoma had significantly lower relative number of CD3+ lymphocytes, and significantly higher relative and absolute numbers of natural killer cells, relative and absolute numbers of CD3+DR+ lymphocytes, relative and absolute numbers of CD3+CD69+ lymphocytes, relative numbers of CD8+CD57+ lymphocytes and CD14+DR+ monocytes and relative and absolute numbers of CD14+CD16+ monocytes. A significant correlation was observed before the initiation of therapy between urinary neopterin and the relative numbers of CD3+CD4+ lymphocytes (rs = - 0.411, p < 0.01), absolute numbers of CD3+CD4+ lymphocytes (rs = - 0.313, p < 0.05), relative number of CD3+CD8+ lymphocytes (rs = 0.352, p < 0.05), CD4+/CD8+ ratio (rs = -0.404, p < 0.01), relative numbers of CD3+DR+ lymphocytes (rs = 0.343, p < 0.05), absolute numbers of CD3+DR+ lymphocytes (rs = 0.306, p < 0.05), and relative numbers of CD8+CD57+ lymphocytes (rs = 0.410, p < 0.01). Urinary neopterin and peripheral blood leukocyte phenotype was followed in 44 breast carcinoma patients treated by primary chemotherapy with doxorubicin and paclitaxel before the start of the treatment and on 3 subsequent visits in approximately monthly intervals. Compared to pretreatment values, urinary neopterin, relative and absolute numbers of CD3+, CD3+CD4+ and CD8+CD28+ lymphocytes were significantly increased throughout the course of treatment. No significant changes were observed in relative and absolute numbers of NK cells, CD8+- CD57+, CD3+DR+, CD3+CD25+, and CD3+CD69+ lymphocytes. In contrast, the relative and absolute numbers of CD19+ lymphocytes and CD19+CD23+ lymphocytes were significantly decreased throughout the course of therapy. The relative and absolute numbers of monocytes were significantly increased throughout the course of therapy. Significantly increased absolute numbers were also observed for CD14+DR+ and CD14+CD16+ monocytes. Among 37 evaluable patients, pathological complete response of the primary tumor, including regional lymph nodes, was observed in 6 cases. In patients with pathological complete response relative and absolute numbers of lymphocytes and absolute numbers of CD4+ lymphocytes were significantly lower at baseline. A total of 18 patients had evidence of pathological involvement of the lymph nodes. Compared to patients with lymph node involvement detected in surgical specimen, 19 patients without lymph node involvement had at baseline significantly lower relative and absolute number of lymphocytes, absolute numbers of CD3+, CD3+CD4+, CD3+DR+ and CD8+CD57+ lymphocytes. When ratio of peripheral blood leukocyte counts at visit 2/visit 1 was calculated, patients without lymph node involvement at surgery also had significantly increased ratio of relative lymphocyte numbers, relative and absolute CD14+DR+ monocyte numbers. In conclusion, systemic immune activation in breast carcinoma patients treated with doxorubicin and paclitaxel is associated with significant changes of peripheral blood leukocyte phenotype, including an increase of relative and absolute numbers of CD3+CD4+ lymphocytes.