Adding paclitaxel to trastuzumab enhances antibody-dependent cell-mediated cytotoxicity via increment of natural killer cells in patients with Her-2 overexpressing breast cancer

Abstract

10548 Background: One of the mechanisms by which trastuzumab (TZ) inhibits the growth of Her-2 overexpressing breast cancer cells is the activation of a host tumor response via antibody-dependent cell-mediated cytotoxicity (ADCC). We questioned whether adding PTX to TZ enhances ADCC and also investigated kinetics of effector cells in ADCC. Methods: In ADCC, 5 cases with metastatic breast cancer receiving TZ (4mg/kg as a loading and 2 mg/kg weekly) with PTX (2qw, 100 mg/m2) were investigated. ADCC was analyzed by 51Cr releasing assay using SK-BR-3 cell line and white blood cells taken at the time of pretreatment, after 4 mg/kg of TZ, before/after 2 mg/kg of TZ, and before/after 2 mg/kg of TZ plus PTX. In of effector cell studies, we investigated fractions of natural killer (NK) cell, monocyte, and neutrophil taken at pre-administration and 10 minutes post-administration in 16 patients with Her-2 overexpressing breast cancer receiving weekly TZ and PTX (80 mg/m2). We defined NK cells as being both CD16+ (FcγRIII) and CD56+ and neutrophils as CD64+ (FcγRI) by flow cytometry. Results: Compared with pretreatment ADCC level, cytotoxicity were enhanced to 220% (median, ranging 30–259) after 4 mg/kg of TZ, 129% (78–210) after 2 mg/kg of TZ, and 148% (42–557) after the combination of TZ and PTX, whereas suppressed to 94% (48–163) after PTX alone. 2 weeks after the combination therapy, ADCC was significantly enhanced to 169% (113–257, p<0.05), compared with pre-treatment. In effector cells, NK cells increased in 131% (74–175, p<0.05) by TZ and in 224% (169–286, p<0.05) by the combination therapy. No significant changes were found in monocytes (98%, 50–160) and in neutrophils (100%, 50–160) by TZ alone, however monocytes decreased to 44% (34–50, p<0.05) and also neutrophils did to 49% (9–133) by the combination. Conclusions: Higher doses of TZ induced NK cell recruitment and the combination of TZ and PTX has a significant increase in recruitment and activation of NK cells. Adding PTX to TZ significantly enhanced ADCC via the rapid kinetics of NK cells. This may reflect that the combination of TZ and PTX has a strong synergistic effect than we expected in patients with Her-2 overexpressing breast cancer. [Table: see text]