-Original-

Paclitaxel Enhances Antibody-dependent Cell-mediated Cytotoxicity of Trastuzumab by Rapid Recruitment of Natural Killer Cells in HER2-positive Breast Cancer

Daishu Miura^1,2, Kimiyasu Yoneyama³, Yoshiaki Furuhata⁴ and Kazuo Shimizu¹

¹Department of Endocrine Surgery, Nippon Medical School Hospital
²Department of Breast and Endocrine Surgery, Toranomon Hospital
³Department of Breast Surgery, National Cancer Center East
⁴Department of Surgery, Japanese Red Cross Medical Center

Introduction: An important mechanism by which trastuzumab inhibits the growth of human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells is the activation of a host tumor response via antibody-dependent cell-mediated cytotoxicity (ADCC). Although paclitaxel has a synergistic effect in combination with trastuzumab, whether ADCC is enhanced by paclitaxel is not known. In the present study we examined whether adding paclitaxel to trastuzumab enhances ADCC and also investigated the kinetics of effector cells in ADCC.
Materials and Methods: The subjects were 20 patients with HER2-positive breast cancer: 9 received the combination of trastuzumab (4 mg/kg as a loading dose and 2 mg/kg weekly) and paclitaxel (80 mg/m² weekly) and 19 received monotherapy with trastuzumab. In blood samples (mononuclear cells) obtained before and 10 minutes after administration of chemotherapy, ADCC and the number of effector cells, including natural killer (NK) cells, monocytes, and CD64+ cells, were compared in each case. The ADCC was analyzed with a ⁵¹Cr releasing assay using the SK-BR-3 cell line, and the fractions of NK cells (both CD16+ [FcγRIII] and CD56+) and CD64+ (FcγRI) cells were analyzed with flow cytometry.
Results: The mean ADCC level increased 20% after trastuzumab monotherapy and 126% (p<0.05) after combination therapy with trastuzumab and paclitaxel. All 9 patients receiving combination therapy had increased ADCC levels. The number of NK cells increased 51% after trastuzumab monotherapy and 112% (p<0.05) after combination therapy. No significant changes were found in monocytes (39% increase) or CD64+ cells (53% increase) after trastuzumab monotherapy, but monocytes decreased 40% (p<0.05) and CD64+ cells decreased 24% after combination therapy.
Conclusions: Adding paclitaxel to trastuzumab significantly enhances ADCC, with levels twice as great as with trastuzumab monotherapy, through a rapid recruitment of NK cells. This finding suggests that the combination of trastuzumab and paclitaxel has a stronger-than-expected synergistic effect in HER2-positive breast cancer.

J Nippon Med Sch 2014; 81: 211-220

Keywords
antibody-dependent cell-mediated cytotoxicity, human epidermal growth factor receptor 2, natural killer cells, Fcγ receptors, trastuzumab

Correspondence to
Daishu Miura, MD, Department of Breast and Endocrine Surgery, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan
daishu@marine.email.ne.jp

Received, November 5, 2013
Accepted, December 26, 2013