This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Varchetta, S. Articles by Fagnoni, F. F. Search for Related Content PubMed PubMed Citation Articles by Varchetta, S. Articles by Fagnoni, F. F.

Elements Related to Heterogeneity of Antibody-Dependent Cell Cytotoxicity in Patients Under Trastuzumab Therapy for Primary Operable Breast Cancer Overexpressing Her2

¹ Oncology Department, Scientific Institute of Pavia, Fondazione Salvatore Maugeri-Clinica del Lavoro e della Riabilitazione, Istituti di Ricovero e Cura a Carattere Scientifico, Pavia, Italy; ² Department of Experimental Oncology, Fondazione Istituto Nazionale per lo Studio e la Cura dei Tumori; ³ European School of Oncology; and ⁴ Department of Surgery, Istituto Europeo di Oncologia, Milan, Italy

Requests for reprints: Francesco F. Fagnoni, Experimental Oncology Laboratory, Fondazione Salvatore Maugeri-Istituti di Ricovero e Cura a Carattere Scientifico-Clinica del Lavoro e della Riabilitazione, via S. Maugeri, 10, 27100 Pavia, Italy. Phone: 39-0382-592062; Fax: 39-0382-592061; E-mail: francesco.fagnoni{at}fsm.it.

Preliminary results from a pilot trial on trastuzumab's mechanism of action against operable breast tumors overexpressing Her2 suggested a role for antibody-dependent cell cytotoxicity (ADCC). To examine factors affecting ADCC intensity and variability, we extended this study to the phenotypic and functional analysis of circulating mononuclear cells in 18 patients. ADCC was induced by trastuzumab therapy in 15 of 18 patients (83%). Inability to develop ADCC in three patients did not depend on inadequate levels of trastuzumab because further increase in its concentration in vitro was ineffective. Rather, susceptibility to develop ADCC was fairly predicted by test with trastuzumab before therapy and was correlated to the number of lymphocytes coexpressing CD16 and CD56. Phenotypic analysis at the end of ADCC evaluating down-regulation of CD16, and up-regulation of CD69 and CD107a, confirmed that natural killer (NK) cells and CD56⁺ T cells were involved in productive engagement of trastuzumab. Also, the killing efficiency of CD16⁺ lymphocytes was influenced by 158 V/F polymorphism of FcRIII (CD16), whereas variations of CD247 on NK cells were consistent with trends between ADCC before and after therapy. Complete pathologic response was observed in one patient showing ADCC of outstanding intensity, whereas four cases of partial response showed intermediate ADCC; none of the three patients unable to mount ADCC had significant tumor regression. These data indicate that quantity and lytic efficiency of CD16⁺ lymphocytes are major factors for ADCC induction by trastuzumab, and confirm that breast cancer responses to short-term trastuzumab monotherapy may depend on involvement of the ADCC mechanism. [Cancer Res 2007;67(24):11991–9]

This article has been cited by other articles:

				C.-A. Dutertre, E. Bonnin-Gelize, K. Pulford, D. Bourel, W.-H. Fridman, and J.-L. Teillaud A novel subset of NK cells expressing high levels of inhibitory Fc{gamma}RIIB modulating antibody-dependent function J. Leukoc. Biol., December 1, 2008; 84(6): 1511 - 1520. [Abstract] [Full Text] [PDF]

				J. Stagg, J. Sharkey, S. Pommey, R. Young, K. Takeda, H. Yagita, R. W. Johnstone, and M. J. Smyth Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response PNAS, October 21, 2008; 105(42): 16254 - 16259. [Abstract] [Full Text] [PDF]

				T. Iuchi, S. Teitz-Tennenbaum, J. Huang, B. G. Redman, S. D. Hughes, M. Li, G. Jiang, A. E. Chang, and Q. Li Interleukin-21 Augments the Efficacy of T-Cell Therapy by Eliciting Concurrent Cellular and Humoral Responses Cancer Res., June 1, 2008; 68(11): 4431 - 4441. [Abstract] [Full Text] [PDF]

				N. E Hynes ErbB Receptors in Cancer: HER2/ErbB2 as a Therapeutic Target Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 123 - 130. [Abstract] [Full Text] [PDF]

				L. Gianni The "Other" Signaling of Trastuzumab: Antibodies Are Immunocompetent Drugs J. Clin. Oncol., April 10, 2008; 26(11): 1778 - 1780. [Full Text] [PDF]