The “Other” Signaling of Trastuzumab: Antibodies Are Immunocompetent Drugs
Authors: Luca Gianni
Journal: Journal of Clinical Oncology (2008)

The outstanding pace of the clinical success of trastuzumab was always intimately connected to its ability to target and block the erbB2 receptor and to obviate to the malignant consequences of the activation of the intricate network of erbB2-associated intracellular signals. The wealth of data derived from probing the erbB2-associated signals has helped to clarify very relevant features of the mechanisms of sensitivity and resistance to trastuzumab. At the same time, such successful research somewhat obscured the fact that trastuzumab is an immunoglobulin G (IgG) 1 antibody endowed with all of the powerful armamentarium of immunologic effects characteristic of antibodies. In this issue of the Journal of Clinical Oncology, a report from Musolino et al shows that the likelihood of response to trastuzumab is different in carriers of different variants of the IgG fragment C receptor (Fc R) present on immune effectors, such as neutrophils, macrophages, and natural-killer cells. The Fc R engagement by antibodies linked to cancer cells triggers antibody-dependent cellular cytotoxicity (ADCC) in a critically relevant way in model systems. The study by Musolino et al supports the concept that ADCC is a key mechanism of antitumor activity of trastuzumab in humans and opens scenarios relevant to the current and future use of the monoclonal antibody in the clinic. In the 54 consecutive patients with erbB2/neu-amplified metastatic breast cancer studied by Musolino et al, the Fc RIIIa-158 valine/valine (V/V) genotype was significantly correlated with response rate and progression-free survival, and borderline significance was observed for the association between therapeutic effects and Fc RIIa131 histidine/histidine (H/H) genotype. This finding could be predicted based on a number of prior reports in the literature. In a seminal work, Clynes et al showed in a variety of relevant syngeneic and xenograft murine models that engagement of Fc receptors on effector cells was a dominant component of the antitumor activity of trastuzumab, and that knocking out the Fc R left a significantly lower residual antitumor effect of the antibody, presumably linked to the blockade of erbB2 signaling in the tumor. Interestingly, in that report, similar conclusions were reached for rituximab that targets the B-cell marker CD20 and is identical to trastuzumab except for the epitopespecific portion of the variable region of the antibody. That preclinical observation has already been matched by evidence in humans demonstrating the link between the same Fc R polymorphisms indicated by Musolino et al for trastuzumab and the therapeutic benefit of the anti-CD20 antibody. More recently, the association between the same polymorphisms and therapeutic effects was also documented for the chimeric antibody directed to the epidermal growth factor receptor cetuximab when used as single agent in patients with colorectal cancer. Finally, a pilot investigation of preoperative trastuzumab conducted in women with operable breast cancer overexpressing erbB2 already provided preliminary evidence that the antibody’s therapeutic effects could preferentially be driven by ADCC. No matter how well and easily predictable, the results of Musolino et al represent the first conclusive evidence of the crucial role that ADCC modulation plays for trastuzumab’s antitumor activity, and lead to many further considerations. The first and obvious one is the opportunity to test germline DNA of individual patients for Fc R polymorphisms, using the results for deciding whether to treat with trastuzumab. The data presented indicate a huge differential benefit between carriers of V/V or H/H genotype and other variants. A very recent independent report also showed that the differential propensity for triggering ADCC as measured from the quantity and lytic efficiency of CD16-positive effector cells was strongly associated with different type of response after a short course of primary trastuzumab before surgery. The relative comparison of outcome of Musolino et al’s analysis is insufficient to conclude that carriers of other Fc R genotypes than V/V or H/H should be excluded from trastuzumab therapy, but together with the work of Varchetta et al the data strongly support that the predictive hypothesis should be tested. Today’s methodology allows for the extraction and dependable analysis of germline DNA from formalin-fixed paraffin embedded material so that probing of Fc R polymorphisms can be done. In the trials of adjuvant trastuzumab that were recently completed, tumor blocks were collected and proved of outstanding relevance for association studies between different markers, such as c-MYC and topo-II, and likelihood of benefit. Analysis of nontumoral formalin-fixed paraffin embedded material in the same studies could be of outstanding value to define the role of Fc R polymorphisms in dictating the sensitivity to trastuzumab. Such studies would also provide an invaluable and unique source of information with reference to the indication of trastuzumab in women with ebB2-positive breast tumors and unfavorable Fc R because no future study will enroll patients in arms without erbB2-directed therapy. As a consequence, none of the ongoing or future trials in patients eligible for trastuzumab will ever clarify whether some benefit is present irrespective of Fc R genotype. The establishment of the immunocompetence of trastuzumab as a leading mechanism of therapeutic effect in humans triggers some JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 11 APRIL 1