Immunoglobulin G fragment C receptor polymorphisms and response to trastuzumab-based treatment in patients with HER-2/neu-positive metastatic breast cancer Free

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Background: The humanized anti-HER-2/neu monoclonal antibody Trastuzumab has been shown to engage both activation (FcγRIIIa; FcγRIIa) and inhibitory (FcγRIIb) antibody receptors on myeloid cells and FcγRpolymorphisms have been identified that may affect the antibody-dependent cytotoxicity (ADCC) of natural killer cells and macrophages. In this study, we tested whether FcγR polymorphisms are associated with clinical outcome of breast cancer patients who received trastuzumab.

Patients and methods: Forty consecutive HER-2/neu-amplified metastatic breast cancer patients receiving trastuzumab plus taxane (paclitaxel or docetaxel) as first-line therapy were examined for the FcγRIIIa 158 valine (V)/phenylalanine (F), FcγRIIa 131 histidine (H)/arginine (R), and FcγRIIb 232 isoleucine (I)/threonine (T) polymorphisms. A PCR based single-base extension method (SNaPshot^TM , Applied Byosistems) using genomic and complementary DNA was performed for FcγRIIa and FcγRIIIa genotyping, respectively.FcγRIIb analysis was performed on cDNA using PCR amplification followed by direct sequencing. Patients’ peripheral blood mononuclear cells were drawn before treatment initiation and their trastuzumab-mediated killing function was measured by ⁵¹Cr release using a HER-2/neu-expressing human breast cancer cell line as a target. Case-matched controls comprised patients treated with taxane-based therapy without trastuzumab (n = 20).

Results: The FcγRIIIa 158 V/V genotype was significantly correlated with the response rate (RR) and Progression Free Survival (PFS). Also, there was trend significance in RR and PFS when patients with FcγRIIa 131 H/H genotype were compared with patients with H/R or R/R genotype. A significant difference was found between the trastuzumab-mediated ADCC of patients’ immune effector cells with 158 V/V and/or 131 H/H versus those without either genotype.

Conclusions: These data support for the first time the hypothesis that ADCC plays an important role in the clinical effect of trastuzumab at the level of the effector cell. Results from the 232 I/T polymorphism analysis will be presented at the meeting.